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1
Mokdsi, George. "Antitumour Metallocenes." Thesis, The University of Sydney, 2000. http://hdl.handle.net/2123/794.
Full textAbstract:
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.
2
Mokdsi, George. "Antitumour Metallocenes." University of Sydney. Chemistry, 2000. http://hdl.handle.net/2123/794.
Full textAbstract:
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.
3
Gate, Ernest N. "Investigations on new antitumour agents." Thesis, Aston University, 1985. http://publications.aston.ac.uk/12512/.
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4
Skelton, Lorraine Ann. "Pyridyl quinazolines as potential antitumour agents." Thesis, Institute of Cancer Research (University Of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294789.
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5
Shi, Dong-Fang. "The medicinal chemistry of antitumour benzazoles." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283645.
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6
Langnel, David Antoine Fernand. "New synthetic routes to antitumour imidazotetrazines." Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311742.
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7
Shahbakhti, Hassan. "Structure/activity relationships of antitumour diazridinylquinones." Thesis, University of Salford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308289.
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8
Ayuko, Washington O. "Free radicals as potential antitumour agents." Thesis, Aston University, 1991. http://publications.aston.ac.uk/12521/.
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The aim of this work was to use extremely low concentrations of free radical generating compounds as a 'catalyst' to trigger endogenous free radical chain reactions in the host and to selectively eliminate neoplastic cells in the host. To test the hypothesis, a number of free radical generating compounds were screened on several malignant cell lines in vitro to select model compounds that were used against tumour models in vivo. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and its derivatives were selected at the model compounds for in vivo experiments in view of their high cytotoxic potency against several malignant cell lines in vitro. The water soluble derivative, 2,2-diphcnyl-l-(2', 4'-dinitro-6'-sulphophenyl) hydrazyl (DDSH) given by subcutaneous injections demonstrated significant antitumour activities against the MAC 16 murine colon adcnocarcinoma implanted subcuta-ncously in male NMRI mice at nanomolar concentration range. 40-60% of long term survival of over 60 days was achieved (compared with control survival of 20 days) with total tumour elimination. This compound was also active against both P388 leukaemia in male BDF1 mice and TLX5 lymphoid tumour in male CBA/CA mice at a similar concentration range. However, some of these animals died suddenly after treatment with no evidence of disease present at post mortem. The cause of death was unknown but thought to be related to the treatment. There was significant increase in scrum level of malondialdchydc (MDA) following treatment, but did not correlate to the antitumour activities of these compounds. Induction of supcroxide dismutasc (SOD), and glutathione peroxidase (GPx) occurred around day 8 after the administration of DDSH. Histological sections of MAC16 tumours showed areas of extensive massive hacmorrhagic necrosis and vascular collapse associated with perivas-cular cell death following the administration of nanomolar concentration of DDSH which was probably compatible with the effects of free radicals. It was concluded that the antitumour activities of these compounds may be related to free radical and cytokinc production.
9
Horspool, Keith R. "Structure-activity studies on antitumour imidazotetrazinones." Thesis, Aston University, 1988. http://publications.aston.ac.uk/12550/.
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10
Rafferty, Karen. "Novel organometallic compounds as potential antitumour agents." Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487773.
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11
Thompson, Andrew M. "Synthetic studies on a potential antitumour compound." Thesis, University of Canterbury. Chemistry, 1991. http://hdl.handle.net/10092/7832.
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Mycalamides A and B, isolated recently from a marine sponge of the genus Mycale, show strong in vitro and in vivo antiviral and antitumour properties. In this research, the chemistry of the mycalamides was explored and structure-activity relationships were determined, with the overall objective of producing analogues with better, or more selective biological activities. Along with this, the conformational behaviour of the mycalamides and a related compound, pederin, was examined.
Simple esters, silyl and alkyl ethers of the hydroxyl and amide functionalities were prepared during initial studies. While many of these proved to be inactive, they were still useful as protected intermediates for use in acid and base catalysed hydrolysis reactions. In the course of the acid catalysed reactions, the acetal groups were partially or completely hydrolysed, eliminated, or exchanged and cleavage fragments were isolated. The exocyclic double bond was hydrogenated, epoxidised and rearranged in further studies. Base catalysed hydrolysis, elimination and rearrangement reactions were examined extensively and many interesting and unexpected products were obtained, including epimers and further cleavage fragments. Reduction and oxidation reactions also provided a source of important and potentially useful derivatives.
In all, more than one hundred and ten derivatives of mycalamides A and B were prepared, characterised and tested for biological activity. The central portion of the structure, including the a-hydroxy amide and neighbouring groups, was shown to be crucial for the biological activity. A simple model structure was prepared containing some of these elements. The structure-activity relationships described in this work, combined with a better knowledge of the chemistry and conformational behaviour of these compounds, should together provide renewed stimulus for the ongoing study and development of these potential antitumour compounds.
12
Chew, Eng-Hui. "Development of antitumour quinols : a mechanistic approach." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430303.
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13
Wong, Pui Ee. "Novel aza-cyclic derivatives as antitumour agents." Thesis, University of Strathclyde, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432099.
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14
Pass, M. "Synthesis of the antitumour antibiotic CC-1065." Thesis, Imperial College London, 1987. http://hdl.handle.net/10044/1/47592.
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15
Citossi, Francesca. "Self-assembling antitumour prodrugs for localised drug delivery." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33345/.
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Localised cancer therapy is a developing strategy used to overcome the systemic toxicity associated with intravenous systemic chemotherapy, which still represents the primary route of administration for the majority of current anticancer agents. Low molecular weight gelators (LMWGs) have recently gained increasing popularity as drug delivery platforms for localised cancer therapy: they are small molecules, which self-assemble into a 3D network via non-covalent interactions. Due to their inherent biocompatibility, LMWGs represent a viable alternative to the extensively explored polymer based drug delivery systems. One such drug delivery approach, based on LMWGs, involves the synthesis of gelator-based prodrugs of chemotherapeutic agents; however, to date, there remains a limited number of anticancer prodrugs that have gelation properties. Therefore, the present work aims to find new chemotherapeutic agents that display gelation properties by modification of the parent drug with known self-assembling groups. Two anticancer agents have been evaluated: the clinical antimetabolite methotrexate (MTX) and the experimental benzothiazole derivative 5F 203, both characterised by significant anticancer activity but systemic toxicity. Therefore, formulation of MTX and 5F 203 as LMWGs-based prodrugs for localised cancer therapy was considered a useful strategy to overcome the systemic toxicity of these antitumour drugs. Different synthetic approaches were explored to formulate self-assembling MTX prodrugs. The most successful one involved the synthesis of MTX derivatives bearing alkyl chains and aromatic groups at the α or both α and γ carboxylic acid terminals of MTX. Unfortunately, preliminary gelation tests performed on MTX acyl derivatives via a solvent-switch method, revealed lack of self-assembling properties. Therefore, the MTX conjugates developed were not suitable for localised drug delivery applications. Due to the absence of self-assembling properties of MTX conjugates, the potential gelation behaviour of novel derivatives of another anticancer candidate, the benzothiazole agent 5F 203, was considered, and two amide prodrugs series of 5F 203 were investigated. Amongst the compounds tested for gelation, 5F 203 succinic acid conjugate (68a) revealed formation of a hydrogel at physiological pH. Rheological measurements confirmed its LMWG nature, showing formation of a cross-linked gel network. In vitro growth inhibitory assays against breast (MCF-7) and ovarian (IGROV-1 and OVCAR-4) carcinoma cell lines showed overall activity of 5F 203 amide prodrugs in inhibiting cell proliferation. Release studies from the gel matrix of 68a revealed a release of the derivative and the active drug over 3 days, thus confirming its potential application as a depot formulation for localised delivery of 5F 203. In order to improve the rate of conversion of prodrugs into the parent amine 5F 203, compared to the previous amide series developed, acyloxyalkoxycarbonyl derivatives of 5F 203 were synthesised. Gelation tests displayed self-assembling behaviour for derivatives 76a-76c and rheological studies confirmed the LMWG nature of the new entities. The acyloxyalkoxycarbonyl prodrugs revealed in vitro potencies similar to those displayed by 5F 203, when tested against MCF-7 and IGROV-1 cell lines. The isobutyl carbamate prodrug (76a) proved to be the most potent of the series, showing hydrolysis into the active drug 5F 203, when incubated in either PBS buffer, rat or human plasma; release from the gel matrix also showed release of 5F 203 in PBS within 72 h. The outcomes from this work have therefore provided a basis for future optimisation and development of LMWG derivatives of 5F 203, as depot formulations for localised delivery of this anticancer agent.
16
Flasz, Jakub Tadeusz. "Total synthesis of the antitumour natural product, (-)- echinosporin." Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.601477.
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The following dissertation describes a collection of results that led to a successful formal total synthesis of a naturally-occurring antitumour antibiotic, (-)..echinosporin. To achieve that, various synthetic strategies were developed and examined, all of which relied on a cycloadditive event as a key step to prepare the [3.4.0J-bicyclic framework of (-)-echinosporin. The synthesis was eventually accomplished using the Padwa [3+2] cycloaddition-elimination of allenylphenylsulphone to a chiral sugar enone 6 as a key transformation. it provided the first recorded example of this reaction used in complex natural product total synthesis. Following a series of functional group interconversions on this cycloadduct, a mild new method for the C-carboxyalkylation of bromomagnesium ketone enolates was applied to install the C(11)~carboxylic group of (-)- echinosporin. The quaternary OH-bearing stereocentre was introduced via a substrate~directed osmylative dihydroxylation on a i3-keto ester enol 71 . The resulting ketone 77 was advanced into 70 via Barton deoxygenation. Following that, the crucial C(8)-C(9) unsaturation was introduced starting from the ketone 70 through a three-step sequence based on the Barton vinyl iodide synthesis and Pd(O)-mediated dehalogenation. Next, a TEMPO-based oxidation was used to bring the C(10)- position to a correct oxidation state. Following protection as the allyl ester, an E1cb silyloxy elimination installed the remaining C(4)-C(5) unsaturation. The allyl ester 90 was finally transformed into a primary amide and the C-2 ethyl glycoside was chemoselectively hydrolysed using aqueous HBF4 to reveal Smith's intermediate 1.
17
Nightingale, Karl. "DNA sequence recognition by the antitumour antibiotic bleomycin." Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241056.
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O'Sullivan, Noeleen. "Synthesis and reactions of cyclopropamitosenes and related pyrrolo[1,2-a]indoles." Thesis, Loughborough University, 1992. https://dspace.lboro.ac.uk/2134/14132.
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The use of Mitomycin C in the treatment of a wide range of neoplastic conditions is discussed. The mechanism of action of mitomycin anticancer antibiotics under reductive activation conditions using either enzymes, sodium dithionite, catalytic hydrogenation or chromium (Il) perchlorate is examined, as is the alkylation of DNA. An intramolecular [3+2] cycloaddition strategy has been employed to synthesise the pyrrolo[I,2-aJ]indole nucleus for a wide range of cyclopropamitosenes, whereas the key step in the synthesis of pyrrolo[I ,2-a]indoles without the cyclopropane ring was a modified Wittig reaction. From the onset of the work it was important to investigate the role of the 7 -methoxy group. Hence a variety of cyclopropamitosenes or related pyrrolo[I,2-a]indoles were subjected to C-7 exchange reactions with either (i) other alkoxides or (ii) cyclic / acyclic amines. In this way, structural modification at C-7 can be related to the biological results. Biological and electrochemical data were recorded for the cyclopropamitosenes and related pyrrolo[I,2-a]indoles and correlated with their structures.
19
Spencer-Evans, Victoria Louise. "Design, synthesis and evaluation of linkers for the solid phase synthesis of pyrrolo [2,1-c][1,4] benzodiazepines." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289331.
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Trapini, Valentina. "The development of Phortress : from molecule to mechanism." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269467.
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21
Griffiths, Jonathan. "Structural modification of DNA." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315114.
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22
Robson, Claire. "Biochemical probes for folate-metabolising enzymes." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240965.
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23
Jones, Garry B. "Design, synthesis and evaluation of DNA-binding oxazolo[2,3-c][1,4]benzodiazepines and pyrrolo[2,1-c][1,4]benzodiazepines." Thesis, University of Portsmouth, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293269.
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24
Croker, Stephen John. "Synthetic studies towards a novel DNA targeted cross-linking agent based on DC-81 and CC-1065." Thesis, University of Portsmouth, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310416.
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Murray, Clare Louise. "A new approach to the synthesis of DNA-interactive pyrrolo-[1,4]-benzodiazepin-5-ones." Thesis, University of Liverpool, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321143.
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Fletcher, Michael Crawford. "Estimating the kinetic parameters of DNA sequence-selective drugs by footprinting." Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295695.
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27
Cui, Zong Jie. "Photodynamic drug action on rat pancreatic acinar cells." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306352.
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28
Cook, Richard Thomas. "Synthetic studies towards the sesbanimide group of antitumour agents." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329012.
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Gdarah, Khaled M. "The synthesis of some nucleoside analogues as antitumour agents." Thesis, Brunel University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.332000.
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30
McCaig, Avril E. McCaig. "The synthesis of imidazole nucleosides as potential antitumour agents." Thesis, Heriot-Watt University, 1988. http://hdl.handle.net/10399/1989.
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31
Matthews, Charles S. "Investigations into the mechanism of action of antitumour quinols." Thesis, University of Nottingham, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659198.
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Antitumour quinols containing the 4-hydroxycyclohexa-2,5-dienone pharmacophore potently inhibit human tumour cell growth in vitro and in vivo. This activity is postulated to occur via inhibition of the thioredoxin/thioredoxin reductase (TrxlTrxR) redox system which reduces numerous substrates involved in cellular proliferation, signal transduction, redox homeostasis and apoptosis. Similar to the archetypal quinol, PMX 464, its eventual successor, PMX 290, induced caspase-dependent apoptosis, cell cycle arrest and oxidative stress in sensitive tumour cells whilst depletion of glutathione increased tumour cell sensitivity to PMX 290. The ability of PMX 464 and PMX 290 to induce cellular responses understood to occur downstream of TrxlTrxR inhibition that could account for their antitumour activity were investigated. Quinol activity was shown to be independent of oxidative stress. Colon cancer cells stably overexpressing catalase retained sensitivity to PMX 464 and PMX 290 yet were resistant to hydrogen peroxide whilst the use of radical scavengers failed to abrogate quinol activity. Trx binds to and inhibits apoptosis signalling kinase 1 (ASK1), a mitogen activated protein kinase (MAPK) kinase kinase responsible for stress-induced apoptosis via sustained activation of the MAPKs c-jun N-terminal kinase (JNK) and p38. PMX 464 and PMX 290 disrupted cellular ASK1 :Trx1 complexes and induced sustained JNKlp38 phosphorylation yet overexpression of dominant negative ASK1 or pharmacological inhibition of JNKlp38 did not prevent quinol-induced apoptosis. Additionally, knockdown of Trx1 using siRNA did not impact quinol activity suggesting additional mechanisms of action. PMX 290 induced endoplasmic reticulum (ER) stress at apoptosis-inducing concentrations below those required to inhibit cellular TrxlTrxR. Upregulation of ER stress proteins, translation-inactivating phosphorylation events and ER distension occurred in response to PMX 290 alongside the accumulation/aggregation of ubiquitinated proteins prior to the onset of apoptosis. Proteasome inhibition was not responsible for these effects. A definitive cellular target for PMX 290 was not identified, however, useful tools have been generated which could be applied to investigate the actions of other redox homeostasis modulating therapies.
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Leong, Chee-Onn. "Antitumour benzothiazoles : analysis of DNA damage induced by Phortress." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396792.
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Stanslas, Johnson. "Mechanisms of the antitumour activities of novel polycyclic acridines." Thesis, University of Nottingham, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263005.
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El-Sokkary, Ahmed Mohamed Adel. "The evaluation of new ruthenium complexes as antitumour agents." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440638.
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Kadri, Hachemi. "Design, synthesis and biological evaluation of novel antitumour compounds." Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/54364/.
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Cancer is a leading cause of death worldwide. Chemotherapy is the main approach used currently for the treatment and management of this disease especially disseminated malignant tumours. Traditional anticancer drugs have a limited selectivity as they target mainly DNA synthesis or cell proliferation leading to severe side effects. However, the newer anti-cancer drugs are more selective in targeting certain aberrant signalling pathways in cancer cells. In the first part of this work, a series of benzimidazole and indole analogues of a potent antitumour benzothiazole lead compound were synthesised to enhance its pharmaceutical properties. Their antitumour activity was tested against different human cancer cell lines. In most cases, these analogues did not display any significant activity except for some of the N-substituted ones with Moluenesulfonyl group, which yielded submicromolar GI50 values. The second part of the work focuses on the design and synthesis of antitumour agents targeting the Wnt signalling pathway. The aberrant activation of this signalling pathway has been implicated in a wide spectrum of cancers. Disheveled PDZ domain is an essential protein-protein interaction mediator in the Wnt signalling pathway. Novel antitumour agents were designed using molecular modelling approaches to selectively inhibit the PDZ domain and hence abolish tumouregenic effects associated with the aberrant activation of Wnt signalling. Biochemical binding assays showed that one of the hits obtained through high-throughput docking binds specifically to the Disheveled PDZ domain. Structural optimisation studies of this hit were also carried out in order to improve activity.
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George, Jonathan Harry. "Synthetic studies on the azinothricin family of antitumour antibiotics." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1446467/.
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A first synthesis of the acyl side chain of azinothricin and a second-generation route to the A83586C side chain is described in this thesis. The successful strategy was based on an asymmetric aldol reaction, a stereoselective Roush-type crotylboration and a Trost asymmetric allylic alkylation reaction to set the stereocentres of the key intermediates 3.95 and 3.5, which were subsequently coupled together to give the side chain fragment 3.105 after 10 further steps. The total synthesis of several A83586C/azinothricin analogues is also described. These hybrid structures have been formed via a chemoselective coupling between the N-hydroxybenzotriazole activated ester of the acyl side chain and the appropriate fully deprotected cyclodepsipeptide hydrochloride salt. The first total syntheses of the natural products azinothricin and kettapeptin have also been achieved by this strategy.
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Clark, Alan S. "Antitumour imidazotetrazines: probes for the major groove of DNA." Thesis, Aston University, 1991. http://publications.aston.ac.uk/12602/.
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The antitumour imidazotetrazinones are believed to act as prodrugs for the triazene series of alkylating agents, showing a marked pteference for the alkylation of the middle guanine residue in a run of three or more contiguous guanines. However, the. exact nature of the interactions of imidazotetrazinones within the micro~environment of DNA are; as yet unknown. In order to examine such interactions a three pronged approach involving molecular modelling, synthetic chemistry and biological analysis has been undertaken during the course of this project. . Molecular modelling studies have shown that for the 8-carboxamido substituted imidazotetrazinones antitumour activity is dependent upon the. presence of a free NH group which can be involved in the formation of both intramolecular and intermolecular hydrogen bonds, and the presence of a non-bulky substituent with a small negative potential . volume. Modelling studies involving the docking of .mitozolomide into the major groove of DNA in the region of a triguanine sequence has shown that a number of hydrogen bonding interactions are feasible. A series of 8-substituted carboxamide derivatives of mitozolomide have been synthesised via the 8-acid chloride and 8-carboxylic acid derivatives including a number of peptide analogues. The peptide derivatives were based upon the key structural features of the helix-turn-helix motif of DNA-binding proteins with a view to developing agents that are capable of binding to DNA with greater selectivity. An examination of the importance of intramolecular hydrogen bonding in influencing the antitumour activity:of :the imidazotetrazinones has led to the synthesis of the novel pyrimido[4',5' :4,3]pyrazolo[5,1-d]-1,2,3,5-tetrazine ring system. In general, in vitro cytotoxicity assays showed that the new derivatives were less active against the TLX5 lymphoma cell line. than the parent compound mitozolomide despite an increased potential for hydrogen bonding interactions. Due to the high reactivity of the: tetrazinone ring system it is difficult to study the interactions between the imidazotetrazinones and DNA. Consequently a number of structural analogues that are stable under physiological conditions have been. prepared based upon the 1,2,3 triazin-4(3H)-one ring system fused with both benzene and pyrazole rings. Although the 3-methylbenzotriazinones failed to antagonise the cytotoxic activity of temozolomide encouraging results with a 3-methylpyrazolotriazinone may suggest the existence of an imidazotetrazinone receptor site within DNA. The potential of guanine rich sequences to promote the alkylating selectivity of imidazotetrazinones by acting as a catalyst for ring cleavage and thereby generation of the alkylating agent was examined. Experiments involving the monitoring: of the rate of breakdown of mitozolomide incubated in the presence of synthetic oIigonucleotides did not reveal any catalytic effect resulting from the DNA. However, it was noted that the breakdown of mitozolomide was dependent upon the type of buffer used in the incubations and this may indeed mask any catalysis by the oligonucleotides.
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Deans, Bryan. "Studies on the mechanism of action on antitumour imidazotetrazinones." Thesis, Aston University, 1994. http://publications.aston.ac.uk/11048/.
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This thesis attempts to identify the cellular targets important to the cytotoxicity of imidazotetrazinones, to elucidate the pathways by which this damage leads to cell death, and to identify mechanisms by which tumour cells may circumvent this action. The levels of the DNA repair enzymes O6-alkylguanine-DNA-alkyltransferase (O6-AGAT) and 3-methyladenine-DNA-glycosylase (3MAG) have been examined in a range of murine and human cell lines with differential sensitivity to temozolomide. All the cell lines were proficient in 3MAG despite there being 40-fold difference in sensitivity to temozolomide. This suggests that while 3-methyladenine is a major product of temozolomide alkylation of DNA it is unlikely to be a cytotoxic lesion. In contrast, there was a 20-fold variation in O6-AGAT levels and the concentration of this repair enzyme correlated with variations in cytotoxicity. Furthermore, depletion of this enzyme in a resistant, O6-AGAT proficient cell line (Raji), by pre-treatment with the free base O6-methylguanine resulted in 54% sensitisation to the effects of temozolomide. These observations have been extended to 3 glioma cell lines; results that support the view that the cytotoxicity of temozolomide is related to alkylation at the O6-position of guanine and that resistance to this drug is determined by efficient repair of this lesion. It is clear, however, the other factors may influence tumour response since temozolomide showed little differential activity towards 3 established solid murine tumours in vivo, despite different tumour O6-AGAT levels.
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Waern, Jenny Birgitta. "The biological chemistry of the antitumour agent molybdocene dichloride." Thesis, The University of Sydney, 2005. https://hdl.handle.net/2123/28105.
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This thesis reports a study of the coordination chemistry, cytotoxicity, and cellular uptake of molybdocene dichloride and a range of derivatives. These studies were performed to provide information about the mechanism of antitumour action and hence to evaluate the potential of molybdocene dichloride to proceed to clinical trials.
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Waring, M. A. "Studies related to chromenequinones." Thesis, University of Newcastle Upon Tyne, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233290.
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O'Connor, P. M. "Crosslinking reactions of the dimethane sulphonates within chromatin." Thesis, University of Manchester, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383233.
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Morris, Stephen James. "Design, synthesis and evaluation of a sequence-selective DNA cleaving agent based on the pyrrolo[2,1-c][1,4]benzodiazepine ring system : investigation of the DNA-reactive species." Thesis, University of Portsmouth, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340240.
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Thompson, Stephen. "The synthesis of novel DNA-interactive pyrrolo-(2,1-c)[1,4]-benzodiazepin-5-ones." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367072.
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Holmes, Jennifer Jane. "Metabolism and mechanisms of action of novel pyrazoloacridone and anthraquinone cytotoxic agents." Thesis, University of Strathclyde, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249821.
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Bull, Vincent L. "Studies on the mode of cytotoxicity of imidazotetrazinones." Thesis, Aston University, 1988. http://publications.aston.ac.uk/12506/.
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The irnidazotetrazinones are a novel group of anti tumour agents which have demonstrated good activity against a range of murine tumours and human xenografts. They possess a structure activity relationship similar to the anti tumour triazenes, with the chloroethyl (mitozolomide) and methyl (temozolomide) analogues being active antitumour agents, whilst the ethyl (CCRG 82019) and higher homologues are inactive. This thesiS attempts to elucidate the biological mechanisms responsible for the strict structure-activity relationship observed amongst the imidazotetrazinones. Mitozolomide is the only agent chemically capable of cross-linking DNA , which has been suggested to be responsible fo r the cytotoxicity of this group of agents. Only mitozolomide and ternozolornide Exhibit a marked ditferential toxicity towards the 0 -alkylguanine-DNA alkyltransferase deficient GM892A (Mer-) cell line rather than the proficient Raji cell line (Mer+). The rate of uptake of imidazotetrazinones into cells is similar for all three agents in both cell lines, and does not explain the differing sensitivities to these agents. The effect of drug treatment on the incorporation of precursors into macromolecules, and their pool sizes, was examined. Temozolomide administration was found to alter de novo protein synthesis in both GM892A and Raji cells. Flow cytometric analysis revealed that temozolomide and CCRG 82019 block cells in late S/G2/M phase of the cell cycle , similar to that observed with mitozolomide. The extent of reaction of all three drugs with isolated macromolecules and cellular macromolecules was determined, and differences found, with cellular repair processes influencing the number of alkyl lesions remaining bound to macromolecules. The specific bases formed in calf thymus DNA after treatment with either temozolornide and CCRG 82019 was measured, and it was found that the types and relative amounts of lesions formed, differed, as well as the total level of alkylation. Whereas DNA extracted from imidazotetrazinone treated cells is not affected in its ability to support RNA polymerase activity, an effect is observed on the ability to extract DNA polymerase from drug treated cells. This may suggest that the alkylated DNA must be in intact chromatin for the lesion to manifest its effects. Temozolomide and methyl methanesulphonate do got appear to act with a synergistic mode of action. The 0 -position of guanine is suspected to be a critical site for the action of these types of drugs.
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Chambers, Christopher Steven. "The synthesis of novel analogues of the antitumour antibiotic pyrrolobenzodiazepines." Thesis, University of Huddersfield, 2009. http://eprints.hud.ac.uk/id/eprint/7068/.
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In this thesis, the novel synthesis of tetra- and triazolo-analogues of the pyrrolobenzodiazepines, pyrrolobenzothiadiazepines, benzodiazepines and benzothiadiazepines are described. These compounds are of great interest as synthetic targets due to their potential medical properties. The key processes are the intramolecular 1,3-dipolar cycloaddition between the azide and the nitrile present in compound (1), the azide and the alkyne present in compound (2) the azide and the alkene present in compound (3), to form the novel final compounds of type (4). The synthesis of these precursors from readily available starting materials is discussed. The intramolecular 1,3-dipolar cycloaddition of the alkene with the azide (3) afforded the triazoline(4, Z = CH2) which upon nitrogen extrusion formed either the methyl imine (5) or an aziridine (6) as shown in the Scheme on the next page. Reactions of other alkenes, more highly substituted than compound (3) are also described. This thesis will also describe a general route to triazolobenzodiazepines and triazolobenzothiadiazepines (7, X = CO, SO2; Z = CH). The reactions of the corresponding nitriles (7, X = CO, SO2; Z = N) will also be described, as with other approaches to the pyrrolobenzodiazepines.
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Kemp, Christopher Gary. "Total solid-phase sysnthesis of the mixrins : antitumour cyclic lipopeptides." Thesis, University College London (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540430.
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Lazarides, Linos. "Synthetic studies on the A83586C/GE3 family of antitumour antibiotics." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444925/.
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The A83586C/GE3 class of cyclodepsipeptides are a family of antitumour antibiotics whose antitumour properties have been attributed to their ability to inhibit E2F transcription factors. The latter are critical regulators of cellular proliferation that are potentially important new therapeutic targets for the control of proliferative diseases such as cancer. In this thesis, the asymmetric total synthesis of several A83586C/GE3/Verucopeptin analogues is described. Some of these molecules have provided valuable insights into the actual mechanism of antitumour activity for this class. All of these molecules have been built through a chemoselective coupling strategy involving the fully elaborated pyran /V-hydroxybenzotriazole activated ester 47 and the relevant unprotected cyclohexadepsipeptide. The latter were each synthesised through a 2+2+2 -fragment condensation strategy and macrolactamisation was accomplished with HATU. The approach used is exemplified below by our synthesis of the A83586C/GE3 hybrid 257.
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Kerr, G. "The synthesis of pyrazole C-nucleosides as potential antitumour agents." Thesis, Heriot-Watt University, 1992. http://hdl.handle.net/10399/1454.
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Banks, Jason George. "Development of C8-linker chemistry for the pyrrolobenzodiazipine antitumour antibiotics." Thesis, University of Portsmouth, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323324.
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