Dissertations / Theses: 'Antitumor'

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Costa, PatrÃcia MarÃal da. "AvaliaÃÃo do potencial antitumoral dos hidrobenzofuranÃides isolados das folhas da Tapirira guianensis (anacardiaceae)." Universidade Federal do CearÃ, 2006. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=524.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
Os hidrobenzofuranÃides obtidos da Tapirira guianensis sÃo derivados alquilados da ciclohexanona, que parecem ser possÃveis precursores dos lipÃdios fenÃlicos. O presente trabalho avaliou, inicialmente, a atividade dos nove hidribenzofuranÃides em linhagens de cÃlulas, onde a amostra SJC-8 mostrou a citotoxicidade mais elevada. Posteriormente, foram avaliados os possÃveis mecanismos pelo qual esta amostra desenvolve seu efeito citotÃxico. No teste de MTT em painel de linhagens adicionais a SJC-8 apresentou valores de CI50 variando de 0.3 a 6.2Âg/mL. No teste de toxicidade aguda em nÃuplios de artÃmia e de atividade hemolÃtica em eritrÃcitos de camundongos, a SJC-8 nÃo desenvolveu toxicidade e hemÃlise, respectivamente. O mecanismo de aÃÃo da SJC-8 foi, entÃo, estudado. A viabilidade das cÃlulas HL-60 foi afetada pela SJC-8 apÃs um perÃodo de exposiÃÃo de 24h, quando analisada por exclusÃo por azul de tripan. Nas menores concentraÃÃes nÃo houve aumento do nÃmero de cÃlulas nÃo-viÃveis, mas apenas uma reduÃÃo da proliferaÃÃo celular (aÃÃo citostÃtica), enquanto que nas duas maiores concentraÃÃes, houve reduÃÃo do nÃmero de cÃlulas viÃveis e aumento do nÃmero de cÃlulas nÃo-viÃveis (efeito citotÃxico), o que corrobora com os achados da analise morfolÃgica, onde observou-se um aumento do nÃmero de cÃlulas mortas. A atividade citotÃxica da SJC-8 estÃ relacionada com a inibiÃÃo da sÃntese de DNA, como revelado pela incorporaÃÃo do BrdU, alÃm de poder estar envolvida com a inibiÃÃo da Topoisomerase 1. Submetida ao estudo de toxicogenÃtica pelo teste do cometa em HL-60, a SJC-8 elevou os Ãndices e freqÃÃncias de dano de maneira concentraÃÃo-dependente, sendo observados tipos de danos maiores nas concentraÃÃes mais elevadas. A administraÃÃo de SJC-8 (25 ou 50mg/kg/dia) inibiu o desenvolvimento de tumor sÃlido em camundongos transplantados com Sarcoma 180 em 12,3 e 59,8% respectivamente. A atividade antitumoral da SJC-8 estÃ relacionada com a inibiÃÃo da proliferaÃÃo do tumor. A anÃlise histopatolÃgica mostrou de forma reversÃvel, que o fÃgado Ã o alvo de toxicidade da droga. De fato, a atividade antitumoral da SJC-8 esta relacionada com um efeito antiproliferativo direto nas cÃlulas tumorais, sendo possÃvel assim que esta amostra possa atuar como possÃvel protÃtipo de novos agentes antitumorais.
The hydrobenzofuranoids obtained from Tapirira guianensis are alkylated derivates of cyclo-hexanone, which appear to be precursors of phenolic lipids. The present study initially examined the activity of nine hydrobenzofuranoids in cell lines, where the compound SJC-8 showed the highest cytotoxicity. In later studies, the cytotoxicity of this sample was investigated with regard to the possible mechanism of action. In the MTT assay, SJC-8 showed IC50 values of 0.3 to 6.2Âg/mL in a panel of cell lines. In acute toxicity assays in artemia nauplii and hemolytic activity in mouse erythrocytes, SJC-8 did not demonstrate any toxicity or hemolysis, respectively. The mechanism of action of SJC-8 was then studied. SJC-8 affected cell viability in HL-60 after an exposure period of 24h, when determined by trypan blue exclusion. At lower concentrations, there was no increase in the number of non-viable cells but only a reduction in cell proliferation (cytostatic effect). However, at the two highest concentrations, there was a decrease in the number of viable cells and increase in number of non-viable cells (cytotoxic effect), which corroborate the findings of morphologic analysis showing an increase in the number of dead cells. The cytotoxicity of SJC-8 involves the inhibition of DNA synthesis, as revealed by inhibition of BrdU incorporation into DNA and of topoisomerase 1 activity. SJC-8 was tested for genotoxicity using the comet assay in HL-60 cells, and was found to cause an increase in the frequency of DNA damage in a concentration-dependent manner, where more severe damage was seen at higher concentrations of SJC-8. The administration of SJC-8 (25 or 50 mg/kg/day) inhibited solid tumor growth in mice transplanted with sarcoma 180, by 12.3 and 59.8%, respectively. The antitumor activity of SJC-8 is attributed to inhibition of tumor cell proliferation. Histopathologic analysis showed in a reversible manner that the liver is the target of drug toxicity. In conclusion, SJC-8 has antitumor activity where it has a direct antiproliferative effect on tumor cells, and may therefore serve as a prototype for new antitumor agents.

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Hill, Gordon Craig. "DNA binding studies of antitumor antibiotics and antitumor anthracene derivatives: Computer simulations and spectrophotometric titrations." Diss., The University of Arizona, 1990. http://hdl.handle.net/10150/185221.

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Quinocarcin binds to d(ATGCAT)₂ with a preferred direction of 3' and the R configuration at C4 of the drug. A mode of action involving ring opening of the oxazolidine ring to form an iminium ion which can then alkylate the N2 of guanine has been reinforced by the current computer modeling study. The absolute configuration for quinocarcin should be reversed based on the fact that the optical isomer of the structure arbitrarily assigned in the literature forms a much better binding complex to DNA. Anthramycin binds to the 2-amino group of guanine but its mechanism of action proceeds through a neutral imine. The 3' direction is again favored but for this molecule, the preferred configuration is S. This computer modeling study provided a basis for a 2D NMR study which confirmed that anthramycin forms a 3'S adduct when it binds to d(ATGCAT)₂. Bisantrene and R9 are synthetic anthracene derivatives with antitumor activity. Use of UV spectroscopy provided insight into the ability of these compounds to intercalate between the base pairs of double helical DNA. Standard Scatchard plot analysis proved useless in determining the binding parameters. A McGhee-von Hippel equation was able to describe a portion of the data but a smoothing spline function was able to describe the data completely. Naphthyridinomycin studies indicate that it too prefers a covalent adduct in which the direction is 3' and the configuration is R at C7. When the noncovalent drug binds to d(ATGCAT)₂ it may bind with either the C3a face or the C7 face closest to N2 of guanine. Iminium ion mechanisms have been proposed for the binding of naphthyridinomycin to N2 of guanine in the minor groove of DNA and the computer modeling presents evidence to support such mechanisms. Saframycin A binds much better to d(GATGCATC)₂ as a hydroquinone species but the quinone can still bind in the same site. The 3' direction is clearly preferred with the R configuration at C7. The hydrogen bonding network of the hydroquinone is conserved in the noncovalent, iminium ion, and covalent 3'R models after 32 ps of dynamics. Iminium ion mechanisms have been proposed for the binding of saframycin A to N2 of guanine in the minor groove of DNA and the computer modeling presents evidence to support such mechanisms.

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3

Mokdsi, George. "Antitumour Metallocenes." Thesis, The University of Sydney, 2000. http://hdl.handle.net/2123/794.

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This thesis reports a study of the chemical stability and coordination chemistry of several antitumour metallocenes Cp2MCl2 (Cp = h5-C5H5; M = Ti 1, V 2, Nb 3, Mo 4), as well as derivatives of Cp2TiCl2 1, with nucleic acids, nucleic acid constituents and proteins. These studies were carried out in order to identify the biologically active species and more fully understand the molecular level mechanism of action of the antitumour metallocenes, in particular Cp2TiCl2 1, which is currently undergoing phase II clinical trials. The interactions of Cp2MoCl2 4 with four oligonucleotides were studied by 1H and 31P NMR spectroscopy. In 50 mM salt solutions of Cp2MoCl2 4, hydrolysis of the halide ligands occurred to give a solution with pD -2, containing a species in which both Cp rings remain metal bound for 24 h. At pD -7, partial hydrolysis of the Cp rings (-30percent) occurred after 24 h. Addition of an aqueous solution of Cp2MoCl2 4 in 50 mM salt to the self-complementary sequence d(CGCATATGCG)2, maintaining the pD at 6.0-7.0, showed no evidence for the formation of a metallocene-oligonucleotide complex and only peaks arising from hydrolysis of Cp2MoCl2 4 were detected. A similar result was obtained in titration experiments with the single stranded sequence d(ATGGTA) at pD 6.5-7.0. However, at pD 3.0, new signals assigned to a molybdocene-oligonucleotide complex(es), which was stable for hours at pD 3.0, were detected; while at pD -7 the complex is destabilised and only peaks arising from hydrolysis of Cp2MoCl2 4 were detected. Titration experiments at low pD with Cp2MoCl2 4 and the dinucleotide dCG were consistent with formation of a complex arising due to coordination of molybdenum to guanine N7 and/or cytosine N3. The results obtained showed that stable oligonucleotide adducts were not formed in 50 mM salt at pD -7 and hence it is highly unlikely that formation of molybdocene-DNA adducts in vivo is the primary action that is responsible for the antitumour properties of Cp2MoCl2 4. The rate of hydrolysis of the aromatic rings of Cp2TiX2 (X equals Cl 1, OCOCH2NH3Cl 27) and the dimethylsubstituted derivatives (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41), in aqueous solutions at pD 2-8 was studied by 1H NMR spectroscopy. Rapid hydrolysis of both the halide/glycine and Cp ligands in Cp2TiX2 (X equals Cl 1, OCOCH2NH3Cl 27) occurred and predominantly gave a precipitate at pD -7. In contrast, under the same experimental conditions, the predominant species present in aqueous solutions of (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41) at pH 2-8 contained both MeCp rings metal bound. At pD < 5, Cp2TiX2 (X equals Cl 1, OCOCH2NH3Cl 27) and (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41) formed similar complex(es) with purine nucleotides. However, at pD >5, stable adducts between nucleotides and Cp2TiX2 (X equals Cl 1, OCOCH2NH3Cl 27) were not formed. In contrast, (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41) formed complex(es) with 5'-dAMP or 5'-dGMP, which were stable for 24 h. These results suggest that formation of stable chelates between (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41) and nucleic acid constituents in vivo is possible. However, the methyl substituted derivatives 34 and 41 did not show any antitumour activity against EAT in mice when administered in either 10percentDMSO/90percentsaline or in water at pH 6.2-6.4, which suggests that the labile Cp-Ti bond present in Cp2TiCl2 1 is required for antitumour activity. The synthesis of a range of Cp substituted titanocene derivatives was investigated in an attempt to prepare derivatives with modified Cp stability in comparison to the methyl substituted derivatives. The synthesis of derivatives (CpCH2Y)2TiCl2 where Y equals ?CHO 43, ?CONMe2 44, ?NO2 45, (RCp)2TiCl2 where R equals ?COMe 46, ?COOMe 47 or ?CONMe2 48, (CpNMe2)2TiCl2 62 and (Cp(CH2)2NMe2)2TiCl2 63 was unsuccessful, due to the presence of coordinating substituents on the Cp rings and poor stability in polar, protic solvents. Hence, these derivatives were excluded from further studies. The rate of hydrolysis of the Cp rings of Cp2TiX2 (X equals Cl 1, OCOCCl3 22 and OCOCH2NH3Cl 27) in aqueous solutions, 10percentDMSO/90percentD2O and 100percent DMSO was monitored by 1H NMR spectroscopy. Rapid hydrolysis of both the carboxylate and Cp ligands of Cp2TiX2 (OCOCCl3 22 and OCOCH2NH3Cl 27) occurred in DMSO to give biologically inactive species. The rate of these reactions were concentration dependent as dilution of these samples with saline or water to give the therapeutic conditions of 10percentDMSO/90percentD2O slowed the hydrolysis chemistry. In contrast, samples of Cp2TiX2 (X equals Cl 1 and OCOCH2NH3Cl 27) dissolved in water, gave solutions containing the presumed antitumour active species in which the halide or glycine ligands have been hydrolysed but the Cp rings remain metal bound. Thus, charged X ligands may be incorporated into Cp2TiX2 and will give comparable activity to Cp2TiCl2 1 provided the samples are administered in water. The antitumour metallocenes Cp2MCl2 (M equals Ti 1, V 2, Nb 3, Mo 4) and the inactive derivative (MeCp)2TiCl2 34 were found to inhibit the relaxation of supercoiled plasmid DNA pBR322 by human topoisomerase II in vitro. These results implicated the inhibition of topoisomerase II in the mechanism of antitumour activity although there was no direct correlation between the in vitro results with biological activity against EAT in vivo. UV spectroscopy confirmed that the metallocenes Cp2MCl2 (M equals Ti 1, Mo 4) became associated with and were stabilised to hydrolysis by calf thymus DNA but not with human serum albumin. ICP-AES was used to measure the amount of metal associated with either DNA or human serum albumin after incubation with Cp2MCl2 (M equals Ti 1, Nb 3, Mo 4) and dialysis of these solution. The results confirmed that DNA stabilises or becomes associated with the metallocenes. However, errors associated with the ICP-AES measurements did not allow these results to be quantified. 1H NMR spectroscopy was used to show that the antitumour metallocene Cp2MoCl2 4 formed an adduct with glutathione 72 in the pH range 3-7 through the sulfur donor group. In comparison, the antitumour metallocenes Cp2MCl2 (M equals Ti 1, Nb 3) showed limited adduct formation with glutathione 72 at pH -3 and no adducts were detected at pH > 5.5.

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4

Mokdsi, George. "Antitumour Metallocenes." University of Sydney. Chemistry, 2000. http://hdl.handle.net/2123/794.

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This thesis reports a study of the chemical stability and coordination chemistry of several antitumour metallocenes Cp2MCl2 (Cp = h5-C5H5; M = Ti 1, V 2, Nb 3, Mo 4), as well as derivatives of Cp2TiCl2 1, with nucleic acids, nucleic acid constituents and proteins. These studies were carried out in order to identify the biologically active species and more fully understand the molecular level mechanism of action of the antitumour metallocenes, in particular Cp2TiCl2 1, which is currently undergoing phase II clinical trials. The interactions of Cp2MoCl2 4 with four oligonucleotides were studied by 1H and 31P NMR spectroscopy. In 50 mM salt solutions of Cp2MoCl2 4, hydrolysis of the halide ligands occurred to give a solution with pD -2, containing a species in which both Cp rings remain metal bound for 24 h. At pD -7, partial hydrolysis of the Cp rings (-30percent) occurred after 24 h. Addition of an aqueous solution of Cp2MoCl2 4 in 50 mM salt to the self-complementary sequence d(CGCATATGCG)2, maintaining the pD at 6.0-7.0, showed no evidence for the formation of a metallocene-oligonucleotide complex and only peaks arising from hydrolysis of Cp2MoCl2 4 were detected. A similar result was obtained in titration experiments with the single stranded sequence d(ATGGTA) at pD 6.5-7.0. However, at pD 3.0, new signals assigned to a molybdocene-oligonucleotide complex(es), which was stable for hours at pD 3.0, were detected; while at pD -7 the complex is destabilised and only peaks arising from hydrolysis of Cp2MoCl2 4 were detected. Titration experiments at low pD with Cp2MoCl2 4 and the dinucleotide dCG were consistent with formation of a complex arising due to coordination of molybdenum to guanine N7 and/or cytosine N3. The results obtained showed that stable oligonucleotide adducts were not formed in 50 mM salt at pD -7 and hence it is highly unlikely that formation of molybdocene-DNA adducts in vivo is the primary action that is responsible for the antitumour properties of Cp2MoCl2 4. The rate of hydrolysis of the aromatic rings of Cp2TiX2 (X equals Cl 1, OCOCH2NH3Cl 27) and the dimethylsubstituted derivatives (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41), in aqueous solutions at pD 2-8 was studied by 1H NMR spectroscopy. Rapid hydrolysis of both the halide/glycine and Cp ligands in Cp2TiX2 (X equals Cl 1, OCOCH2NH3Cl 27) occurred and predominantly gave a precipitate at pD -7. In contrast, under the same experimental conditions, the predominant species present in aqueous solutions of (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41) at pH 2-8 contained both MeCp rings metal bound. At pD < 5, Cp2TiX2 (X equals Cl 1, OCOCH2NH3Cl 27) and (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41) formed similar complex(es) with purine nucleotides. However, at pD >5, stable adducts between nucleotides and Cp2TiX2 (X equals Cl 1, OCOCH2NH3Cl 27) were not formed. In contrast, (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41) formed complex(es) with 5'-dAMP or 5'-dGMP, which were stable for 24 h. These results suggest that formation of stable chelates between (MeCp)2TiX2 (X equals Cl 34, OCOCH2NH3Cl 41) and nucleic acid constituents in vivo is possible. However, the methyl substituted derivatives 34 and 41 did not show any antitumour activity against EAT in mice when administered in either 10percentDMSO/90percentsaline or in water at pH 6.2-6.4, which suggests that the labile Cp-Ti bond present in Cp2TiCl2 1 is required for antitumour activity. The synthesis of a range of Cp substituted titanocene derivatives was investigated in an attempt to prepare derivatives with modified Cp stability in comparison to the methyl substituted derivatives. The synthesis of derivatives (CpCH2Y)2TiCl2 where Y equals ?CHO 43, ?CONMe2 44, ?NO2 45, (RCp)2TiCl2 where R equals ?COMe 46, ?COOMe 47 or ?CONMe2 48, (CpNMe2)2TiCl2 62 and (Cp(CH2)2NMe2)2TiCl2 63 was unsuccessful, due to the presence of coordinating substituents on the Cp rings and poor stability in polar, protic solvents. Hence, these derivatives were excluded from further studies. The rate of hydrolysis of the Cp rings of Cp2TiX2 (X equals Cl 1, OCOCCl3 22 and OCOCH2NH3Cl 27) in aqueous solutions, 10percentDMSO/90percentD2O and 100percent DMSO was monitored by 1H NMR spectroscopy. Rapid hydrolysis of both the carboxylate and Cp ligands of Cp2TiX2 (OCOCCl3 22 and OCOCH2NH3Cl 27) occurred in DMSO to give biologically inactive species. The rate of these reactions were concentration dependent as dilution of these samples with saline or water to give the therapeutic conditions of 10percentDMSO/90percentD2O slowed the hydrolysis chemistry. In contrast, samples of Cp2TiX2 (X equals Cl 1 and OCOCH2NH3Cl 27) dissolved in water, gave solutions containing the presumed antitumour active species in which the halide or glycine ligands have been hydrolysed but the Cp rings remain metal bound. Thus, charged X ligands may be incorporated into Cp2TiX2 and will give comparable activity to Cp2TiCl2 1 provided the samples are administered in water. The antitumour metallocenes Cp2MCl2 (M equals Ti 1, V 2, Nb 3, Mo 4) and the inactive derivative (MeCp)2TiCl2 34 were found to inhibit the relaxation of supercoiled plasmid DNA pBR322 by human topoisomerase II in vitro. These results implicated the inhibition of topoisomerase II in the mechanism of antitumour activity although there was no direct correlation between the in vitro results with biological activity against EAT in vivo. UV spectroscopy confirmed that the metallocenes Cp2MCl2 (M equals Ti 1, Mo 4) became associated with and were stabilised to hydrolysis by calf thymus DNA but not with human serum albumin. ICP-AES was used to measure the amount of metal associated with either DNA or human serum albumin after incubation with Cp2MCl2 (M equals Ti 1, Nb 3, Mo 4) and dialysis of these solution. The results confirmed that DNA stabilises or becomes associated with the metallocenes. However, errors associated with the ICP-AES measurements did not allow these results to be quantified. 1H NMR spectroscopy was used to show that the antitumour metallocene Cp2MoCl2 4 formed an adduct with glutathione 72 in the pH range 3-7 through the sulfur donor group. In comparison, the antitumour metallocenes Cp2MCl2 (M equals Ti 1, Nb 3) showed limited adduct formation with glutathione 72 at pH -3 and no adducts were detected at pH > 5.5.

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SOUZA, Pâmella Grasielle Vital Dias de. "Avaliação da ação antitumoral de Cnidoscolus urens sobre tumores sólidos experimentais em camundongos Swiss." Universidade Federal de Pernambuco, 2013. https://repositorio.ufpe.br/handle/123456789/16728.

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FACEPE
Cnidoscolus urens pertence à família das Euphorbiaceae que é considerada uma das seis maiores famílias de Gimnospermas do bioma Caatinga. Esta espécie conhecida popularmente como urtiga branca, em levantamentos etnobotânicos realizados com populares da região do Nordeste, aparece com boa frequência e com o relato de diversas atividades biológicas como anti-inflamatória, antitumoral, antimicrobiana e analgésica. Portanto esta dissertação teve como objetivo, determinar o perfil fitoquímico dos extratos aquoso, N- butanólico e acetato de etila de C. urens, a atividade in vitro dos extratos aquoso e etanólico de C. urens e atividade antitumoral in vivo dos mesmos extratos de C. urens frente à linhagem celular HELA. Assim, para avaliar a eficácia das atividades descritas pela população, iniciou- se a investigação dos constituintes metabólitos secundários produzidos por C. urens através do método de cromatografia de camada delgada (CCD). A citotoxicidade foi determinada pelo método de MTT e para a determinação da atividade antitumoral in vivo, foram induzidos carcinoma de Ehrlich experimentais em camundongos Swiss, a determinação do perfil hematológico foi obtida através de contagem automática das células vermelhas e o perfil bioquímico foi determinado por métodos enzimáticos. Os extratos aquoso, N- butanólico e acetato de etila revelaram a presença de metabólitos majoritários tais como: Flavonóides, açúcares redutores e terpenóidess, além de outros compostos como cumarinas e taninos que apresentaram- se em menor concentração. Os extratos aquoso e etanólico foram efetivos na inibição do crescimento do tumor sólido de carcinoma de Ehrlich (84.4% e 79.2%, respectivamente) inclusive melhorando os parâmetros bioquímicos, sendo mantidos os níveis de ureia, creatinina, colesterol total, HDL-colesterol, glicose e triglicerídios e hematológicos para células sanguíneas vermelhas, células brancas e hemoglobina, indicando uma melhora na resposta imunológica dos animais tratados com os extratos. Os extratos aquoso e etanólico de C. urens não mostraram toxicidade in vitro frente à células HELA, nas concentrações testadas 12,5; 25; 50 e 100 μg/ mL, no entanto, apresentaram potencial antioxidante >50% para as concentrações de 50; 100; 200 e 500 μg/ mL. Diante desses resultados podemos concluir que os extratos aquosos e etanólico C. urens foram eficazes em inibir o crescimento do tumoral.
Cnidoscolus urens belongs to the family Euphorbiaceae which is considered one of the six largest families of gymnosperms of biome Caatinga from Brazil. This species are commonly known as urtiga branca and appears with good frequency and reporting of various biological activities such as anti-inflammatory, antitumor, antibacterial and analgesic in ethnobotanical surveys conducted in Northeast region. Therefore, this thesis aimed to determine the phytochemical profile of aqueous, butanolic and ethyl acetate of C. urens and in vivo antitumoral activity of aqueous and ethanolic extracts of C. urens and in vitro cytotoxic activity of same extracts C. urens in Hela cell line. Thus, to assess the efficacy of proposed activities for this work, it was started the research of metabolites produced by C. urens by thin layer chromatography (TLC) method, cytotoxicity was determined by the MTT method and solid tumors were induced in mice to determine the in vivo antitumoral activity, blood sampling at the orbital plexus was conducted in order to perform hematological and biochemical profile by automated cell count and enzymatic methods, respectively. The aqueous extracts, butanolic and ethyl acetate, revealed the presence of major metabolites such as flavonoids, terpenes and reducing sugars, and other compounds such as coumarins and tannins that are present in lower concentrations. The aqueous and ethanolic extracts were effective in inhibiting tumor growth (84.4% and 79.2%, respectively) and also improving biochemical (maintenance of urea, creatinine, total cholesterol, HDL-cholesterol, triglycerides and glucose levels) and hematologic parameters (red blood cells, white blood cells and hemoglobin), which indicate an improvement of the immune response of animals treated with the extracts. The aqueous and ethanolic extracts of C. urens showed no toxicity in vitro against the Hela cells, otherwise, they showed potential antioxidant activity higher than 50% at concentrations of 50, 100, 200 and 500 mg/mL. From these results we conclude that the aqueous and ethanol extracts of Cnidoscolus urens were effective in inhibiting the growth of Ehrlich tumor models of solids.

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GONÇALVES, Joelma Pessoa. "Avaliação da citotoxicidade e genotoxicidade de extratos orgânicos e ácido barbático isolado do líquen Cladonia salzmannii (Nyl.)." Universidade Federal de Pernambuco, 2015. https://repositorio.ufpe.br/handle/123456789/17320.

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Os metabólitos secundários dos liquens são responsáveis pela maioria das suas atividades biológicas. Muitos destes compostos apresentam relevante atividade antineoplásica. O objetivo deste trabalho foi verificar as atividades citotóxica e genotóxica in vitro dos extratos orgânicos e do ácido barbático (BAR) purificado de Cladonia salzmannii Nyl. Os extratos orgânicos foram obtidos a partir do talo liquênico (22 g) previamente limpo e seco, com os solventes éter dietílico, clorofórmio e acetona, através do método de esgotamento a quente em aparelho de Soxhlet. O ácido barbático foi purificado a partir do extrato etéreo (1,3 g). A análise química dos extratos orgânicos e do BAR purificado foi realizada através de Cromatografia em Camada Delgada (CCD). A pureza do BAR purificado foi observada através de Cromatografia Líquida de Alta Eficiência (CLAE). A atividade citotóxica dos extratos orgânicos e do BAR purificado foi determinada através do Método do MTT [brometo de 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazólio] e do IPBC (Índice de Proliferação com Bloqueio da Citocinese). O potencial genotóxico dos extratos orgânicos e do BAR purificado foram determinados através do teste do micronúcleo e do ensaio cometa. O dimetilsulfoxido (DMSO) foi utilizado como solvente de diluição das amostras em todos os testes de atividade biológica. Os resultados referentes a CI50 demonstraram relevante potencial citotóxico para o extrato etéreo (Ext E) (50 μg/mL) frente as linhagens celulares NCI-H292 (CI50: 29,91 μg/mL), HEp-2 (CI50: 26,75 μg/mL) e HL-60 (CI50: 3,59 μg/mL), e para o BAR purificado (25 μg/mL) contra as linhagens HEp-2 (CI50: 15,79 μg/mL) e MCF-7 (CI50: 18,28 μg/mL). Porém, a avaliação da citotoxicidade considerando o Índice de Proliferação com Bloqueio de Citocinese (IPBC) demonstrou atividade citotóxica para o BAR purificado em todas as concentrações testadas (5, 10, 20 e 40 μg/mL) e para todos os extratos orgânicos (50 μg/mL) frente as células do Carcinoma de Ehrlich. Entretanto, para o Sarcoma 180 apenas o BAR purificado na concentração de 40 μg/mL e os extratos etéreo e clorofórmico (50 μg/mL) foram considerados citotóxicos. O teste do micronúcleo (MN) demonstrou que o BAR purificado na concentração de 5 μg/mL não apresentou potencial genotóxico em ambas as linhagens celulares tumorais. Além disso, o extrato clorofórmico e BAR purificado na concentração de 10 μg/mL não foram considerados genotóxicos para o Sarcoma 180. No ensaio cometa, todos os compostos testados induziram danos ao DNA em ambas as linhagens tumorais. Com base nos resultados, considera-se que os extratos orgânicos e o BAR purificado de C. salzmannii (Nyl). apresentam atividade citotóxica e genotóxica frente as linhagens celulares tumorais testadas.
The secondary metabolites of lichens are responsible for most of their biological activities. Many of these compounds exhibit significant antineoplastic activity. The objective of this study was to evaluate the in vitro cytotoxic and genotoxic activities of organic extracts and purified barbatic acid from Cladonia salzmannii Nyl. The organic extracts were obtained from liquenic thallus (22 g) previously cleaned and dried with the solvents diethyl ether, chloroform and acetone, through hot exhausted method in a Soxhlet apparatus. The barbatic acid was purified from the ether extract (1.3 g). Chemical analysis of the organic extracts and purified BAR was performed by Thin Layer Chromatography (TLC). The purity of purified BAR was observed by High Performance Liquid Chromatography (HPLC). The cytotoxic activity of the organic extracts and purified BAR was determined by the MTT method [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] and IPBC (Cytokinesis-Block Proliferation Index). The genotoxic potential of the organic extracts and purified BAR was determined by the micronucleus test and comet assay. Dimethyl sulfoxide (DMSO) was used as diluting solvent of the samples in all biological tests. The results for IC50 demonstrated significant cytotoxic potential to the ether extract (Ext E) (50 μg/mL) against the cell lines NCI-H292 (IC50: 29,91 μg/mL), HEp-2 (IC50: 26,75 μg/mL) and HL-60 (IC50: 3,59 μg/mL) and to the purified BAR (25 μg/mL) against the cell lines HEp-2 (IC50: 15,79 μg/mL) and MCF-7 (IC50: 18,28 μg/mL). However, the assessment of cytotoxicity considering the Cytokinesis-Block Proliferation Index (IPBC) showed cytotoxic activity for purified BAR at all concentrations tested (5, 10, 20 and 40 μg/mL) and for all organic extracts (50 μg/mL) against Ehrlich carcinoma cells. However, for Sarcoma 180 only BAR purified at a concentration of 40 μg/mL and ether and chloroform extracts (50 μg/mL) were considered cytotoxic. The micronucleus test (MN) showed that the purified BAR at a concentration of 5 μg/mL showed no genotoxic potential in both tumor cell lines. Furthermore, the chloroform extract and purified BAR at a concentration of 10 μg/mL were not considered genotoxic for Sarcoma 180. In the comet assay, all compounds tested induced DNA damage in both tumor lines. Based on the results, it is considered that the organic extracts and the BAR purified from C. salzmannii (Nyl). exhibit cytotoxic and genotoxic activity front of the tested tumor cell lines.

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Loch, Rebecca [Verfasser], and Georg [Akademischer Betreuer] Bauer. "Antimikrobielle Wirkstoffe als potenzielle Antitumor- Mittel." Freiburg : Universität, 2015. http://d-nb.info/1119452147/34.

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Loch, Rebecca. "Antimikrobielle Wirkstoffe als potenzielle Antitumor-Mittel." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-49014.

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Mousinho, Kristiana Cerqueira. "Estudo do Potencial AnticÃncer de um Derivado de Chalcona, 1-(4-Nitrofenil)-3-Fenilprop-2-En-1-Ona, In vitro e In vivo." Universidade Federal do CearÃ, 2010. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=10509.

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CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior
A substÃncia 1-(4-Nitrofenil)-3-fenilprop-2-en-1-ona (CG) Ã um derivado de chalcona, sintetizado a partir da reaÃÃo quÃmica entre a acetofenona e para-nitro benzaldeÃdo. Para avaliar o seu potencial anticÃncer foi realizado um estudo farmacolÃgico de suas propriedades antitumorais em vÃrios modelos biolÃgicos in vitro e in vivo. A CG apresentou potente atividade citotÃxica nas 5 linhagens tumorais testadas, inibindo a proliferaÃÃo das cÃlulas tumorais pelo ensaio do MTT e em cÃlulas mononucleares do sangue perifÃrico (PMCB) humano atravÃs do ensaio do Alamar blue. Todas as linhagens mostraram sensibilidade ao tratamento com a CG, e a CI50 variou de 1,18ÂM em HCT-8 a 3,32ÂM em SF-295. O composto apresentou fraca citotoxicidade (CI50 igual a 7,07ÂM) nas cÃlulas PBMC, com exposiÃÃo a CG em 72h, em relaÃÃo Ãs cÃlulas de HL-60, utilizada como modelo nos demais testes biolÃgicos. O tempo de encubaÃÃo com o composto foi de 24h na maioria dos experimentos. Adicionalmente, a CG nÃo induziu efeitos hemolÃticos. O ensaio de exclusÃo por azul de Tripan revelou diminuiÃÃo da viabilidade celular principalmente apÃs 24h na maior concentraÃÃo testada (4ÂM) com 58,4%. Para os testes de atividade antiproliferativa, LA/BE mostrou em sua morfologia cÃlulas em apoptose nas duas maiores concentraÃÃes, enquanto que o BrdU, apresentou incorporaÃÃo do mesmo nas concentraÃÃes testadas. A morfologia analisada por May-Grunwald-Giemsa mostrou reduÃÃo do volume celular, condensaÃÃo da cromatina e fragmentaÃÃo nuclear. Adicionalmente, a CG induziu apoptose em cÃlulas leucÃmicas HL-60, com participaÃÃo das vias intrÃnseca e maior estÃmulo da via extrÃnseca, de maneira concentraÃÃo-dependente, como observado na integridade da membrana citoplasmÃtica, aumento da fragmentaÃÃo do DNA e externalizaÃÃo da fosfatidilserina. Na anÃlise do ciclo celular, foi observado parada na fase G2/M, sendo ativada as caspases 3, 7, 8 e 9 (a Ãltima na maior concentraÃÃo e confirmada pelo teste do Western blot). NÃo houve ativaÃÃo do Citocromo c. A CG nÃo foi capaz de induzir processos genotÃxicos/ mutagÃnicos (testes do cometa e micronÃcleo in vitro). No ensaio de atividade antitumoral in vivo, observou-se inibiÃÃo tumoral nas doses testadas (25 e 50mg/Kg/dia, via oral) de 54,85 e 69,11% respectivamente. As doses de CG causaram tumefaÃÃo celular e o surgimento de focos inflamatÃrios no parÃnquima ou estroma hepÃtico/renal, necrose nefrotÃxica focal, esteatose microvesicular, pigmentos de hemossiderina, hiperplasia das cÃlulas de Kupffer, congestÃo da polpa vermelha e desorganizaÃÃo dos folÃculos linfÃides esplÃnicos. AlÃm disso, os Ãndices bioquÃmicos mostraram aumento do AST e diminuiÃÃo da urÃia (CG 25mg/Kg/dia), diminuiÃÃo do ALT (5-FU e CG 25mg/Kg/dia); as alteraÃÃes hematolÃgicas mostraram leucopenia e plaquetopenia (5-FU), aumento dos leucÃcitos totais (CG 50mg/Kg/dia), aumento de neutrÃfilos e linfÃcitos em todos os grupos tratados. Todos os resultados nos levam a enfatizar que a CG possui grande potencialidade como molÃcula promissora por suas propriedades anticÃncer.
The substance 1- (4-Nitrofenil)-3- fenilprop-2- en-1-ona (CG) is a chalcone derivative, synthesized from a chemical reaction between acetophenone and p-nitro benzaldehyde. To evaluate its anticancer potential a pharmacological study of its antitumor properties in selected biological models in vitro e in vivo. CG presented a powerful cytotoxic activity in the 5 tested tumor lines evaluated, inhibiting cell proliferation of the tumor lines in the MTT assay and human peripheral mononuclear blood cells (PMBC) through the Alamar Blue assay. All cell lines showed sensitivity to the treatment with the CG, and the IC50 varied from 1,18 ÂM in HCT-8 to 3,32 ÂM in SF-295. The sample presented weak cytotoxic effect (IC50 of 7,07 ÂM) in cells PMBC, with 72h exposure to CG, compared to HL-60 cells (leukemic cell line), used in the next biological tests. The sample was incubated with the cells during 24h for the majority of the experiments. Additionally, CG did not induce hemolytic effects. The Tripan Blue assay showed a decrease of the cellular viability especially after 24h of incubation of the higher tested concentration (4 ÂM) with 58,4%. In assays for antiproliferative activity, OA/BE showed in its morphology cells going under apoptosis in the two higher concentrations, whereas the BrdU assay, presented incorporation of the same in the tested concentrations. The morphology analyzed with the May-Grunwald-Giemsa stain showed a decrease of the cellular volume, chromatin condensation and nuclear fragmentation.CG induced apoptosis in HL-60 cells, with participation of the intrinsic pathway and major stimulation of the extrinsic pathway, in a concentration-dependent manner, as observed in the cytoplasmatic membrane integrity, increase of DNA fragmentation and outsourcing of phosphatidylserine. In the cellular cycle analysis, it was observed a stop in the G2/M phase, activating caspases 3, 7, 8 and 9 (the last one in the highest concentration and confirmed by the Western blot assay). It was not observed activation of Cytochrome c. CG was not capable to induce mutagenic/genotoxic processes (comet assay and micronucleus in vitro). In the in vivo antitumor activity assay, tumor inhibition was observed in the tested doses (25 and 50mg/Kg/day, oral intake) of 54,85 and 69,11%, respectively . The doses of CG caused cellular swelling and the arise of inflammatory focus in the parenchyma or hepatic/renal stroma, focal nephrotoxic necrosis, microvesicular steatosis, hemosiderin pigments, hyperplasia of Kupffer cells, congestion of the red pulp and disorganization of the splenic lymphoid follicles. Furthermore, the biochemical indices had shown increase of AST and reduction of urea (25mg/Kg/day of CG), reduction of ALT (25mg/Kg/day of 5-FU and CG); hematologic alterations showed leukopenia and thrombocytopenia (5-FU), increase of total leukocytes (50mg/Kg/day of CG), increase of neutrophils and lymphocytes in all treated groups. All results led us to emphasize that CG possesses great potential as a promising molecule for its anticancer properties.

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Trazzi, Giordano. "Sintese de lignanas a partir de adutos de Morita-Baylis-Hillman : uma via geral de acesso a lignanas biologicamente ativas." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/250252.

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Orientador: Fernando Antonio Santos Coelho
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: Lignanas são produtos naturais produzidos por plantas, cuja diversidade estrutural e pronunciada atividade biológica têm atraído o interesse acadêmico e industrial há mais de um século, a exemplo do fármaco antitumoral Etoposide® (Sandoz), derivado semi-sintético da podofilotoxina, uma lignana natural até hoje comercialmente obtida por extração vegetal. Dentre as rotas de síntese de lignanas, as mais eficazes empregam uma b-benzil-g-butirolactona como intermediário-chave da estratégia. Nesse contexto, propusemos o emprego da reação de Morita-Baylis-Hillman (MBH) para o preparo de a-(aril-hidroximetil)- acrilatos (adutos de MBH) e sua utilização como materiais de partida para a síntese de b-(aril-silaniloximetil)-g-butirolactonas, novos intermediários-chave para a síntese de lignanas. Partindo paralelamente do piperonal, do 6-bromo-piperonal e da vanilina, empregamos a reação de MBH para preparar os a-(aril-hidroximetil)- acrilatos correspondentes, e então os utilizamos na preparação de suas respectivas b-(aril-silaniloximetil)-g-butirolactonas, de forma diastereosseletiva e com rendimentos globais de 56% a 69%, em 4 etapas a partir dos adutos de MBH. A b-(piperonil-silaniloximetil)-g-butirolactona foi empregada com alta eficiência na síntese total das lignanas naturais (±)-yateína, (±)-podorrizol e (±)-epi-podorrizol. A b-(6-bromo-piperonil-silaniloximetil)-g-butirolactona permitiu a preparação de um intermediário avançado para uma nova proposta sintética para a (±)- podofilotoxina. A b-(guaiacil-silaniloximetil)-g-butirolactona, obtida a partir da vanilina, e um intermediário chave para a síntese racemica da porção aglicona do medusasídeo A, uma nova lignana da classe dos dibenzilbutanodiois, cuja síntese ainda não foi descrita
Abstract: Lignans are plant-produced natural products, which structural diversity and pronounced biological activity has being attracting the interest of academy and industry through the entire last century, taking as example the antineoplasic drug Etoposide® (Sandoz), a semi-synthetic derivative of podophyllotoxin, a natural lignan which is, up to date, commercially obtained only by vegetal extraction. Among the routes of synthesis to lignans, the most efficient ones uses a b-benzyl- g-butyrolactone as the key intermediate. In this scenario, we have envisaged the use of the Morita-Baylis-Hillman reaction to synthetize a-(aryl-hydroxymethyl)- acrylates (MBH adducts) and it¿s use as starting materials to the synthesis of b-(aryl-silanyloxymethyl)-g-butyrolactones, new key intermediates to the synthesis of lignans. Starting alongside from piperonal, b-bromo-piperonal and vanillin, we used the MBH reaction to prepare the corresponding a-(aryl-hydroxymethyl)-acrylates (MBH adducts), and used it in the preparation of it¿s corresponding b-(arylsilanyloxymethyl)- g-butyrolactones, in a diastereoselective way and with global yields from 56% to 69% in four steps. The b-(piperonyl-silanyloxymethyl)-g- butirolactone obtained was used with high efficiency in the synthesis of natural lignans (±)-yatein, (±)-podorrizol and (±)-epi-podorrizol. The b-(6-bromo-piperonylsilanyloxymethyl)- g-butirolactone obtained allowed the preperation of an advanced intermediate to a new synthetic strategy to (±)-podophyllotoxyn. The b-(guaiacylsilanyloxymethyl)- g-butirolactone obtained is a key intermediate to the racemic synthesis of medusaside A aglycone, a new dibenzylbutanediol lignan whose synthesis was not described yet
Doutorado
Quimica Organica
Doutor em Ciências

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Sousa, Alessandra de Paula Alves. "Antitumor potential of alginates isolated from the seaweed brown sargassum vulgare c. agardh (1820)." Universidade Federal do CearÃ, 2006. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=8.

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FundaÃÃo de Amparo Ã Pesquisa do Estado do CearÃ
Alginates are natural polysaccharides composed of linear polymers of 1-4 linked beta-D- mannuronic and alfa-L-guluronic acid residues in widely varying composition and sequential arrangements. The purpose of this study was to evaluate the anti cancer potential of two alginates âV (low viscosity) and +V (high viscosity), isolated from the seaweed Sargassum vulgare. Alginates were tested for cytotoxicity using the brine shrimp lethality assay, sea urchin development assay, hemolysis assay and MTT assay using HL-60, MCF-7, CEM, HCT-8 and B16 tumor cell lines. None of the compounds tested showed in vitro toxicity. On the other hand, alginates showed antitumor activity in vivo against Sarcoma 180 cells transplanted in mice. Both alginates inhibited the growth of solid tumor in mice implanted with 5 x 105 tumor cells after both oral and intraperitoneal administration at 50 and 100 mg/m2, as well as 25 mg/m2 after oral administration. Alginate +V presented higher inhibition effects after oral administration. The association of alginate +V (25 mg/m2) with 5-FU (15 mg/m2) showed an increasing activity against tumor compared to +V individually. Alginates antitumor activity at 50 and 100 mg/m2 was related to the tumor proliferation rate inhibition, as observed by reduction of Ki-67 staining in tumor of the treated-animals. The histopathological analysis revealed that both alginates administrated at 50 and 100 mg/m2 presented hepatotoxicity and nefrotoxicity, being -V was more toxic than +V. The kidney perfusion assay demonstrated that âV was more toxic than +V, corroborating date from histopathological analysis. The histopathological analysis of spleen showed that both alginates cause the enlargement of the white pulp of treated animals, suggesting that the observed antitumor activity could be related to alginates immunomodulatory properties. In fact, the alginates treatment (25 mg/m2) prevents the reduction number of leukocytes and lymphocytes, induced by 5-FU treatment as observed from the hematological analysis.
Alginato Ã um biopolÃmero natural, constituÃdo por ligaÃÃes lineares (1-4) de β-D-Ãcido manurÃnico e α-L-Ãcido gulurÃnico arranjados em seqÃÃncias e proporÃÃes nÃo regulares ao longo da cadeia. Este trabalho visou estudar o potencial antitumoral de dois alginatos com diferentes viscosidades isolados da alga marinha Sargassum vulgare, denominados de âV (menos viscoso) e +V (mais viscoso). Os ensaios atividade antimitÃtica no desenvolvimento do ouriÃo-do-mar, atividade antiproliferativa nas linhagens tumorais HCT-8, MCF-7, HL-60, CEM e B-16, atividade hemolÃtica e toxicidade em Artemia sp, mostraram que ambos os alginatos nÃo possuem toxicidade in vitro. No entanto, os alginatos âV e +V apresentaram atividade antitumoral in vivo no modelo experimental do Sarcoma 180. Ambos os alginatos administrados por via oral e intraperitoneal nas concentraÃÃes de 50 e 100 mg/m2, bem como na concentraÃÃo de 25 mg/m2 por via oral inibiram o crescimento do tumor sÃlido em camundongos transplantados com 5 x 105 cÃlulas tumorais. O alginato +V administrado por via oral apresentou um maior efeito inibitÃrio. O tratamento do alginato +V por via oral (25 mg/m2) associado ao 5-FU (15 mg/m2) promoveu um aumento da resposta contra o tumor quando comparado ao tratamento com o alginato +V isoladamente. A inibiÃÃo da proliferaÃÃo das cÃlulas tumorais, determinada por imunohistoquÃmica com o Ki-67, foi observada em ambos os tratamentos por via oral e intraperitoneal com os alginatos âV e +V nas concentraÃÃes de 50 e 100 mg/m2. As anÃlises histopatolÃgicas revelaram que os alginatos âV e +V administrados nas concentraÃÃes de 50 e 100 mg/m2 por via oral e intraperitoneal possuem toxicidade hepÃtica e renal, no entanto, o alginato âV apresentou maior toxicidade que o alginato +V. O estudo da nefrotoxicidade avaliada no sistema de perfusÃo renal demonstrou que o alginato âV tambÃm apresenta um maior efeito que o alginato +V. A anÃlise histopatÃlogica do baÃo revelou que ambos os alginatos levam a uma hiperplasia da polpa branca nos animais tratados, o que sugere que a atividade antitumoral esteja relacionada Ãs propriedades imunomoduladoras desses compostos. De acordo com a anÃlise hematolÃgica, os animais tratados com o 5-Fu (15 mg/m2) apresentaram leucopenia e linfocitopenia, sendo este quadro revertido com o tratamento associado com os alginatos âV e +V (25 mg/m2).

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Wei, Linyi Lee Kuo-Hsiung. "New tylophorine analogs as potential antitumor agents." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,278.

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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.
Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in School of Pharmacy." Discipline: Pharmacy; Department/School: Pharmacy.

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Li, Geqiang. "Antiviral and antitumor functions of RNase L." Connect to text online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1097095517.

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Matos, Adriana Arruda. "Avaliação do efeito antiproliferativo da apocinina e diapocinina em células de osteossarcoma humano." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/25/25149/tde-24052018-175418/.

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O osteossarcoma (OS) é o tumor maligno primário mais comum do tecido ósseo, caracterizado pela formação de osteócitos anormais. Apesar do avanço nas terapias convencionais (quimioterapia e retirada do tumor), essas não conseguem eliminar totalmente as células tumorais e impedir a progressão da doença. Recentemente, agentes derivados de fontes naturais ganharam considerável atenção por causa de sua segurança, eficácia e disponibilidade imediata. Nesse sentido, a apocinina, inibidor do complexo NADPH-oxidase, vem sendo estudada como agente antitumoral em alguns tipos de câncer como: pâncreas, próstata, pulmão e mama. Apocinina é um pró-fármaco e sua ação parece estar relacionada à sua conversão produzindo a diapocinina, a qual se mostrou mais efetiva do que a apocinina. Portanto, o objetivo desse estudo é avaliar, in vitro, o potencial antitumoral da apocinina e diapocinina em células de osteossarcoma humano. Para isso, foram utilizados osteoblastos humanos normais (HOb) e osteossarcoma humano imortalizadas (SaOS-2) tratados ou não com apocinina e diapocinina em diversas concentrações. Foram realizados os ensaios de viabilidade celular, alterações morfológicas, apoptose celular, produção de espécies reativas de oxigênio (EROs), formação de colônias, migração, invasão e expressão do fator indutor de hipóxia-1alfa (HIF-1). Também foram conduzidos ensaios para verificar a atividade de metaloproteinase de matriz (MMP) 2 e 9. Os resultados em SaOS-2 mostraram que o tratamento com apocinina nas concentrações de 1,5 e 3 mM; e diapocinina nas concentrações de 0,75 e 1,5 mM reduziram a viabilidade; aumentaram o número de células em apoptose e diminuíram a produção de EROs; sem causar danos às células HOb. Além disso, essas mesmas concentrações inibiram a migração e invasão celular; diminuíram a expressão de HIF-1; e reduziram a atividade de MMP-2 em SaOS-2. Considerando os resultados obtidos, concluímos que a apocinina e diapocinina podem atuar como possíveis moduladores de células tumorais, sendo que a diapocinina mostrou ser mais efetiva nos parâmetros testados.
Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue, characterized by the formation of abnormal osteocytes. Despite advances in conventional therapies (chemotherapy and surgery) they cannot completely eliminate tumor cells and prevent the progression of the disease. Recently, agents derived from natural sources have achieved considerable attention because of their safety, efficacy and immediate availability of therapies. In this way, apocynin, an inhibitor of the NADPH-oxidase complex, has been studied as an antitumor agent in some types of cancer, such as pancreas, prostate, lung and breast. Apocynin is a prodrug and its action indicate to be related to its conversion to diapocynin, which has been shown to be more efficient than apocynin itself. Thus, the aim of this study is to evaluate, in vitro, the antitumor potential of apocynin and diapocynin in human osteosarcoma cells. For this, normal human osteoblasts (HOb) and immortalized human osteosarcoma cells (SaOS-2) were treated or no-treated with apocynin and diapocynin in various concentrations. Cell viability assay, morphological alterations, cellular apoptosis, reactive oxygen species (ROS) production, colony formation, migration, invasion and expression of hypoxia-inducible factor-1 alpha (HIF-1) were performed. We also performed assays to verify the activity of matrix metalloproteinase (MMP) 2 and 9. The results in SaOS-2 showed that treatment with apocynin at concentrations of 1,5 e 3 mM; and diapocynin at concentrations of 0,75 e 1,5 mM reduced cell viability; increased the number of cells in apoptosis and decreased the production of ROS; without damaging HOb cells. Moreover, these same concentrations inhibited cell migration and invasion; decreased HIF-1 expression; and reduced MMP 2 activity in SaOS-2. Considering the results, we suggest that apocynin and diapocynin may act as possible modulators of tumor cells, and diapocynin has been shown to be more effective.

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Oliveira, Ruth Medeiros de. "Avalia??o das atividades antioxidante, anticoagulante e antiproliferativa de extratos aquosos de marsdenia megalantha." Universidade Federal do Rio Grande do Norte, 2011. http://repositorio.ufrn.br:8080/jspui/handle/123456789/12576.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior
The species of the genus Marsdenia, Apocynaceae, are widely used in folk medicine of several countries. In Brazil is found several species belonging to this genus. The in vitro antioxidant, anticoagulant and antiproliferative activities were evaluated to aqueous extracts of stalk, leaf and root of Marsdenia megalantha. In the total antioxidant capacity assay (expressed as ascorbic acid equivalents) the stalk extract showed 76.0 mg/g, while leaf and root extracts 141.3 mg/g and 57.0 mg/g, respectively. The stalk and leaf extracts showed chelating activity around 40% at 1.5 mg/mL, while root extract, at the same concentration showed, 17%. Only the leaf extract showed a significant ability in superoxide scavenging (80% at 0.8 mg/mL). Any extract was able in scavenge hydroxyl, as well anticoagulant activity. The antiproliferative activity of the extracts was evaluated against HeLa tumor cell line. The extracts inhibited in a dose-dependent manner the cell growth. However, the leaf extract showed 80% of inhibition at 1.0 mg/mL, while stalk and root extracts inhibited 63% and 30%, respectively. To assess the mechanism of cell death caused by the leaf extract in HeLa, was performed flow cytometry and western blot. The results show that leaf extract induces cell death by apoptosis through an activation caspase-independent pathway. These data indicate that stalk and leaf extracts obtained have potential to be used as antioxidants and anticancer drugs
As esp?cies do g?nero Marsdenia, Apocynaceae, s?o bastante utilizadas na medicina popular de v?rios pa?ses. No Brasil s?o encontradas v?rias esp?cies pertencentes a esse g?nero. As atividades antioxidante, anticoagulante e antiproliferativa foram avaliadas para os extratos de caule, folha e raiz de Marsdenia megalantha. Na capacidade antioxidante total (expressa como equivalente de ?cido asc?rbico), o extrato do caule apresentou 76,0 mg/g, enquanto os extratos da folha e raiz apresentaram, respectivamente, 14,3 mg/g e 57,0 mg/g. Os extratos do caule e da folha mostraram habilidade quelante em torno de 40% na concentra??o de 1,5 mg/mL, enquanto o extrato da raiz, na mesma concentra??o, apresentou 17%. Apenas o extrato da folha apresentou uma capacidade significante em sequestrar radicais super?xidos (80% em 0,8 mg/mL). Nenhum extrato mostrou capacidade em seq?estrar radicais hidroxila, bem como atividade anticoagulante. A atividade antiproliferativa dos extratos foi avaliada contra a linhagem tumoral HeLa. Os extratos inibiram, de forma dose-dependente, o crescimento celular. Entretanto, o extrato da folha foi capaz de inibir em 80% a prolifera??o celular na concentra??o de 1,0 mg/mL, enquanto os extratos de caule e raiz inibiram 63% e 30%, respectivamente. Para avaliar o mecanismo de morte celular causada pelo extrato da folha nas c?lulas HeLa, foi realizada citometria de fluxo e western blot. Os resultados mostraram que o extrato da folha induz morte celular por apoptose atrav?s de uma via de ativa??o independente de caspase. Estes resultados indicam que os extratos de caule e folha obtidos t?m potencial para serem futuramente utilizados como f?rmacos antioxidantes e antic?ncer

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Gonçalves, Caroline da Costa Silva. "Síntese total das basiliskamidas A e B e síntese do fragmento C1-C9 da dictiostatina." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/248477.

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Orientador: Luiz Carlos Dias
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: Síntese Total das Basiliskamidas A e B: As basiliskamidas A e B são agentes antifúngicos isolados em 2002 por Anderson e colaboradores, a partir de uma cultura de bactérias marinhas Bacillus laterosporus (MK-PNG-276). Nesta primeira parte do trabalho, descrevemos a síntese total das basiliskamidas A e B. As basiliskamidas A e B são oriundas de um intermediário comum, o diol 1.4. As etapas chave incluem uma reação aldólica do tipo anti, mediada por (CHx)2B e uma reação de redução diastereosseletiva sob as condições de Narasaka. A basiliskamida B (1.2) foi obtida em 12 etapas e 6% de rendimento global e a basiliskamida A (1.1) em 14 etapas e 2,5% de rendimento global, a partir da etilcetona 1.47 (considerando a rota linear mais longa para ambas).Síntese do Fragmento C1-C9 da (-)-Dictiostatina (2.1): A (-)-dictiostatina (2.1) é uma macrolactona com potente atividade antitumoral, isolada em 1994 por Pettit e colaboradores, a partir da esponja marinha Spongia sp. e, posteriormente por Wright e co-autores a partir da esponja da família Corallistidea. Nesta segunda parte do trabalho, descrevemos a síntese do fragmento C1-C9 da (-)-dictiostatina (2.1). Os centros esterogênicos em C6 e C7 foram construídos através de uma reação de epoxidação enantiosseletiva de Sharpless seguido da abertura regio e diastereosseletiva do epóxido com Me2CuCNLi2. O fragmento C1-C9 (2.103) foi obtido em 13 etapas e 5% de rendimento global a partir do álcool 2.115, considerando a rota linear mais longa.
Abstract: Total Synthesis of Basiliskamides A and B: Basiliskamides A and B are antifungal agents isolated by Andersen and co-workers in 2002 from the marine bacterium Bacillus laterosporus (MK-PNG-276). The first chapter describes the total synthesis of basiliskamides A and B. Basiliskamides A and B were prepared from a common intermediate, 1,3-diol 1.4. Notable features of this approach include an anti-aldol reaction and a diastereoselective reduction using Narasaka's methodology. Basiliskamide B (1.2) was obtained in 12 steps and 6% overall yield and basiliskamide A (1.1) was prepared in 15 steps and 2.5% overall yield from ethyl ketone 1.47. Synthesis of C1-C9 fragment of (-)-Dictyostatin (2.1): The macrolactone (-)-dictyostatin (2.1) showed potent growth inhibition against a range of human cancer cells lines. This compound was isolated from the marine sponge Spongia sp by Petit and co-workes in 1994 and from Corallistidea sponges in 2001 by Wright and co-workers. The second chapter describes the synthesis of C1-C9 fragment of (-)-dictyostatin (2.1). The two stereocenters (C6 and C7) were created via a Sharpless's epoxidation followed by a diastereoselective epoxide opening mediated by Me2CuCNLi2. The synthesis of C1-C9 (2.103) fragment was achieved after 13 steps in 5% overall yield starting from alcohol 2.115.
Doutorado
Quimica Organica
Doutor em Ciências

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Gomes, Juliana Cristina 1983. "Morita-Baylis-Hillman na síntese de antitumorais." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/250255.

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Orientador: Fernando Antônio Santos Coelho
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: O importante papel desempenhado pela aromatase na síntese de estrógenos qualificou essa enzima como alvo para o desenvolvimento de inibidores seletivos, que podem ser utilizados no tratamento do cancer de mama. Recentemente, pesquisadores descreveram o isolamento de uma diidrocumarina da planta brasileira conhecida popularmente como sempre-viva. Essa substância apresentou-se como um importante inibidor de aromatase, o que nos impulsionou a propor uma síntese total para essa substância natural. A síntese proposta envolve apenas 10 etapas reacionais sendo que sete etapas já foram concluídas. A segunda parte deste trabalho destina-se a preparação diastereosseletiva de derivados de tetraidro-1,8- naftiridinas 3,4- substituídas através de adutos de Morita-Baylis-Hillman. Esta classe de compostos tem atraído considerável atenção devido, principalmente, a presença do esqueleto estrutural [1,8]-naftiridínico estar presente em muitos compostos naturais e sintéticos, que exibem várias propriedades biológicas. A síntese de vários derivados de [1,8]-naftiridinas foi realizada através de uma metodologia fácil, eficiente e que envolve apenas 3 etapas, com rendimentos globais variando de 18- 60%. O método é baseado em uma sequência em cascata envolvendo uma reação de adição de Michael e uma reação de substituição nucleofílica aromática, na qual formam um ciclo e controlam a estereoquímica relativa dos dois centros em uma única etapa
Abstract: The important role played by aromatase in the synthesis of estrogen makes this enzyme an important therapeutic target for the development of new selective inhibitors to be used in the treatment of breast cancer. Recently, a dihydrisocumarine having a remarkable inhibitory effect against aromatase has been isolated from a brazilian plant popularly known as ¿sempre-viva¿. The biological activity of this new substance stimulated us to propose an appproach to the total synthesis of this natural compound. The initially proposed synthetic approach involves 10 steps. In this work seven steps have been performed. In the second part of this work we describe a new diastereoselective approach to the preparation of 3.4-substituted tetrahydro-1,8- naphthyridines from Morita-Baylis-Hillman adducts. This class of compounds has attracted considerable attention, mainly because the [1,8]-naphthyridyl skeleton is present in many natural and synthetic biologically active compounds. The syntheses of several [1,8]-naphthyridine derivatives were accomplished using a facile and efficient methodology, in 3 steps and overall yield ranging from 18-60%. The method is based on a cascade sequence involving a Michael addition reaction, followed by a nucleophilic aromatic substitution reaction. In a one single step, a new cycle is formed and the relative stereochemistry of the two asymmetric centers is controlled
Mestrado
Quimica Organica
Mestre em Química

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Esposito, Breno Pannia. "Estudo dos produtos de reação entre carboxilatos de ródio (II) e amidas." Universidade de São Paulo, 1997. http://www.teses.usp.br/teses/disponiveis/46/46134/tde-03102006-141717/.

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Foram estudados os produtos da interação entre o acetato e o trifluoroacetato de ródio (respectivamente, Rh2(OAc)4 e Rh2(TFA)4) com amidas (formamida, FA; acetamida, AA; N-metil-acetamida, MA; benzamida, BA; N-fenil-acetamida, NFAA; trifluoroacetamida, TMA; ciclofosfamida, CFA), objetivando caracterização química e avaliação do potencial anti-tumor. Foram sintetizados por refluxo em clorofórmio dois adutos de Rh2(OAc)4 (Rh2(OAc)4-2FA e Rh2(OAc)4-2AA) e sete adutos inéditos de Rh2(TFA)4, de fórmula geral Rh2(TFA)4-2L (L = AA, BA, CFA, FA, MA, NFAA e TMA). Também obtivemos o novo amidato de Rh(II), Rh2(CF3CONH)4(CF3CONH2)2 (Rh2(TFACAM)4-2TMA), por fusão de Rh2(OAc)4 com TMA. Através da fusão de Rh2(TFA)4 com MA, obtivemos um composto que formulamos como Rh2(CF3COO)2(CH3CONCH3)2. Os resultados de análise elementar foram satisfatórios. Os adutos apresentaram bandas de absorção características dos carboxilatos de ródio (~ em 600, 450, 250 - ombro - e 220 nm). O modo de coordenação do ligante axial, pelo átomo de oxigênio da amida, foi determinado pela diminuição da freqüência de estiramento C-O na região do infravermelho (IV). Os amidatos apresentaram apenas uma banda na região do visível, e na região do IV os valores de?estiramentos característicos dos principais grupos orgânicos. Estudos comparativos dos espectros Raman mostraram que a freqüência Rh-Rh diminui ao se passar de um carboxilato para um amidato. Medidas de susceptibilidade magnética atestam o diamagnetismo de todas as moléculas (ligação Rh-Rh simples). O mecanismo de termodecomposição do Rh2(TFA)4 e dos seus adutos com amidas envolve mais de uma etapa, sendo que os intermediários podem apresentar estruturas do tipo Rh2(CF3COO)4-x(L)n (x e n = 1 ou 2). Avaliação do potencial citostático (frente a células U937, K562 e ascite de Ehrlich) e da DL50 (camundongos Balb-c) do complexo Rh2(TFACAM)4-2TMA mostraram atividade in vitro superior e toxicidade in vivo semelhante às da cisplatina.
We studied the interaction products of two Rh carboxylates (acetate, AC; and trifluoroacetate, TFA) with amides (formamide, FA; acetamide, AA; N-methyl-acetamide, MA; benzamide, BA; N-phenyl-acetamide, NFAA; trifluoroacetamide, TMA; cyclophosphamide, CFA). Two adducts of AC (AC-2FA e AC-2AA) and seven new adducts of TFA (TFA-2FA, TFA-2AA, TFA-2MA, TFA-2BA, TFA-2NFAA, TFA-2TMA, TFA-2CFA) were synthesized by reflux in CHCl3 solution. We obtained also the new Rh(II) amidates Rh2(CF3CONH)4(CF3CONH2)2 (TFACAM-2TMA) and a compound formulated as Rh2(CF3COO)2(CH3CONCH3)2 (\"Semi-MACAM\"), by fusion of the appropriate reagents. Elemental microanalysis results were satisfactory. Thermal decomposition mechanism of TFA and its adducts involves more than one step, and the intermediates can exhibit structures as Rh2(CF3COO)4-x(L)x (x = 0 or 1). Citostatic potential evaluation (towards U937, K562 and Ehrlich ascites cells) and of LD50 (Balb-c mice) of the compound TFACAM-2TMA showed superior in vitro activity and similar in vivo toxicity when compared with cisplatin.

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Mithani, Salim. "Synthetic studies related to reductively activated antitumor antibiotics." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq21413.pdf.

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Hurley, Laurence H. "Biosynthesis and mechanism of action of antitumor antibiotics." Thesis, University of Bath, 1996. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760690.

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21

Li, Geqiang. "The Antiviral and Antitumor Function of RNase L." Case Western Reserve University School of Graduate Studies / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=case1097095517.

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Vicioso, Mora Yorleny M. "ENHANCING THE ANTITUMOR IMMUNE RESPONSE OF NATURALKILLER CELLS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1594296228120994.

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23

Rahim-Bata, Rayhana. "Augmentation of the differentiation response to antitumor quinolines." Morgantown, W. Va. : [West Virginia University Libraries], 2004. https://etd.wvu.edu/etd/controller.jsp?moduleName=documentdata&jsp%5FetdId=3775.

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Thesis (Ph. D.)--West Virginia University, 2004.
Title from document title page. Document formatted into pages; contains xiii, 152 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 141-149).

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Rocha, Fillipe Vieira [UNESP]. "Estudo da atividade biológica de compostos de paládio (II)." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/97918.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Quatro complexos mononucleares inéditos de Pd(II) do tipo [PdX2(tdmPz)] {X = Cl - (1), Br - (2); I - (3); SCN- (4); tdmPz = 3,5-dimetil-1-tiocarbamoilpirazol} foram sintetizados. O composto 1 foi formado a partir da substituição da acetonitrila do complexo [PdCl2(MeCN)2] pelo 3,5-dimetil-1-tiocarbamoilpirazol. Os demais compostos foram obtidos através da substituição dos íons cloreto por brometo (2), iodeto (3) e tiocianato (4). Todos os complexos foram isolados, purificados e caracterizados por análise elementar, espectroscopia na região do infravermelho e ressonância magnética nuclear de 1 H e 13 C{ 1 H}. Os dados experimentais sugerem que, em todos os casos, a coordenação do tdmPz ocorreu através do átomo de enxofre do grupo tiocarbamoil e pelo nitrogênio piridínico do anel pirazólico. O comportamento térmico dos compostos foi investigado por termogravimétria (TG) e Análise Térmica Diferencial (DTA). Pela temperatura inicial de decomposição, a estabilidade térmica dos complexos pode ser ordenada da seguinte maneira: 3 < 4 ≡ 2 < 1. O produto final da termodecomposição foi caracterizado como paládio metálico por difração de raios X de pó. Os complexos, o ligante e a cisplatina tiveram sua citotoxicidade investigada, in vitro, pelo método do MTT frente a 3 linhagens de células cancerosas murinas: adenocarcinoma mamário (LM3 e LMM3) e adenocarcinoma pulmonar (LP07), bem como frente a macrófagos peritoneais murinos. Efeitos citotóxicos promissores (in vitro) foram encontrados para o [PdI2(tdmPz)] (3), mostrando valor de IC50 = 24.5 µM frente a linhagem LM3, para [PdBr2(tdmPz)] (2) com IC50 = 28.7 µM frente as células LP07, e para [Pd(SCN)2(tdmPz)] (4) que se mostrou mais seletivo e citotóxico que a cisplatina frente a linhagem LMM3
Four new mononuclear Pd(II) complexes of the type [PdX2(tdmPz)] {X = Cl - (1), Br - (2); I - (3); SCN- (4); tdmPz = 1-thiocarbamoyl-3,5-dimethylpyrazole} have been synthesized. Compound 1 is formed by the displacement of acetonitrile from [PdCl2(CH3CN)2] by the 1- thiocarbamoyl-3,5-dimethylpyrazole. Complex 2, 3 and 4 were readily obtained by metathesis of the chloride from [PdCl2(tdmPz)2] (1) by the bromide, iodide and thiocyanate ions, respectively. Both complexes have been isolated, purified and characterized by means of elemental analysis, IR spectroscopy, 1 H and 13 C{ 1 H}-NMR experiments. The experimental data suggested that in all cases the coordination of the tdmPz takes place through the sulfur atom from the thioamide moiety and the pyridine-like nitrogen from the pyrazolyl ring. The thermal behavior of the complexes 1-4 has been investigated using thermogravimetry (TG) and differential thermal analysis (DTA). From the initial decomposition temperatures, the thermal stability of the complexes can be ordered in the sequence: 3 < 4 ≡ 2 < 1. The final products of the thermal decompositions were characterized as metallic palladium by X-ray powder diffraction. All the complexes and the ligand together with cisplatin have been tested in vitro by MTT assay for their cytotoxicity against three murine cancer cell lines: mammary adenocarcinoma (LM3 and LMM3) and lung adenocarcinoma (LP07) as well towards normal murine peritoneal exsudate cells (PEC). Promising in vitro cytotoxic effect has been found for [PdI2(tdmPz)] (3), showing the IC50 value of 24.5 µM against LM3, for [PdBr2(tdmPz)] (2) with the IC50 value of 28.7 µM against LP07, and [Pd(SCN)2(tdmPz)] (4) which was more selective and cytotoxic than cisplatin against the cell line LMM3

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Vasconcellos, Marne Carvalho de. "Estudo do potencial antineoplÃsico da biflorina, о- naftoquinona isolada das raÃzes de Capraria biflora L." Universidade Federal do CearÃ, 2007. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=1123.

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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico
CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
A biflorina Ã uma 1,4 â orto-naftoquinona isolada de raÃzes de Capraria biflora, que possui uma ampla distribuiÃÃo nas amÃricas do Sul e do Norte. O objetivo desse trabalho foi avaliar se a biflorina apresentava um potencial citotÃxico e antitumoral utilizando modelos in vitro e in vivo. O presente estudo tambÃm avaliou a genotoxicidade dessa molÃcula em linfÃcitos perifÃricos humanos e em outros modelos como cÃlulas V79, bactÃrias, leveduras bem como em medula Ãssea de camundongos. Frente a dezesseis linhagens tumorais, dentre elas 15 humanas e 1 murina, a biflorina mostrou-se bastante citotÃxica, uma vez que teve sua CI50 variando de 0,43 e 14,61 Âg/mL. Para avaliar sua seletividade, ela foi testada tambÃm em linfÃcitos humanos estimulados com fitohemaglutinina, onde se pode concluir que ela nÃo Ã seletiva. A biflorina nÃo foi capaz de inibir o desenvolvimento de ovos de ouriÃo-do-mar e nem causar ruptura na membrana de hemÃcias de camundongos. Para avaliar seu mecanismo de aÃÃo e seu potencial antitumoral in vivo a linhagem B16 (Melanoma) foi escolhida para que os testes in vitro e in vitro pudessem ser realizados com a mesma cÃlula. Os estudos in vitro realizados por coloraÃÃo diferencial e por citrometria de fluxo sugerem que a biflorina induz morte celular por apoptose, uma vez que as cÃlulas tratadas apresentaram reduÃÃo do volume nuclear, condensaÃÃo de cromatina e formaÃÃo de corpos apoptÃticos. A citometria de fluxo confirmou a fragmentaÃÃo de DNA induzida na maior concentraÃÃo de biflorina e demonstrou que as cÃlulas tratadas apresentaram despolarizaÃÃo da mitocÃndria significante. AlÃm disso, por citometria a integridade de membrana nÃo foi alterada e nÃo exibiu aumento da percentagem de cÃlulas nÃo viÃveis, sendo o mesmo observado com as cÃlulas avaliadas por exclusÃo por azul de tripan. A atividade in vivo da biflorina foi avaliada em trÃs modelos, sarcoma 180, carcinoma de Erlich e melanoma B16. A biflorina inibiu o crescimento dos tumores dos animais transplantados com sarcoma 180 e carcinoma de Erlich, bem como foi capaz de aumentar a resposta antitumoral e diminuir a toxicidade sistÃmica do 5-FU quando associada com ele. Nos animais transplantados com B16 a sobrevida dos animais tratados com biflorina aumentou significativamente. Foi demonstrado tambÃm que a biflorina possui aÃÃo imunoadjuvante aumentando a produÃÃo de anticorpos contra ovalbumina, o que pode estar relacionada com suas propriedades antitumorais. TambÃm foi estudada a interaÃÃo da biflorina com o DNA de fita dupla e de fita simples, mostrando que ela inibe diretamente o DNA, mas nÃo inibe Topoisomerase I, sugerindo que outro mecanismo deve estar associado a essa interaÃÃo, podendo estar relacionado Ã induÃÃo de dano ao DNA. Contudo a biflorina mostrou-se genotÃxica apenas no teste do cometa, onde a freqÃÃncia e o Ãndice de danos em linfÃcitos humanos aumentaram significativamente, sem, no entanto induzir efeito clastogÃnico pelo teste de aberraÃÃes cromossÃmicas. Por outro lado, por sua comprovada atividade antioxidante, possivelmente associada Ã remoÃÃo de grupos hidroxil, a biflorina demonstrou ter uma atividade antimutagÃnica, contra cÃlulas V79 e linhagens de Saccharomyces cereviseae tratadas com H2O2, quando usada em baixas concentraÃÃes, alÃm de nÃo causar peroxidaÃÃo lipÃdica bem como diminuir a peroxidaÃÃo lipÃdica medida pelos nÃveis de TBARS em cÃlulas V79. Ainda para descartar quaisquer dÃvidas em relaÃÃo a nÃo induÃÃo de mutagenicidade pela biflorina, outros dois testes sugeridos pelos protocolos internacionais como testes padrÃo para comprovaÃÃo de seguranÃa de muitos quÃmicos incluindo biocidas e fÃrmacos, foram realizados os testes de Ames em Salmonella thyphimurium e o teste de micronÃcleos em medula Ãssea de camundongos, ambos com resultados negativos. Todos esses dados compilados sugerem que a biflorina Ã uma droga com uma potente atividade citotÃxica em cÃlulas neoplÃsicas, antitumoral, atividade imunoadjuvante, potencial antioxidante que interage diretamente com DNA de fita simples e de fita dupla, mas nÃo inibe topoisomerase, porÃm mostra-se genotÃxica, mas nÃo mutagÃnica quando testada em vÃrios modelos biolÃgicos
Biflorin is a 1,4 - o-naftoquinone isolated from the roots of Capraria biflora, which has an ample distribution among North and South AmÃrica. The goal of this study was to evaluate the antitneoplastic potential of biflorine in vitro and in vivo models. Genotoxic effects in human peripheral lymphocytes and other cell models, such as V79, bacteria and yeasts, as well as in mice bone marrow. Was also accessed biflorin was highly cytotoxic against 15 human tumor cell lines and 1 murine cell line, with IC50 ranging from 0.43 to 14.61 Âg/mL. Cell selectivity was was not observed, since in was equally toxic to normal human lymphocytes stimulated with phytoheamaglutinin. No inhibitory effect on see-urchin egg development or lysis of mouse erythrocyte was observed following biflorin treatment. Mode of action studies and antitumor potential was evaluated on the B16 melanoma cell line, which enables in vitro and in vivo studies. The in vitro data suggests that biflorin induces cell death by apoptosis, as treated cells showed a decrease in nucleus size, chromatin condensation and formation of apoptotic bodies. Flow cytometry confirmed DNA fragmentation and a significant mitochondrial depolarization on the highest concentration tested. Membrane integrity disruption was not observed when analyzed by flow cytometry and no increase in non viable cells was registered. The later result was also seen on the trypan blue exclusion cell count. In vivo antitumor activity was evaluated in three tumor models: Sarcoma 180, ErlichÂs Carcinoma and Melanoma B16. Biflorin inhibited tumor growth in S-180 and Erlich transplanted animals and increased the antitumor effect of 5-FU where decreasing its toxicity. On B16 transplanted animals, survival span of biflorin-treated animals increased significantly. It was demonstrated that biflorin possess immune-adjuvant proprieties, increasing the production of anti-albumin antibodies, which can be related to its antitumor activity. Interaction of biflorin with single and double stranded DNA was confirmed, but was shown that it does not inhibit topoisomerase I, suggesting that a different mechanism is associated with this interaction, probably DNA damage induction. Biflorin showed genotocicity only on the comet assay, in which frequency and damage index towards human lymphocytes were significantly increased, without, however, inducing clastogenic effect on chromosome aberration assessment. On the other hand, due to its antioxidant effect, possibly associated to removal of hydroxi groups, biflorin, in lower concentrations, showed antimutagenic activity towards V79 cells and Saccharomyces cereviseae treated with H2O2. Moreover, it does not induce lipidic peroxidation, thus reducing this effect in V79 cells, as seen by assessment of TBARS levels. To discard any doubts on biflorinÂs non-mutagenic proprieties; the Ames test in Salmonella thyphimurium and the micronucleus assay on mouse bone marrow was carried out, both presenting a negative result. Taken together, these results suggest that biflorin is a strong cytotoxic compound against neoplastic cells as possess antitumor, immune-adjuvant and antioxidant potential, interacts directly with single and double stranded DNA, but not topoisomerase I, has a genotoxic but not mutagenic effect and increases survival rate in treated mice

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Oliveira, CecÃlia Carvalho de. "Estudos ToxicolÃgicos PrÃ-ClÃnicos e Antitumorais do Extrato AcetÃnico das Folhas de Annona muricata L." Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=10352.

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CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior
Annona muricata, conhecida popularmente como gravioleira no Brasil, Ã uma planta usada amplamente na medicina popular na forma de chÃs e infusÃes para o tratamento de diversas doenÃas, incluindo o cÃncer. O trabalho teve como objetivo avaliar o perfil toxicolÃgico, genotoxicolÃgico e antitumoral do extrato acetÃnico das folhas de Annona muricata e foi realizado utilizando ensaios de curta e longa duraÃÃo in vivo e in vitro. Inicialmente foi avaliada a citotoxicidade in vitro contra vÃrias linhagens tumorais humanas, havendo resposta tÃxica a muitas delas, principalmente K-562, HCT-8, HCT-116 e SF-295 com concentraÃÃo inibitÃria mÃdia (CI50) de 0,1452 Âg/mL, 0,2457 Âg/mL, 0,2956 Âg/mL e 0,2191 Âg/mL respectivamente. Os estudos de toxicidade aguda foram realizados in vivo e a dose letal mÃdia (DL50) foi de 310,2 mg/Kg. Os estudos de toxicidade crÃnica foram realizados utilizando-se as doses 12,5 mg/Kg, 25 mg/Kg e 50 mg/Kg do extrato acetÃnico. Os resultados mostraram poucas alteraÃÃes nos animais nos parÃmetros fisiolÃgicos, bioquÃmicos e hematolÃgicos, mostrando que o extrato Ã bem tolerado e pouco tÃxico. Os estudos de genotoxicidade foram realizados in vivo. Os animais foram tratados, por via oral, com trÃs doses do extrato acetÃnico (12,5 mg/Kg, 25 mg/Kg e 50 mg/Kg). ApÃs 24 h e 48 h, o sangue perifÃrico e a medula Ãssea foram coletados. No ensaio do cometa nÃo houve detecÃÃo de nenhum cometa de grau elevado, sendo as doses testadas estatisticamente semelhantes ao controle negativo. No ensaio do micronÃcleo, todas as doses testadas do extrato acetÃnico nÃo induziram a formaÃÃo de micronÃcleos, sendo semelhantes estatisticamente em relaÃÃo ao controle negativo, ao contrÃrio do observado no controle positivo. Os ensaios antitumorais mostraram que o extrato apresenta atividade inibidora do crescimento tumoral, tanto em ratos, no modelo do carcinossarcoma de Walker 256, como em camundongos, no modelo Sarcoma 180. Todos esses resultados indicam que o extrato acetÃnico das folhas de Annona muricata apresenta poucas aÃÃes tÃxicas e significante atividade inibidora do crescimento tumoral nos modelos testados
Annona muricata, popularly known as soursop in Brazil, is a plant widely used in vernacular medicine as teas and infusions for the treatment of various diseases, including cancer. This study aimed to evaluate the toxicological, genotoxicological and antitumor profile of the acetone extract from the leaves of Annona muricata and test it using short-and long-term in vivo and in vitro assays. We initially assessed in vitro cytotoxicity against several human tumor cell lines. There was a toxic response to many of them, especially K-562, HCT-8, HCT-116 and SF-295 with average inhibitory concentration (IC50) of 0.1452 Âg/mL, 0.2457 Âg/mL, 0.2956 Âg/ml and 0.2191 Âg/mL respectively. Acute toxicity studies were performed in vivo and the average lethal dose (LD50) was 310.2 mg/kg. Chronic toxicity studies were performed using doses of 12.5 mg/kg, 25 mg/kg and 50 mg/kg of acetone extract. Results showed little change in animalsâ physical, biochemical and hematological parameters, showing that the extract is well tolerated and not very toxic. Genotoxicity studies were performed in vivo. Animals were given three oral doses of the acetone extract (12.5 mg/kg, 25 mg/kg and 50 mg/kg). After 24 and 48 hours peripheral blood and bone marrow were collected. In the comet assay no high grade comet was detected and tested doses were statistically similar to the negative control. In the micronucleus test, none of the tested acetone extract doses induced the formation of micronuclei. They were statistically similar to the negative control, unlike what was observed in the positive control. Antitumor testing showed that the extract has tumor growth inhibitory activity, both in rats, in the Walker 256 carcinosarcoma model, and in mice, in the Sarcoma 180 model. All such results indicate that the acetone extract from the leaves of Annona muricata has little toxic action and significant activity inhibiting tumor growth in the models we tested.

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Bueno, Luciana de Moura. "Estudo da síntese de análogos benzil alquil éter da miltefosina e da erufosina." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-21112016-091213/.

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O câncer corresponde a um conjunto de doenças que vem aumentando sua incidência durantes os anos e atualmente é considerado um problema mundial. Os tratamentos tradicionais em sua grande maioria agem no maquinário genético e causam citotoxicidade, debilitando o paciente. Desta forma, a busca por novos fármacos é de fundamental importância para se encontrar moléculas mais seletivas e menos tóxicas para o paciente. A classe dos alquilfosfolipídeos tem se destacado por apresentar vários análogos com atividade antitumoral atuando na membrana celular, sendo a miltefosina o protótipo estrutural. A miltefosina exibe potente atividade antitumoral in vitro e frente a alguns modelos tumorais, sendo aprovada clinicamente para o uso tópico em metástases cutâneas de câncer de mama. No entanto, este fármaco apresenta toxicidade gastrointestinal e ação hemolítica. A partir desse protótipo, novos análogos foram sintetizados chegando à estrutura da erufosina, análogo homocolínico da miltefosina, com atividade antitumoral e com administração via intravenosa, por ser menos hemolítica. Outros estudos evidenciam que grupos volumosos na parte apolar também reduzem a atividade hemolítica. Portanto, nesse trabalho estudamos a síntese de análogos benzil alquil éter da miltefosina e da erufosina. Tentativas de síntese foram realizadas por meio da síntese de intermediários éteres ω-hidroxibenzilalquílicos, sendo a obtenção desses intermediários otimizada por meio de planejamento fatorial e mudança do reagente haleto de benzila. A melhor condição reacional foi definida a temperatura ambiente por 6h, com rendimento reacional de 38% e 43% para 10-(benziloxi)decan-1-ol e 12-(benziloxi)dodecan-1-ol, respectivamente. Para a formação dos análogos benzil alquil éter da miltefosina e da erufosina, diversas condições foram testadas empregando-se a reação dos éteres ω-hidroxibenzilalquílicos com oxicloreto de fósforo e, subsequentemente, com N-metiletanolamina ou N-metilpropanolamina, para análogos da miltefosina e da erufosina, respectivamente. Na sequência, a N-metilação com iodeto de metila foi realizada para os análogos da erufosina. No caso da miltefosina, estudou-se a síntese de um análogo N-metilfosfoetanolamínico. A confirmação dos respectivos produtos de interesse e o grau de pureza foram inferidos por análises de RMN. Devido à complexidade das rotas e, principalmente, à dificuldade de purificação pelo caráter anfifílico das moléculas sintetizadas, os compostos ainda não foram obtidos em quantidade e grau de pureza suficientes para testes biológicos in vitro. Entretanto, esse estudo aponta para a possibilidade da utilização da rota proposta para obter os compostos planejados, com necessidade de se aprimorar a etapa final de purificação dos compostos obtidos.
Cancer corresponds to a group of diseases with increasing incidence over the years, and is currently considered a global problem. Traditional treatments mostly act on the genetic machinery causing cytotoxicity and debilitating patients. Therefore, the search for new drugs is of paramount importance to find more selective and less toxic drugs. The class of alkylphospholipids deserves attention for presenting several analogs with antitumor activity by acting on the cell membrane. This class has miltefosine as a structural prototype. Miltefosine exhibits potent antitumor activity in vitro and against some tumor models, and has been clinically approved for topical use in cutaneous metastases of breast cancer. However, this drug is associated with gastrointestinal toxicity and hemolytic activity. From this prototype, new analogs were synthesized resulting in erufosine, which besides antitumor activity is capable of stimulating the production of human bone marrow cells and can be administered intravenously, since it is less hemolytic. Other studies show that the presence of bulky groups in the nonpolar moiety of alkylphospholipids also reduces the hemolytic activity. In this work, we designed benzyl alkyl ether analogs of miltefosine and erufosine. We studied the synthesis of ω-hydroxibenzylalkyl ethers intermediates by means of a factorial design and studying the alkyl halide to be employed. Best reaction condition was defined as room temperature and reaction time of 6h, with yields of 38% and 43% for 10-(benzyloxy)decane-1-ol and 12-(benzyloxy)dodecane-1-ol, respectively. For the benzyl alkyl ether analogs, several reaction conditions were investigated by reacting the ω-hydroxibenzylalkyl ethers with phosphorus oxychloride and subsequently with N-methyl propanolamine (for erufosine analogs) or N-methyl ethanolamine (for miltefosine analog). In the sequence, N-methylation with methyl iodide was carried out for erufosine analogs. For mitefosine, the analog obtained was an N-methylphosphoethanolamine. Structures confirmation was based on NMR analysis. Owing to the complexity of the synthetic routes and mainly difficulty in purification of amphiphilic molecules, the analogs panned were not obtained in adequate quantities and degree of purity to be submitted to in vitro biological test. Nonetheless, this study already points to the possibility of the synthetic routes investigated to obtain the compounds designed, with need to improve final purification steps.

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28

Brink, Susanna. "Structure-activity relationships of titanocene complexes with antitumor properties." Pretoria : [s.n.], 2003. http://upetd.up.ac.za/thesis/available/etd-09052005-101713/.

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29

Fortune, Grady Thomas Jr. "Structure-activity relationships in semisynthetic pyrrolizidine alkaloid antitumor agents." Diss., Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/27371.

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30

Attardo, Giorgio G. (Giorgio Giovanni). "Drug design and synthesis of novel heteroanthracycline antitumor drugs." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74641.

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Novel heteroanthracycline antitumor drugs were designed based on structure activity relationship studies and known mechanisms of drug action. Their preparation required the development of a general synthetic approach.
After extensive studies, three methodologies were developed for the general synthetic plan. The first method involved photoenolisation of 2,5-dimethoxybenzaldehyde and SO$ sb2$ entrapment of the o-quinodimethane to give 4,7-dimethoxy-1-hydroxy-1,3-dihydrobenzo(2,3-c) thiophene-2,2-dioxide. This compound served as a general intermediate towards the synthesis of several heteroanthracyclinones. It could be reduced to the oxathiin-2-oxide derivative which thermally extruded SO$ sb2$ to yield the o-quinodimethane. Reentrapment of this latter intermediate with various glyoxalates gave key isochroman derivatives. The second method is an improvement over the first. Isochromandiones with a C-1 hydroxyl functionality were prepared from oxidative demethylation of 1-hydroxyisochromans. These were obtained after acid hydrolysis of the coupling products between epoxides and the cuprate of 2,5-dimethoxy-6-methylbenzaldehydedioxane acetal. The third method involved a sequential cycloaddition routine with two o-quinodimethanes.
By combining newly developed techniques with known methods, a general synthetic plan was developed. Consequently, the total synthesis of six tetracyclic structural hybrids of the naphthoquinone(2,3-c) pyranyl class of antibiotics was accomplished; along with the total synthesis of (R) and (S) 1-(4$ sp prime$-O-p-nitrobenzoyl-N-trifluoroacetyldaunosamine)-$ 1,3$-dihydrothioxantho(2,3-c) thiophene-2,2-dioxide, p-nitrobenzyl(5,12-dihydroxy-3,4-dihydrothioxantho(2,3-c) and (3,2-c) pyran-3-yl)formate, and eight novel heteroanthracyclines with the 5,12-dioxo-2,3,5,12-tetrahydroanthraceno(2,3-c) pyranyl backbone. The diastereomeric mixture of (1$ sp prime$S, 1R, 3S) and (1$ sp prime$S, 1S, 3R) methyl(11-hydroxy-1-$(2 sp prime,3 sp prime,6 sp prime $-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-$5,12 $-dioxo-3,4,5,12-tetrahydroanthraceno(2,3-c) pyran-3-yl) formate was found to possess equipotent antileukemic activity to doxorubicin with no cross resistance.

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31

Wu, Chongming Jr. "Structural and Synthetic Studies of Potential Antitumor Natural Products." Diss., Virginia Tech, 1998. http://hdl.handle.net/10919/30682.

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Bioassay directed fractionation of the methyl ethyl ketone extract of Chiloscyphus rivularis yielded eight sesquiterpenoids, and detailed spectroscopic interpretation led to the assignment of their structures as 12-hydroxychiloscyphone, chiloscypha-2,7-dione, 12-hydroxychiloscypha-2,7-dione, chiloscypha-2,7,9-trione, rivulalactone, 4-hydroxy oppositant-7-one, chiloscyphone, and intermedeol. The structure and stereochemistry of rivulalactone, a novel trinorsesquiterpenoid, was confirmed by its synthesis starting from chiloscyphone. 12-Hydroxychiloscyphone, chiloscypha-2,7-dione, 12-hydroxychiloscypha-2,7-dione, chiloscypha-2,7,9-trione, rivulalactone are new. 12-Hydroxychiloscyphone showed selective bioactivity towards DNA repair-deficient yeast mutants and cytotoxicity to human lung carcinoma cells. In order to improve the activity of cytotoxic furanonaphthoquinones by affixing a hydroxyamino side chain, 2-methyl-2-[2'-(4',9'-dihydronaphtho[2',3'-b]furan-4',9'-dionyl methyl)amino]-1,3-propanediol and its analogs have been synthesized. Bioassay data showed they act by a different mechanism of action than their parental furanonaphthoquinone derivatives.
Ph. D.

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32

Russell, Luke Russell. "Oncolytic Virus Expression of PTENα Directs Antitumor Immune Response." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1511979972361293.

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33

Brown, Douglas L. "Synthesis of Polyhydroxybenzene Derivatives for Evaluation as Antitumor Agents." VCU Scholars Compass, 1986. http://scholarscompass.vcu.edu/etd/4380.

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In order to prepare more effective inhibitors of ribonucleotide reductase a series of 4-substituted and 4,5-disubstituted catechols were synthesized and tested. The derivatives synthesized were also examined for their antitumor activity against L1210 leukemia in mice. A free radical scavenging assay was performed to establish what electronic parameters may govern in vitro and/or in vivo activity. The molecular features of the most potent compounds were compared to the features of the natural substrate of reduction, CDP, UDP, GDP and ADP. The results obtained from the free radical assay did not show any correlation to the results observed either in vitro or in vivo. Enhanced activity, both in vitro andin vivo, was shown when the amide function of 3,4-dihydroxybenzamide was substituted with a hydroxyethyl or a dimethylaminoethyl side chain. Reversal of the amide bond, ex. N-(3,4-dihydroxyphenyl)acetamide, resulted in a log unit increase as an inhibitor of ribonucleotide reductase. Antitumor activity was also substantially increased. The most potent compounds found in this study appear to physically resemble the molecular features found in the natural substrates.

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34

Lee, Chih-Yin, and 李芷穎. "Antitumor Activity of Chinese Medicines VIII：The Antitumor Activity of Natural Products on Leukemia." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/94259377502274348964.

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碩士
台北醫學院
生藥學研究所
88
Leukemia is one of the most common and worldwide malignant tumors, and could be treated effectively by chemotherapy. Several previous studies demonstrated chemotherapy for leukemia caused resistance and side effects on patients, therefore, development of effective therapeutic agents on leukemia is an important and urgent topic in the future. Chinese medicines and natural products are the important sources for developing new antitumor drugs and several well-known effective antitumor compounds are derived from them such as taxol. Based on this paper, 15 kinds of natural plants from Chinese herbal medicines full of polyphenols were used to screen their cytotoxic effects on human leukemia cells (HL-60) by trypan blue and MTT. The most suitable cell concentration which HL-60 cells in 96-well plate is 1.5 × 104 cells/ml. The doubling time of HL-60 cells is 83.9 hours. The test time for observation is two days after treating with the tested compounds. We found that the most effective plant is Syzygium jambos L. Alston (Myrtaceae). The cytotoxicity percentage of the extract of S. jambos (100μg/ml) is 92%. Therefore, the components of S. jambos were surveyed. In the present investigation on the tannins of S. jambos, we have isolated two hydrolyzable tannins. They are 1-O-galloyl castalagin and casuarinin, respectively. The IC50 of 1-O-galloyl castalagin and casuarinin were 10.8 and 12.5μM, respectively. Therefore, we studied the mechanisms of 1-O-galloyl castalagin and casuarinin. Meanwhile, 16 kinds of compounds were also submitted to screen their cytotoxic effects against HL-60 cells. We found that xanthoangelol and 4-hydroxyderricin were effective and the IC50 were 12.9 and 45.7μM, respectively. The distribution of DNA content in the cell population was evaluated by flow cytometry, and found that the presence of apoptotic cells with sub-G1. Light-microscopic study was applied to find those apoptotic bodies. The apoptosis induced by these compounds also was demonstrated by DNA fragmentation assay and microscopic observation. These results suggest that cytotoxic mechanism of 1-O-galloyl castalagin, casuarinin, xanthoangelol and 4-hydroxyderricin might induce apoptosis in HL-60 cells. On the analysis of cytotoxic activities of these compounds on normal blood cells, the results demonstrated that the cytotoxic activities of 1-O-galloyl castalagin and casuarinin were far less than those of xanthoangelol and 4-hydroxyderricin. These data provided more beneficial evidences to indicate that 1-O-galloyl castalagin and casuarinin showed the promising potential to develop as anticancer agents.

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35

Schroeder, Benjamin Ray. "Carbohydrate analogues of antitumor agents /." 2008. http://wwwlib.umi.com/dissertations/fullcit/3322489.

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Liang, Hui-Ru, and 梁惠如. "Antitumor compound of freshwater clam." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/88324941178312027840.

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碩士
國立臺灣海洋大學
食品科學系
93
Abstract Recently, the marine shellfish have shown to inhibit cancer proliferation and other bioactivities. Hard calm, oyster and the abalone have been reported that could suppress the growth of liver carcinoma and gastric carcinoma, as well as antiviral and immunomodulated activities. In addition, local people believe that the soup made with freshwater clam have hepatoprotective activity. Although the freshwater calm aqueous extract has demonstrated to inhibit the proliferation of human liver carcinoma and induce the apoptosis of carcinoma and possess significant hepatoprotective activity, the study of bioactive compounds was not extensive. The goal of this study was to search the bioactive compound based on the anti-cancer activity-guided approach. In the preliminary study, the ethyl acetate fraction after partition with water of freshwater calm methanolic extract induced apoptosis of Hep-J2 cell line. FC-Me-EA was further purified with column chromatography including Al2O3, SiO2 column chromatography and reverse phase high performance liquid chromatography based on bioactivity-guided approach. Different cell-lines including 6KK, HepG2 (human liver hepatoma) and HL-60 (human premyelocytic leukemia) were employed to study the cytotoxicities of fresh-clam extract and used to guide to isolate active fraction. This study demonstrated that the lipophilic fraction of fresh-clam possessed anti-cancer activities. One of fraction 112-5 was demonstrated to have significant anti-hepatoma activity (4 μg/ml). After further purification, a pure compound 200-7 consisting sterol skeleton was obtained.

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37

Paciello, Rolando. "Human antitumor and antiviral Immunoagents." Tesi di dottorato, 2015. http://www.fedoa.unina.it/10104/1/TESI%20dottorato%20Paciello%20Rolando.pdf.

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Immunotherapy is a precious strategy to fight cancer and viral infections. Phage display technology allows for the production of fully human immunoagents specific for tumor associated antigens (TAA) or for cell surface receptors involved in virus infection. By using this technology we isolated fully human antibody fragments (scFvs) specific for the extracellular loops of Claudin-1 (CLDN-1), a tight junction protein essential for hepatitis C virus (HCV) cell entry and following infection. The selected scFvs have been converted in human IgG4 antibodies and characterized. They show high selective binding affinities for CLDN-1-positive cells, recognize distinct epitopes of the protein, and specifically inhibit HCV infection in a dose-dependent manner in cell cultures of human hepatocytes. An attractive TAA for cancer immunotherapy is ErbB2, a tyrosine kinase receptor overexpressed on many different types of tumor cells, such as breast and gastric cancer, whereas it is expressed at low levels on normal cells and only on certain epithelial cell types. A human antibody fragment (scFv), named Erbicin, specific for ErbB2 receptor has been isolated in our laboratory by using phage display technology. Erbicin was fused with a human pancreatic RNase (HP-RNase) variant resistant to the cytosolic inhibitor, to obtain a novel anti-ErbB2 immunoRNase (IR), which was called Erb–HPDDADD-RNase. The novel IR binds with high affinity to a panel of ErbB2-positive gastric tumor cells and inhibits their growth more efficiently than the parental immunoRNase, which is not resistant to the inhibitor. Moreover, Erb–HP-DDADD-RNase is endowed with an antitumor activity for Herceptin-resistant cancer cells both in vitro and in vivo. Similar results were obtained fusing Erbicin with the Fc region of a human IgG1 to obtain a construct, which was called Erb-hcAb for its compact size (100 kDa) if compared with the full size (155 kDa) of a natural IgG. Here we report on the antitumor effects on gastric cancer cells of Erb-hcAb which targets a different epitope of ErbB2 with respect to trastuzumab (Herceptin) and pertuzumab (Omnitarg), the only anti-ErbB2 antibodies currently in clinical use for breast cancer therapy. The results demonstrate that the growth of gastric cancer cells is efficiently inhibited in vitro and in vivo by Erb-hcAb, which shows antitumor effects on the NCI-N87 cell line more potent than those observed for Herceptin. In conclusion, these human immunoagents may represent valuable tools for both antitumor and antiviral therapies in association or in alternative to conventional therapies currently used.

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38

Chen, Ying-Ying, and 陳瑩穎. "Antitumor Activity of Chinese Drugs VII The Antitumor Activity of Natural Tannins on Cervical Carcinoma." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/80159184024020641056.

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碩士
台北醫學院
生藥學研究所
87
Carcinoma of the cervix is one of the most common malignancies in women worldwide. In clinical, cervical cancer is curable in most patients by surgery, radiotherapy, or chemotherapy. However, we found many drugs used for chemotherapy caused resistance and have many side effects in clinical. Therefore, it is urgat to develop new antitumor drugs. In this study, we used the human cervical carcinoma cell line (HeLa cell line) to establish a system for cytotoxic compounds screening by using trypan blue staining and MTT. We found that the most suitable cell concentration which cells in 96 well plate is 40000 cells/ml. The doubling time of HeLa cells is 57.02 hours. The test time for observation is three days after treated with drug. Chinese medicine and natural products are the sources to develop new antitumor drugs. In this paper 37 kinds of natural tannins were surveyed the cytotoxic activity to cervical canner cell line-HeLa. The results of cytotoxic effects of the tested tannins, hirtellin B (HB) exhibited the most cyotoxic potency to HeLa cell line. The IC50 of HB was 14.7 mM by treated for 48 hours. And it's selective index is more than the others. Therefore, we isolated and purifiied hirtellin B for the study of its mechanism. The DNA, RNA, and protein syntheses were measured by the cellular incorporation of 3H-thymidine, -uridine, -leucine. We found that hirtellin B lead HeLa cell death by it's cytotoxicity, and leaded the DNA, RNA, and protein biosyntheses decreased. And the distribution of DNA content in the cell population was evaluated by flowcytometry, and found that it has no significant inhibition to the cell cycle of HeLa clls. Light-microscopic and electron- microscopic (TEM)studies were applied to find that it has vacular on cytoplasma, and mitochondria swelling. But no significant change on cell nucleus. The above results showed that hirtellin B had cytotoxic effect to HeLa cell, and it is a non-specifical cell cycle drug.

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39

Lee, Sheng-Fu, and 李勝馥. "Antitumor Activity of Chinese Medicines Ⅹ: The Antitumor Activity of Pharbitis nil Choisy on Colorectal Carcinoma." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/50077746228488108384.

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碩士
台北醫學院
生藥學研究所
90
Colorectal carcinoma is one of the leading causes of cancer deaths in Taiwan. Several previous studies demonstrated chemotherapy for colorectal carcinoma caused resistance and side effects on patients. Therefore, the new anticolorectal tumor drugs are going to develop from Chinese herbs. In this study, the cytotoxicity effects of the 50% ethanol extracts of Chinese herbs were screened by MTT assay in human colon adenocarcinoma cell lines (CoLo 205, HT-29). The cytotoxicity effects of 50% EtOH extracted-Pharbitidis Semen Atrum were exerted stronger in CoLo 205 cells than Chang normal liver cell (CNL). The cytotoxic principles of semen were isolated by bioassay-guided fractionation. The semen were extracted with methanol and chromatographed over Diaion HP-20 column with 70% aqueous acetone Moreover, the cytotoxicity effect of 70% acetone fraction (D-70A) showed stronger than the other fractions in CoLo 205 cells and IC50 was 17.38 μg/ml for 48h. Furthermore, the cytotoxic mechanisms of D-70A were measured by agarose gel electrophoresis, fluorescence flow- cytometry, Giemsa stain, Western blot analysis. The results showed that D-70A could induce apoptosis in CoLo 205 dells. Gibberellin was isolated from D-70A with RP-18 column chromatography. The IC50 value of gibberellin was 20.36 μg/ml and induced apoptosis in CoLo205 cells for 48h. Moreover, treatment with catalase prevented gibberellin-induced cytotoxicity. In according to the results, we suggested that gibberellin might produce free radicals and induce apoptosis in CoLo 205 cells. However, the cytotoxic effect of bibberellin was lesser than D-70A in CoLo 205 cells. Therefore, we suggested the D-70A fraction extract is good for antitumor effects. In the future, gibberellin will be a biosubstance to control the quality of D-70A.

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40

Wang, Ching-Chiung, and 王靜瓊. "Antitumor Activity of Natural Occurring Polyphenols." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/37256931809854327165.

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博士
台北醫學院
藥學研究所
87
Cancer has been reported as the important disease cause of death in human. However many drugs of chemotherapy caused resistance that has been reported in clinical studies. Therefore, it is very necessary to develop new antitumor drugs. Chinese medicines and natural products have been widely used in traditional therapy, that are good sources to be developed as new antitumor drugs by a well screening system. In our screening system, we initially used KB cell line to screen the cytotoxic effects of natural products by MTT assay, and then continued to use another tumor cell line. If the compound has antitumor effects with in vitro system, we further explored in vivo antitumor effects and the mechanism of its antitumor effects. Moreover we used flow cytometry, incorporation of radioactive precursors into macromolecules, agarose gel electrophoresis, Western blot, the alteration of cellular morphology and other methods to study its mechanism of causing cell death. In this study, we screened 36 kinds of ellagitannins in vitro. The results showed that tellimagrandin II-geraniin type dimers (euphorbins G, F) were more cytotoxic than PGG-geraniin type dimers (euphorbins A, B ). All of the macrocyclic hydrolyzable tannins such as cuphiin D1 (KB, IC50=20.0ug/ml), cuphiin D2 (KB, IC50=20.7ug/ml), oenothein B (KB, IC50=26.8ug/ml), and woodfordin C (KB, IC50=28.9ug/ml) showed potent effects. However, trimeric and tetrameric ellagitannins did not increase the cytotoxicity index. The results suggested the antitumor effects of tannin need certain ellagitannin monomer units. We evaluated the antitumor activities of four macrocyclic hydrolyzable tannin dimers, cuphiins D1, D2, oenothein B and woodfordin C. All the macrocyclic dimer tannins significantly inhibited the growth of the human carcinoma cell lines KB, HeLa, DU-145, Hep 3B, and the leukemia cell line HL-60. The macrocyclic dimer tannins showed less cytotoxicity than adriamycin against normal cell lines (WISH and Chang normal Liver). All four compounds inhibited the viability of S-180 tumor cells in an in vitro assay and an in vivo S-180 tumor-bearing ICR mice model. Furthermore, in the in vitro treatment of mononuclear cells from human, cuphiins D1, D2, oenothein B and woodfordin C stimulated release of an IL-1b from cells. The results suggest that cuphiin D1 and woodfordin C exert their antitumor effects through potentiation of host-immune defense via activation of macrophages and cuphiin D1 was the most potential than the others. However, HL-60 cells treated with 30ug/ml cuphiin D1 for 36h exhibited chromatin condensation, a marker for apoptosis by electron micrographs. Moreover, HL-60 cells treated with cuphiin D1 for 36h showed a dose-dependent decrease in cell viability and the uptake of 3H-thymidine, -uridine, -leucine. Flow cytometric analysis demonstrated apoptotic cells with low DNA content, a decrease of G2/M cells and a concomitant increase of G1 cells. Cuphiin D1 also caused DNA fragmentation and inhibited Bcl-2 expression in the cells, detected by electrophoresis. Taken together, these results suggested that inhibition Bcl-2 expression in HL-60 cells might account for the mechanism of cuphiin D1-induced apoptosis. In summary, cuphiin D1 has antitumor effects in vitro and in vivo and may have potential for antitumor applications.

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41

"Antitumor activities of tremella aurantialba polysaccharides." 2002. http://library.cuhk.edu.hk/record=b5891146.

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Choi Pui-yu.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2002.
Includes bibliographical references (leaves 113-123).
Abstracts in English and Chinese.
Abstract --- p.i
Abstract (Chinese Version) --- p.iii
Acknowledgements --- p.v
List of Abbreviations --- p.vi
Table of Contents --- p.viii
List of Tables --- p.xii
List of Figures --- p.xiii
Chapter Chapter 1 --- Introduction --- p.1
Chapter Chapter 2 --- Literature Review
Chapter 2.1 --- Mushroom Polysaccharides with Antitumor Activities --- p.7
Chapter 2.1.1 --- Antitumor β-Glucans --- p.7
Chapter 2.1.2 --- Antitumor Heteroglycans --- p.9
Chapter 2.1.3 --- Antitumor Polysaccharide-Protein Complexes --- p.12
Chapter 2.2 --- Antitumor Activities and Structural Characteristics of Mushroom Polysaccharides --- p.15
Chapter 2.3 --- Antitumor Effects of Mushroom Polysaccharides In Vitro --- p.19
Chapter 2.4 --- Antitumor Effects of Mushroom Polysaccharides In Vivo --- p.21
Chapter 2.5 --- Immunomodulatory Activities --- p.24
Chapter 2.6 --- Activation of Cytokines by Mushroom Polysaccharides --- p.28
Chapter 2.7 --- Induction of Nitric Oxide Synthase by Mushroom Polysaccharides --- p.32
Chapter 2.8 --- Tremella aurantialba --- p.34
Chapter Chapter 3 --- Materials and Methods --- p.35
Chapter 3.1 --- Extraction --- p.35
Chapter 3.1.1 --- Extraction of Crude Tremella aurantialba Polysaccharide --- p.35
Chapter 3.1.2 --- Fractionation --- p.38
Chapter 3.1.3 --- Polysaccharide and Protein Content Determination --- p.38
Chapter 3.1.3.1 --- Phenol-Sulfuric Assay --- p.39
Chapter 3.1.3.2 --- Lowry-Folin Method --- p.39
Chapter 3.1.4 --- Gas Chromatography (GC) --- p.40
Chapter 3.1.5 --- Modified Carbazole Assay --- p.41
Chapter 3.1.6 --- High Performance Liquid Chromatography (HPLC) --- p.42
Chapter 3.2 --- In Vitro Studies --- p.43
Chapter 3.2.1 --- Maintenance of Cell Lines --- p.43
Chapter 3.2.2 --- Effect on Cancer Cell Lines --- p.43
Chapter 3.2.2.1 --- Trypan Blue Exclusion Methods --- p.44
Chapter 3.2.2.2 --- MTT Assay --- p.44
Chapter 3.2.3 --- Effect on Normal Cell Line --- p.45
Chapter 3.2.4 --- Coulter Counter --- p.46
Chapter 3.3 --- In Vivo Studies --- p.47
Chapter 3.3.1 --- Animals --- p.47
Chapter 3.3.2 --- Maintenance of Sarcoma 180 Cell Line --- p.47
Chapter 3.3.3 --- Effect of TAP Fractions on Sarcoma 18 Solid Tumor --- p.48
Chapter 3.3.3.1 --- Injection of TAP Fractions 24 h After Transplantation --- p.48
Chapter 3.3.3.2 --- Injection of TAP Fractions 72 h After Transplantation --- p.49
Chapter 3.4 --- Effect of TAP Fractions on Modulating mRNA Expression of Cytokines and Nitric Oxide Synthase --- p.51
Chapter 3.4.1 --- Treatment of Mice --- p.51
Chapter 3.4.2 --- Isolation of Splenocytes and Peritoneal Exduate Cells --- p.51
Chapter 3.4.3 --- Extraction of Total mRNA from Splenocyte and Peritoneal Exduate Cells --- p.52
Chapter 3.4.4 --- Reverse Transcription-Polymerase Chain Reaction (RT-PCR) --- p.53
Chapter 3.4.4.1 --- Reverse Transcription --- p.53
Chapter 3.4.4.2 --- Polymerase Chain Reaction --- p.56
Chapter 3.4.5 --- DNA Sequencing --- p.57
Chapter 3.5 --- Statistical Analysis --- p.58
Chapter Chapter 4 --- Results --- p.59
Chapter 4.1 --- Isolation and Characterization of TAP Fractions --- p.59
Chapter 4.1.1 --- Percentage Yield of TAP Fractions --- p.59
Chapter 4.1.2 --- Polysaccharide and Protein Content of TAP Fractions --- p.59
Chapter 4.1.3 --- Relative Monosaccharide Contents in TAP Fractions --- p.60
Chapter 4.1.4 --- Results of HPLC --- p.60
Chapter 4.2 --- Effects of TAP Fractions In Vitro --- p.69
Chapter 4.2.1 --- Effects of TAP Fractions on Suspension Cancer Cell Lines --- p.69
Chapter 4.2.2 --- Effects of TAP Fractions on Adhesion Cancer Cell Lines --- p.69
Chapter 4.2.3 --- Effects of TAP Fractions on Normal Cell Line --- p.70
Chapter 4.2.4 --- Effect of TAP 2 on HL-60 Cell Line as Evaluated by Coulter Counter --- p.70
Chapter 4.3 --- Antitumor Effect of TAP Fractions In Vivo --- p.78
Chapter 4.4 --- Effect of TAP Fractions on Modulating mRNA Expressions of Cytokines and Nitric Oxide Sythase (NOS) --- p.83
Chapter 4.4.1 --- Results of RT-PCR --- p.83
Chapter 4.4.2 --- Sequencing --- p.84
Chapter Chapter 5 --- Discussion --- p.91
Chapter 5.1 --- Characterization of TAP Fractions --- p.91
Chapter 5.2 --- Antitumor Effects of TAP Fractions In Vitro --- p.96
Chapter 5.3 --- Furhter Study --- p.109
Chapter Chapter 6 --- Conclusion --- p.111
References --- p.113

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42

Oliveira, Ana Catarina Freitas Salazar. "Fucoidan-based strategies envisioning antitumor therapies." Doctoral thesis, 2020. http://hdl.handle.net/1822/76431.

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Tese de doutoramento em Engenharia de Tecidos, Medicina Regenerativa e Células Estaminais
Current cancer treatments present some drawbacks, namely unwanted side effects of chemotherapeutics, due to their toxicity over healthy tissues. Trying to overcome this impactful limitation, the use of natural compounds that may present diminished effects over non-cancer cells is of great interest. Among them, fucoidan, a sulfated polysaccharide extracted from brown algae, has been highlighted over the last years due to its interesting biological features. Since different fucoidans may present distinct antitumor behaviors, one of the main goals of this PhD work was to optimize fucoidan usage by developing more effective antitumor therapies. Accordingly, in Chapter III, different fucoidan extracts from Fucus vesiculosus were tested over human breast cancer and normal cells. Three types of biological outcomes were observed: i) toxicity to cancer and normal cells; ii) toxicity to cancer cells at lower concentrations than normal cells (an effective antitumor behavior) and iii) toxicity to normal cells at lower dosages than cancer cells (for high concentrations). These discrepant activities were attributed to differences in the sulfates position and branching of fucoidan. The anti angiogenic potential of the effective fucoidan extract (type ii) was also validated by an endothelial cell tube formation assay (in vitro) and a Chick Chorioallantoic Membrane assay (in vivo) (Chapter IV). The cytotoxic effect of the same fucoidan extract was also demonstrated to human melanoma cells (Chapter V). In a complementary approach, a skin patch to treat melanoma was developed by the immobilization of fucoidan at the surface of an electrospun nanofibrous mesh. Empowering the use of this marine-origin polymer, the fucoidan extract type iii was chosen to develop a drug delivery system for breast cancer. Gemcitabine, a chemotherapeutic drug, was successfully encapsulated into fucoidan/chitosan nanoparticles showing higher toxicity to cancer cells than to normal endothelial cells (Chapter VI). Aiming to reduce gemcitabine side-effects and to develop more precise therapies, an ErbB-2 antibody was immobilized at the surface of the previously described nanoparticles (Chapter VII). The targeting to cancer cells was confirmed in a co-culture system (increased toxicity to cancer cells) and in vivo, observing the impaired tumor growth and reduced lungs metastasis. These studies proposed fucoidan-based strategies (either extracts or systems) that should be further explored in the development of more effective antitumor therapies based in natural compounds.
Os tratamentos atualmente utilizados para o cancro apresentam algumas limitações. A utilização de compostos naturais, que poderão apresentar efeitos reduzidos sobre células não cancerígenas, constitui uma potencial alternativa. De entre os vários compostos, a fucoidana, um polissacarídeo sulfatado extraído de algas castanhas, apresenta propriedades biológicas interessantes. Uma vez que diferentes fucoidanas podem apresentar diferentes comportamentos antitumorais, um dos principais objetivos deste trabalho de doutoramento foi otimizar a utilização da fucoidana para o desenvolvimento de abordagens terapêuticas. Neste sentido, no Capítulo III, diferentes fucoidanas extraídas de Fucus vesiculosus foram testadas sobre células tumorais de mama e células normais. Três comportamentos biológicos distintos foram observados: i) toxicidade para células tumorais e normais; ii) toxicidade para células tumorais a concentrações mais baixas do que para células normais (i.e. comportamento antitumoral efetivo) e iii) toxicidade para células normais a concentrações mais baixas que células tumorais (para concentrações elevadas). A discrepância entre estes comportamentos foi atribuída a diferenças na posição dos grupos sulfato e às ramificações na cadeia polimérica. O potencial anti angiogénico do extrato antitumoral efetivo foi validado através de um ensaio de formação de vasos (in vitro) e implantação na membrana corioalantóide (in vivo) (Capítulo IV). Os efeitos citotóxicos deste extrato foram também demonstrados sobre uma linha celular de melanoma. Numa abordagem complementar, uma membrana para o tratamento do melanoma foi desenvolvida mediante imobilização da fucoidana na superfície de malhas de nanofibras produzidas por electrofiação (Capítulo V). Para potenciar o uso deste polímero de origem marinha, a fucoidana tipo iii foi utilizada no desenvolvimento de um sistema de libertação de fármaco para o tratamento do cancro da mama. Gemcitabina, um fármaco quimioterapêutico, foi eficazmente encapsulada em nanopartículas (NPs) de fucoidana/quitosano, demonstrando maior toxicidade sobre células tumorais do que sobre células endoteliais (Capítulo VI). Tendo por objetivo reduzir os efeitos secundários do fármaco e para desenvolver terapias mais precisas, um anticorpo (ErbB-2) foi imobilizado à superfície das NPs (Capítulo VII). A capacidade das NPs serem direcionadas para as células tumorais foi confirmada através de um sistema de co-cultura (maior toxicidade para as células tumorais). Ensaios in vivo, demonstraram comprometimento do crescimento dos tumores e metastização nos pulmões. Estes estudos apresentam estratégias à base de fucoidana (quer na forma de extratos quer de sistemas) tendo em vista o desenvolvimento de terapias antitumorais mais eficientes.
I would like to acknowledge all the funding that allowed me to perform all this work referred specifically in each chapter and Norte 2020, for financing my PhD scholarship “Norte-08-5369-000037”.

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43

Mao-Chia, Yuan, and 袁茂嘉. "Synthesis of Dihydrophenanthrenes with Antitumor Activity." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/51265054666742312170.

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碩士
中國文化大學
應用化學研究所
97
The Chinese herbal medicine “Shi-Hu” is prepared from the dried stalks of Dendrobium species and has been used for treatment of stomach, liver, spleen, lung, kidney, and eyes disease. In Taiwan, Ephemerantha lonchophylla is also used as a source of “Shi-Hu”. Recently, 2,5,6,7-tetramethoxy-9,10-dihydrophenanthren-1-ol and 2,3,4,7-tetramethoxy-9,10-dihydrophenanthrene were isolated from Ephemerantha lonchophylla and showed strong antitumor activity. It prompted us to synthesize these dihydrophenanthrenes and their derivatives. In this thesis, a variety of benzaldehydes were reacted with triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide to give stilbenes. After catalytic hydrogenation and cyclization with PhI(OCOCF3)2 and BF3˙Et2O, a serial of 9,10-dihydrophenanthrenes were obtained. They will be tested for antitumor activity in order to understand their structure and activity relationship.

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44

Zhang, Z., F. Chen, and Lijun Shang. "Advances in antitumor effects of NSAIDs." 2018. http://hdl.handle.net/10454/16607.

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Yes
In recent years, the reports on using nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer prevention and treatment have been on the rise. In 2017, the US Preventive Services Working Group issued primary prevention guidelines on the use of NSAIDs, especially aspirin, for cardiovascular disease and colorectal cancer, and formally established the role and status of aspirin in cancer prevention. However, the mechanism of NSAIDs on preventing cancer is still not clear. In this paper, the progress of the application of NSAIDs, especially aspirin, in the prevention and treatment of tumors in recent years is summarized, and new ideas and directions for the follow-up study are also discussed.

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45

Yang, Fei. "Antitumor Activity of Py-lm Polyamides." Thesis, 2014. https://thesis.library.caltech.edu/7920/4/Cover_page.pdf.

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Molecules that inhibit DNA dependent processes are the most commonly used agents for the treatment of cancer. The genotoxicity associated with their mechanisms of action, unfortunately, make them extremely toxic to the patient and cancer cells alike. The work presented in this thesis outlines the development of Py-Im polyamides as non-genotoxic DNA-targeted antitumor molecules that interfere with RNA polymerase II elongation. We initially characterized the pharmacokinetic profiles of two hairpin polyamides to establish their bioavailability in the serum and tissues after a single administration. We next determined the molecular mechanism that contributes to toxicity of a hairpin polyamide in human prostate cancer cells in cell culture and we demonstrated antitumor effects of the compound against LNCaP xenografts in mice. Finally, we conducted animal toxicity experiments on 4 polyamides that vary on the gamma-turn with respect to the substitution of amino and acetamide groups at the alpha and beta positions. From this study we identified a second generation compound that retains antitumor activity with significantly reduce animal toxicity. This work sets the foundation for the development of Py-Im polyamides as DNA targeted therapeutics for the treatment of advanced prostate cancer.

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46

Chang, Chia-Chen, and 張嘉蓁. "Antitumor Activity of Chinese Medicines Ⅸ:The Antitumor Activity of Myrica rubra var. acuminata on Cervical Carcinomaa var." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/41116807488838947187.

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碩士
台北醫學院
生藥學研究所
89
Abstract Cervical carcinoma is one of the most common cancers in women worldwide. Despite advances in diagnosis and therapy, the morbidity and mortality from this malignancy are still high. In this study, fourteen kinds of plants were collected from northern Taiwan and their cytotoxicity in human cervical carcinoma cells, HeLa were evaluated. The 70% acetone extract of Myrica rubra var. acuminata (Myricaceae) exerted the strongest cytotoxic effects on HeLa cells from a preliminary screening of 14 plants and less cytotoxicity to primary culture normal cervical fibroblasts by MTT assay. Bioassay- guided fractionation was performed to isolate the cytotoxic principles from M. rubra var. acuminata . After a series of chromatographic separation, (-)-epigallocatechin 3-O-gallate (EGCG) and Epigallocatechin (4β®8’,2β®O®7’) epigallocatechin gallate (Di-EGCG) were isolated from the leaves of M. rubra var. acuminata as the anticancer principle in first time and yield were 0.0036% and 0.0013% respectively. The cytotoxic effects of these compounds were exhibited the dose-dependent manner at 5~40 μg/ml in HeLa cells for 24, 48 and 72h. The IC50 value of EGCG and Di-EGCG were 9.34 μg/ml and 38.50 μg/ml respectively in HeLa cells for 48h. And the selective index (SI) value of EGCG was higher than Di-EGCG. Furthermore, the cytotoxic mechanism of EGCG and Di-EGCG were measured by DNA fragmentation analysis, fluorescence flowcytometry and Giemsa stain. The results showed that EGCG induced DNA fragmentation and chromatin condensation at 10 μg/ml and Di-EGCG induced apoptotic bodies production at 40 μg/ml in HeLa cells for 24h. Therefore, we suggested EGCG and Di-EGCG could induce apoptosis in HeLa cells. Pretreatment of cells with a caspase-3-specific inhibitor prevented EGCG and Di-EGCG -induced PARP cleavage. The induction of apoptosis by EGCG and Di-EGCG via activation of caspase-3 /CPP32-like protease may provide a mechanistic explanation for its antitumor effects. However, the cytotoxic effect of EGCG was significantly reduced at cultured with catalase (375U/ml). According to above results, we suggested that EGCG produced free radicals and induced apoptosis in HeLa cells via caspase-3 dependent pathway.

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47

Liang, Tzu-Wen, and 梁慈雯. "The Antitumor Materials Produced by Bacillus amyloliquefaciens V656 and Monascus purpureus BCRC31499 Enzymes and Their Antitumor Actions." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/63895872476608307720.

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博士
大葉大學
生物產業科技學系
95
The biological function of protease, chitinase and hydrolysates were investigated in this study. In the first part, the protease of M. purpureus BCRC31499 was produced under the optimized culture condition. In the first step, the protease was precipitated and dialyzed by using ammonium sulfate. The further purification and separation procedures of the protease were processed by the use of DEAE Sepharose CL-6B ionic exchange chromatography. Purification was 27-fold with the crude enzyme solution. The overall activity yield of the purified protease was 6%, with specific protease activities of 10 U/mg. The final amount of the protease obtained was 1.6 mg. The protease had a molecular weight of 40 kDa and a pI of 7.9. The optimal pH, optimum temperature, pH stability of the protease were pH 7-9, 40℃, pH 5-9, and 40℃, respectively. In addition to protease activity, amino acids and peptides from the hydrolysis of the SCSP proteins by proteases also exhibited activity of enhancing vegetable growth. The protease would be used to produce biofertilizer in the future. In the second part, we investigated the optimized hydrolysis condition for chitinous materials (water-soluble chitosan, chitin and colloidal chitin). The chitinous materials were hydrolyzed by B. amyloliquefaciens V656 crude enzyme solution. The optimized hydrolysis conditions were that 1% of water-soluble chitosan or 1% of chitin or 3% of colloidal chitin with 20% of crude enzyme solution, pH 5, at 40℃. The composition of the hydrolysates were analyzed by HPLC. It was found that the optimum temperature and reaction time for production of (GlcNAc)6 were 40℃ and 12 hours. Longer reaction time lead to the generation of (GlcNAc)n with lower DP’s. In the third part, we investigated the antitumor actions of the hydrolysates produce by B. amyloliquefaciens V656 and M. purpureus BCRC31499 crude enzymes on the growth of colon carcinoma cell line, CT26. However, we found that the hydrolysates of crude enzyme solution produce by M. purpureus BCRC31499 had no significant effect on the growth of CT26 cell. But colon carcinoma cell was challenged with the hydrolysates of chitinous materials by B. amyloliquefaciens V656 crude enzyme solution for 1,2,3 days. The cell growth has been measured by MTT assay. The change of cell cycle distribution and induction of apoptosis caused by the hydrolysates of chitinous materials were examined by flow cytometry. Results indicated that when cells were treated with 500 g/mL of the hydrolysates, cell proliferation rate was significantly inhibited. The hydrolysates-treated cells indicated a block of S-phase and an elevated level of DNA fragmentation. Additionally, sub-G1 fraction (apoptotic cells) increased with increasing concentrations of the hydrolysates as analyzed by flow cytometry, using agarose gel electrophoresis to analyze the hydrolysates-treated cells, a similar result was found as that of flow cytometry. For the hydrolysates-induced apoptosis, loss of mitochondrial membrane potential was noted. These results suggested that the hydrolysates of chitinous materials by B. amyloliquefaciens V656 crude enzyme solution inhibited the growth of colon carcinoma cell line, CT26 through an accumulation of cell cycle at S-phase and an induction of apoptosis. We expect that these results will provide a new strategy for therapy of colon carcinoma in human beings.

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48

Wang, Shih-Sheng, and 王士昇. "Antitumor Constituentes from Taiwan yew Taxus mairei." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/85618234415550522973.

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碩士
國立中山大學
海洋資源學系研究所
90
ABSTRACT To search for practical sources of potential useful taxoids and study the structure and activity relationship of taxoids, the leaves of Formosan Taxus mairei was extracted with n-hexane, ethanol, acetone and methanol, respectively. Extensive column and preparative thin layer chromatography by bioassay-directed screening resulted in the isolation of 8 taxoids. Their structures were identified as 2-deacetoxy taxinine J （77）、1β-hydroxy-5α-deacetyl baccatin I（78）、taxumairol Z（79）、taxayuntin G（80）、taxuspine F（81）、 wallifoliol（82）、taxumairol Q （83）、1-deacetyl baccatin III（84）. The compound 82-containg fraction from another batch of material was acylated to yield a series of derivatives and their structures were identified as 7, 13-diacetylwallifoliol（85）、9, 13 - diacetyltaxumairol W（86）、7, 13-dibenzoylwallifoliol（87）、10, 13 - dibenzoyltaxacustin（88）、7, 9-dibenzoyl taxumairol P（89） primarily on the basis of 1- and 2-D NMR techniques including DEPT, COSY and HMBC experiments as well as chemical correlation with know compounds. Among them, compound 79 、83 was first isolated in nature, compounds 78 and 80-82 were first isolated from T. mairei and compounds 85-89 were new derivatives. All of these compounds were sent to National Research Institute of Chinese Medicine for antitumor test in vitro. The investigation of their structure and activity relationship is now in progress.

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49

Lin, China-Hung, and 林家宏. "Antitumor and antimicrobial compound from Macrotomia euchroma." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/88182115450366120272.

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碩士
中國文化大學
應用化學研究所
89
Shikon is derived from Boraginacea species, Lithospermum plant. We took Macrotomia euchroma as experimental material. The purpose of the study is to search the bioactive components from M.euchroma. The results showed that shikonin and its deri- vatives had antitumor and antibacterial activity. We isolated two pure compounds from M. euchroma, which were acetylshikonin [ I ] and isobutylshikonin [IV]. Two shikon- in derivatives were obtained by using organic synthesis method, they are β,β-dimethylacrylshikonin [III] and isovalerylshikonin [VI]. The structures of compound [ I ]、[III]、[Ⅳ]、[VI] were confirmed by spectroscopic analysis. These shikonin derivatives [ I ]、[III]、[Ⅳ]、[VI] showed inhibition on cancer cell lines and some antibiotics resistant bacteria. Key words: shikonin、Macrotomia euchroma、antitumor、antibacterial agents

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50

Tsai, Ya-Chuan, and 蔡雅娟. "Synthesis and Antitumor activity of Diarylisoxazole Derivatives." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/00877831864574111782.

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Abstract:

碩士
中國文化大學
應用化學研究所
92
Abstract Combretastatin A-4(CA-4), isolated from the bark of the South African tree Combretum caffrum is one of the most potent antimitotic agent. The structure of the CA-4 is similar to colchicine. It has been found to be a potent antimitotic agent that binds to tubulin on the colchicine binding site and also has strongly inhibitory activity on tubulin polymerization. This compound shows strong cytotoxicity against a wide variety of human cancer cells, including multi-drug resistant cell lines. A water-soluble sodium phosphate produrg (CA-4P) is currently in phase I/II clinical trials now. However, cis-combretastatin analogues are prone to isomerize to trans-forms during storage and administration. The trans-forms of those compounds display dramatic reduction in antitubulin activity and antitumor activity. Thus, we attempted to synthesize a series of 5-membered hetercycles in place of the olefinic position to fix conformation in cis-forms. In this thesis, TYC01 was synthesized and exhibited strong cytotoxicity against human cervical epitheloid carcinoma cell line, human hepatocellular carcinoma cell line, and human ovarian adenocarcinoma cell line. The CD50 is 0.085 g/mL, 0.161 g/mL and 0.295 g/mL, respectively.

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Dissertations / Theses on the topic 'Antitumor'

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