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Wheate, Nial Joseph Chemistry Australian Defence Force Academy UNSW. "Platinum anti-cancer complexes." Awarded by:University of New South Wales - Australian Defence Force Academy. School of Chemistry, 2001. http://handle.unsw.edu.au/1959.4/38704.
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[Formulae and special characters can only be approximated here. Please see the pdf version of the Abstract for an accurate reproduction.] Several inert platinum complexes were synthesised: [(en)Pt([special character]-dpzm)2Pt(en)]4+, [{Pt(dien)}2[special character]-dpzm]4+, [{Pt(dien)}2[special character]-H2N-(CH2)6-NH2]4+, cis-[(NH3)2Pt([special character]--dpzm)2Pt(NH3)2]4+, trans-[Pt(NH3)2([special character]-dpzm)2]2+. Three active complexes, all with chloro ligands, were also synthesised: trans-[{Pt(NH3)Cl2}2[special character]-dpzm)], trans-[{Pt(NH3)2Cl}2[special character]-dpzm]2+ (di-Pt) and trans-[trans-{Pt(NH3)2Cl}2{trans-[Pt(NH3)2([special character]-dpzm)2]}]4+ (tri-Pt). 1H NMR established that multi-nuclear platinum complexes will preferentially associate in the DNA minor groove with a preference for A/T sequences, and with a binding constant [special character]-105 M-1, regardless of the charge, linking ligand, length or shape. Using [(en)Pt([special character]-dpzm)2Pt(en)]4+ and the oligonucleotide d(GC)5 it was determined that the metal complex binds G/C rich sequences also in the minor groove, but with a much reduced binding constant, 103 M-1. CD studies showed [(en)Pt([special character]-dpzm)2Pt(en)]4+ was able to induce a DNA conformation change from B-type to what appeared to be a partial Z-type. Transcription assays showed that even though the metal complex does not bind DNA covalently, it is still able to inhibit DNA transcription at particular sites. The complexes di-Pt, tri-Pt, [{Pt(dien)}2[special character]-dpzm]4+ and trans-[Pt(NH3)2([special character]-dpzm)2]2+ were tested for anti-cancer activity in the L1210 murine leukaemia cell line, and gave values of 3.8, 2.5, [special character]200 and 64 [special character]M respectively. In the cisplatin resistant line (L1210/DDP), trans-[Pt(NH3)2([special character]-dpzm)2]2+ showed an increase in activity with a drop to 32 [special character]M, while both di-Pt and tri-Pt showed decreases in activity to values of 8.8 and 3.6 [special character]M. In the human ovarian carcinoma 2008 cell line and its cisplatin resistant derivative C13[special character]5, both complexes showed good activity with values of 2.5 and 20.9 [special character]M respectively, but again both showed decreases in activity in the resistant line with values of 17.8 and 37.7 [special character]M respectively. To help explain the difference between activity of these complexes and the complexes BBR3464 and BBR3005, cell uptake and DNA interstrand cross-linking experiments were performed. The cell uptake studies showed that both di-Pt and tri-Pt are taken up by cells at very high levels, when administered at 100 [special character]M, thus indicating that the difference is unlikely to be due to large differences in cell uptake. The DNA interstrand cross-linking studies showed both complexes readily form interstrand adducts (50% interstrand cross-linking at 12 nM and 22 nM respectively, c.f cisplatin 3 [special character]M). These results suggest that the rigid nature of the dpzm linker may be affecting the DNA adducts formed, with more interstrand links being formed than BBR3464. Possibly, it is this that causes the large differences in cytotoxicity. The DNA binding of di-Pt and tri-Pt was examined with the nucleosides adenosine and guanosine and the dinucleotide d(GpG). Both complexes bound at the N7 of guanosine, but 2-fold slower than cisplatin. In addition, di-Pt bound at the N7 and either the N1 or N3 of adenosine, 7-fold slower than guanosine. Di-Pt forms a large variety of cross-links between two d(GpG) molecules, however it could not be established whether the 1,2-intrastrand adduct could be formed. Di-Pt, however, forms a 1,2-GG interstrand adduct with the oligonucleotide d(ATGCAT)2 resulting in a conformation change away from B-type DNA. The sugar pucker of the G3 nucleoside changes from 2[special character]-endo towards 3[special character]-endo, and the position of the nucleotide relative to the sugar changes from anti to syn. The ability of multi-nuclear platinum complexes to form covalent adducts in the DNA minor groove remains unclear. It appears that di-Pt can form up to 33% minor groove adducts with the oligonucleotide d(AT)5, but when added to the oligonucleotide d(GCCAAATTTCCG)2 no definite minor groove adducts are seen and the major adduct appears to be a 1,2-interstrand cross-link between the two A6's or between the G1 and G11. Finally, a study of the encapsulation of platinum complexes within cucurbit[7]uril (Q7) as a means of reducing drug toxicity was made. For complex A and di-Pt, encapsulation of the linker ligand occurred. The effect of Q7 on the rate of hydrolysis of di-Pt was at least a 3-fold reduction as compared to free di-Pt with guanosine. Studies with [{Pt(dien)}2[special character]-dpzm]4+/Q7 and the oligonucleotide d(CGCGAATTCGCG)2 showed that the metal complex could dissociate from the Q7 and associate with the oligonucleotide, where an equilibrium is achieved with 15 % of the metal complex bound to the oligonucleotide and 75 % encapsulated in Q7. Tests in the L1210 and L1210/DDP cancer cell lines showed that di-Pt/Q7 has almost the same activity compared to free di-Pt.
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Bugarcic, Tijana. "Ruthenium arene anti-cancer complexes." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/13265.
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This thesis is concerned with the synthesis and characterization of novel RuII arene anti-cancer complexes, containing different arenes and chelating ligands, especially arenes that can act as intercalators and chelating ligands that are redox-active. Synthesis and characterization of complexes of the type [(H6-arene)Ru(en)Cl]+, where the arene is ortho-, meta- or para-terphenyl (o-, m- or p-terp) are reported. [(H6-p-terp)Ru(en)Cl]+ has a similar potency to cisplatin and much higher activity against cancer cell lines than o- and m-terp analogues. The p-terp complex binds to DNA rapidly and quantitatively and the experimental data are consistent with combined intercalative and monofunctional (coordination) binding mode of [(H6-p-terp)Ru(en)Cl]+. The o- and m-terp analogues bind to DNA preferentially through coordination of ruthenium. The synthesis and characterization of RuII arene complexes containing 2,2’-bipyridine (bipy), 2,2’-bipyridine-3,3’-diol (bipy(OH)2) or deprotonated 2,2’-bipyridine-3,3’-diol (bipy(OH)O) as chelating ligands and different arenes are reported, including several x-ray crystal structures. In aqueous solution only the deprotonated (bipy(OH)O) form of the 2,2’-bipyridine-3,3’-diol is present in the complexes. Hydrolysis of these complexes in aqueous solution is relatively fast (37°C) and when the arene is biphenyl, initial aquation is followed by partial arene loss. Complexes with bipy(OH)O as chelating ligands, in general exhibit good cytotoxicity towards A2780 human ovarian cancer cells. Oxidation of the o-phenylenediamine (o-pda) chelating ligand in [(H6-arene)Ru(o-pda)Cl]+ to o-benzoquinonediimine (o-bqdi) leads to loss of cytotoxic activity. The x-ray crystal structures of [(H6-p-cym)Ru(o-pda)Cl][PF6] and [(H6-hmb)Ru(o-bqdi)Cl][PF6] are reported.
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Kuh, Hyo-Jeong. "Target site pharmacokinetics of anti-AIDS and anti-cancer agents /." The Ohio State University, 1997. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487943341527965.
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Lau, Kelvin Kar Wing. "Vascular targeting of anti-cancer therapy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311869.
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Cao, Siyu. "Designer bacteria as anti-cancer agents." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/366498.
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To date, cancer persists as one of the most devastating diseases worldwide. Problems such as inoperable primary tumours due to late stage diagnosis, presence of metastatic tumours, and tumour resistance to chemotherapy and radiotherapy have remarkably limited the therapeutic effects of existing treatments. To address these problems, cancer gene therapy has been under rapid development over the past two decades, which is specifically designed to deliver therapeutic genes to treat cancers using vector systems. However, the lack of an ideal vector has been a major drawback. Recent understanding of hypoxic and necrotic regions within solid malignancies and rapid development of recombinant DNA technology have reignited the idea of using anaerobic bacteria such as Clostridium as novel intra-tumoural delivery systems for anti-cancer therapeutics. These bacterial vectors have unique advantages over other delivery systems and are likely to become the vector of choice for cancer therapy in the near future. At present, Clostridium-mediated cancer therapy has shown some promising therapeutic efficacy against a number of solid malignancies, providing an opportunity for the development of novel anti-cancer gene therapies. In the last decade, targeted cancer therapy has witnessed its most impressive progress. Anti-cancer monoclonal antibodies (mAb) and recombinant immunotoxins against specific tumour cell surface antigens such as epidermal growth factor receptor (EGFR) have shown encouraging therapeutic efficacy against a large spectrum of cancers. However, difficulties such as insufficient intra-tumoural drug delivery have been preventing the therapy from reaching its full therapeutic potentials.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Lyu, Jun Fang. "Discovery of cholesterol trafficking inhibitors as novel anti-angiogenic and anti-cancer agents." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3953967.
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Deng, Zhao. "Anti-microbial and Anti-cancer activity of Traditional Chinese Medicine extracts." Thesis, Griffith University, 2020. http://hdl.handle.net/10072/401446.
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Currently, the treatment of pathogenic microbial infections involves the use of a suitable antibiotic or combination of antibiotics. Unfortunately, the development of drug resistance in microbes is a serious problem. Hence it is necessary to find alternative treatments. Traditional Chinese medicines (TCMs) have been widely used since ancient times in China to treat the diseases caused by microbial infections. This suggests that the TCMs can potentially have anti-microbial activity against selected pathogenic microbes.
This study firstly focused on the anti-microbial activity of 24 selected TCM extracts and demonstrated anti-microbial activities of several TCM extractss against three reference microbial strains (P. aeruginosa (Gram negative), S. aureus (Gram positive), and C. albicans (Fungus)). Two TCM extracts were shown to have inhibitory activity against P. aeruginosa, 14 TCM extracts were effective against S. aureus, and 3 TCM extracts were effective against the growth of C. albicans.
In addition to the development of antibiotics, TCMs also has been used as additives in health products to overcome health problems caused by microbes and improve human body health. For example, body odour is caused by the overgrowth of C. jeikeium. Thus, the treatment of body odour can be achieved by inhibiting the growth of C. jeikeium. This study tested the anti-bacterial activity of 24 selected TCM extracts against C. jeikeium, 10 of which inhibited this bacteria’s growth. Those 10 TCM extracts can be potentially used as resources from which new deodorant ingredients could be developed.
From preliminary data, three TCM extracts were selected for further investigation. Of those selected TCM extracts, TARAXACI HERBA (Pu Gong Ying, TH), which had efficacy against P. aeruginosa, was also tested for its ability to inhibit the growth of P. aeruginosa in shampoo. However, results showed that TARAXACI HERBA did not inhibit the growth of P. aeruginosa in the shampoo tested in this project.
Cancer is a disease with severe adverse effects. Multiple myeloma (MM) is an incurable blood cancer that has concerned human society for a long time. Although recent chemotherapy advances have successfully improved the overall survival of MM patients, the development of drug resistance to current treatments makes it necessary to develop a new therapy. All three selected TCMs (COPTIDIS RHIZOMA (CR), TARAXACI HERBA (TH), and LONICERAE JAPONICAE FLOS (LJF)) have previously demonstrated anti-cancer or anti-tumour activity and another TCM, which was available in our lab (Xanthium), also has reported anti-cancer activity. Thus, four TCM extracts were tested for their ability to inhibit the proliferation of myeloma cells. Results showed that all four TCM extracts inhibited the cell proliferation of three different myeloma cell line including a bortezomib (BTZ) resistant RPMI cell line. However, only CR and TH have no toxicity to human fibroblast cells when they are killing cancer cells.
A further study was conducted to determine whether the cell proliferation inhibition activity of the four TCM extracts is due to the ability to inhibit thioredoxin reductase (TrxR) activity. Although results indicate that all four TCM extracts can have significant effects on the reactive oxygen species (ROS) level in different myeloma cell lines, only treatment with LJF resulted in the inhibition of TrxR activity in myeloma cell lines. In conclusion, this project confirmed the anti-microbial activity of several TCM extracts among the original 24 selected TCMs. Interestingly, three of the TCM originally selected due to their anti-microbial activity are also able to inhibit cell proliferation of myeloma cells, including a BTZ resistant cell line. However, only one TCM extract (LJF) has the ability to inhibit TrxR activity in myeloma cells.Thesis (Masters)
Master of Science (MSc)
School of Environment and Science
Science, Environment, Engineering and Technology
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Qi, Ji. "Cane Toad Skin Extracts as Anti-Inflammatory and Anti-Cancer Agents." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/365729.
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The skin of the toads is known to be rich in bufadienolide compounds (a group of cardiac glycosides) that exhibit antitumor activity. For example, Huachansu (Cinobufacini), the aqueous extracts from the dried toad skin of Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, has been widely used in clinical therapy for various cancers in China. Clinical data have indicated that Cinobufacini may have significant anticancer activity with low toxicity and few side effects. Data to date suggest that treatment with Cinobufacini may also enhance the quality of life for patients with cancer. Huachansu contains several groups of compounds including peptides, bufadienolides/cardiac glycosides, cholesterols, indole alkaloids, bufogargarizanines, organic acid, and others. Bufadienolides, such as bufalin, cinobufagin, resibufogenin, and telocinobufagin, are responsible for the anti-cancer properties of Huachansu through disruption of the cell cycle and consequent inhibition of cell proliferation, induction of apoptosis, suppression of the NF-B pathway, immunomodulation and reversal of multi-drug resistance. The Australian cane toad (Bufo marinus) is also known as a source of bufadienolides, therefore is also considered as a new source of candidate lead compounds for drug development. Previous studies have shown that cane toad skin aqueous extracts (CTSAE) exhibited a stronger cardiac glycosides-like activity than the extracts of other organic solvents and have a suppression effect on Na+, K+‐ATPase in experimental models. However, no assay was performed to clarify the chemical constituents and pharmaceutical effects of CTSAE on cancer cells in previous studies.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Wu, Na. "Identification of anti-resorptive and anti-cancer activities of epigenetic inhibitors." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:9ae1e4e5-32b2-40e7-8249-5983d3e1bd6e.
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Multiple myeloma is a plasma cell malignancy and develops in the bone marrow. The myeloma bone disease is present in the majority of the myeloma patients and is characterised by the excessive numbers and increased resorptive functions of osteoclasts. In order to identify novel targets controlling both osteoclastogenesis and myeloma cell growth, a library of epigenetic compounds was screened in an osteoclast differentiation assay and myeloma cell viability assay. Some compound classes, such as BET bromodomain inhibitors and HDAC inhibitors, showed inhibitory effects on both osteoclast differentiation and myeloma cell proliferation, suggesting that chromatin modifying reagents are possible therapeutic targets in multiple myeloma treatment. To rapidly screen for anti-osteoclast effects, an osteoclast RANKL gene card was successfully developed and applied to selected inhibitors in osteoclast assays. Moreover, the transcriptomic analysis was used to investigate the underlying mechanisms of selected epigenetic compounds in myeloma cells, and we found that cell cycle related pathways have been regulated by several inhibitors. Furthermore, an antibody panel for CyTOF (Mass cytometry) has been developed to characterise the bone marrow microenvironment of myeloma patients, and the CyTOF experiments demonstrated that GSK-J4 and rocilinostat activate the apoptosis marker caspase3 only in myeloma cells without affecting other cell populations. GSK-J4, an inhibitor for KDM5 and KDM6, was shown to upregulate the metallothioneins and induce the ATF4-mediated stress response in myeloma cells, whereas the KDM5B inhibitors causes cell cycle arrest rather than apoptosis.
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Trapika, I. Gusti Made Gde Surya Chandra. "Anti-Cancer Activity of Dendrobium chrysotoxum in human prostate cancer cells." Thesis, The University of Sydney, 2020. https://hdl.handle.net/2123/22501.
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Dendrobium is one of the most valuable herbs in traditional Chinese medicine (TCM). It’s bibenzyl compounds demonstrate promising anti-cancer properties. Prostate cancer is the second most common cancer in men with estimated 1.1 million new cases and 0.8 million deaths per year in 2012. While Dendrobium’ anti-cancer activities has been explored in several cancer cell lines, the investigation of their bioactivity on prostate cancer is generally limited. Therefore, this thesis examines bioactivity and molecular mechanisms of selected Dendrobium species and their isolated chemical constituents in the three prostate cancer cell lines, LNCaP, an androgen dependent prostate cancer cell line, PC3 and DU-145, two non-dependent androgen cell lines. The study began with the screening of ten Dendrobium species commonly used in TCM practice, Dendrobium anosnum, D. aphyllum, D. devonianum, D. officinale, D. nobile, D. loddigesi, D. parisii, D. fimbriatum, D. aduncum, and D. chrysotoxum. Bioassay-guided fractionation techniques were applied to isolate and characterise the active compounds of the Dendrobium species that possess anti-cancer activity against the three prostate cancer cells. The crude extract of all ten Dendrobium species showed promising inhibitory effects on the three selected prostate cancer cell lines at a concentration of 20µg/mL. D. chrysotoxum exhibited the strongest anti-cancer activity which was then subjected to further investigation. Isolation, purification and elucidation procedures revealed that erianin is the predominant bibenzyl compound in D. chrysotoxum and is responsible for its anti-cancer activity. Our initial findings confirmed that erianin, is highly abundant in D. chrysotoxum, whereas other studies showed it is present in a much lower amounts in other Dendrobium species. Dendrobium species vary widely in their chemical constituents, and several factors including geographic, climatic and season of harvesting influence their quantity and quality. Hence, the almost exclusive presence of erianin in D. chrysotoxum could be applied for standardization and quality control of the anti-cancer properties of this Dendrobium species. Erianin exhibited anti-cancer activity in prostate cancer cells with an IC50 value below 50nM signifying its potency as a promising anti-cancer agent. At 24 hours of treatment, the IC50 of erianin for LNCaP cells is about twice the IC50 of PC3, while at a longer treatment times, the IC50 values of the two prostate cancer cells lines were similar, of 32.96nM for LNCaP and 36.06nM for PC3, at 72 hours of treatment. While erianin exhibits strong inhibition of cancer cell viability, erianin has no effect on the migration of either LNCaP and PC3 cells. The anti-cancer mechanism of erianin was further explored on LNCaP and PC3 cells representing the two different types in androgen dependence of prostate cancer. Erianin showed a different anti-cancer mechanism of action between the two prostate cancer cell lines. In androgen sensitive LNCaP, erianin induced apoptosis and autophagy. However, in androgen insensitive PC3 cells it induced autophagy and G2/M phase arrest. This thesis then compares erianin’s anti-cancer mechanism in prostate cancer cells with the mechanisms that have been identified in other previously studied cancer cell lines and discusses the underlying mechanism of erianin anticancer bioactivity. The anti-cancer activity of erianin on prostate cancer cell lines through induced apoptosis, autophagy and cell cycle arrest aligns with its bioactivity in other cell lines. Our study lays the essential findings of the potency of erianin against both androgen dependent and androgen independent prostate cancer cells, further elucidation of the mechanism and validation with in vivo experiments are required.
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Lau, Kai Chi. "Quantum chemical studies of anti-cancer complexes /." Zürich : ETH, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17547.
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Lam, Fong Ki. "Discovery and evaluation of anti-cancer agents." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11242/.
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Cancer is the most common cause of the human death in the UK. Every year 3.2 million Europeans are diagnosed with cancer, and the figure is projected to rise due to the aging population. Although significant advances are being made in the fight against the disease, cancer remains a key public health concern and a tremendous burden on UK society in financial and social terms. This thesis evaluated two classes of compounds that can be potentially developed as anti-cancer agents. 4-(4-Methyl-2-(methylamino)thiazol-5-yl)-2-(4-methyl-3-(morpholinosulfonyl)phenylamino)pyrimidine-5-carbonitrile (S-134, 5g) is a novel cyclin-dependent kinase 9 (CDK9) inhibitor showing nano-molar growth inhibitory potentials in established human cell lines. Biochemical assays have confirmed that S-134 primarily inhibits CDK9 at the protein and cellular levels, respectively. The detailed mechanistic investigation demonstrated that the compound caused wild-type p53 stabilisation and cell cycle arrest at the G2/M transition. Cancer cell death induced by S-134 was proven by Annexin-V/PI staining, caspase-3 assay and PARP cleavage. Transcription and expression of anti-apoptotic proteins Mcl-1, Bcl-2 and XIAP were reduced by the inhibitor, as proved by RT-PCR and Western blots respectively. Compound 2-methoxy-5-(3,4,5-trimethoxyphenethyl)phenyl 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylate-N-oxide (ZJU-6, 6g) a semi-synthetic derivative of the natural medicinal compound Erianin (6a) was designed to introduce anti-oxidant property and enhance anti-angiogenic activity of Erianin. The study of ZJU-6 revealed that while the effect of cellular growth inhibition and the transcription of Bcl-2 were reduced by the structural modification, the suppression of tubulin polymerisation and anti-angiogenic properties were enhanced compared to Erianin. Compound BI 2536, 4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (10), is one of the most potent and selective inhibitors of Polo-like kinase 1 (Plk1) and is a current experimental candidate for the treatment of cancer. A racemic BI 2536 was synthesised using multiple synthesis routes, which aimed to use as a lead compound for the discovery of novel Plk1 inhibitors.
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Davison, Zoe. "Transcutaneous delivery of anti-breast cancer agents." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/54343/.
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Breast cancer is the most common female malignancy in the western world. Currently, tamoxifen remains the gold standard anti-hormone for ER+ breast cancer. However de novo resistance to tamoxifen is a huge clinical problem. What is more, as many as 50% of initial responders develop acquired resistance to tamoxifen and relapse. Aberrant growth factor signalling has been linked to the resistant phenotype, in particular EGFR and IGF-IR signalling and often gives a more aggressive disease type and poorer patient outlook. There is a substantial clinical need for new anti-breast cancer therapeutics that target the resistant phenotype or prevent this from occurring. One hypothesis is to combine both anti-hormonal therapies with anti-EGFR therapies, in hope of preventing resistant growth. Many downstream pathways of EGFR have been targeted to develop novel therapeutics against however, these compounds are almost certain to give severe adverse reactions, furthermore a complex tablet regime or IV injections have a negative effect on patient compliance. A novel transcutaneous delivery system would give a more patient friendly alternative, with patients re-applying a patch or cream once a day, with rapid termination of dosing in the event of adverse event This would also go some way to prevent endometrial complications associated with tamoxifen use. The in vitro simultaneous delivery of 4-hydroxytamoxifen and signal transduction inhibitors LY294002 and PD98059 along with EPA determined that all compounds were capable of permeating porcine skin and nipple. Masses able to permeate were 5.14 0.93,6.97 0.99, 5.06 0.93 and 1121.6 143 μgcm2 across skin respectively and 21.14 2.75,18.2 2.55,25.1 6.89 and 3081.2 252.7 μgcm2 across porcine nipple. These compounds were formulated with 2.5% v/v DMSO and ethanol and 4% w/v Cab-o-sil. Fish oil was shown to be a skin friendly vehicle. Ki-67 assays confirmed that incubation with fish oil maintained skin viability and H & E staining confirmed no obvious histological effects. Growth Studies were performed on MCF-7 and TamR cells and showed that the combination of these compounds was able to reduce cell growth to 4.04 0.15 and 2.47 1.4 % of control growth when incubated at 25 μM PD98059 μM LY294002 x 10
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Boys, Sarah K. "Tyrosine derivatives and their anti-cancer applications." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6243.
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The incorporation of a propargyl group to a natural product target allows for a streamlined approach to the investigation of structure activity relationships (SARs) and target identification in forward chemical genetics programmes using a ‘click’-based approach. To this end, an efficient synthesis of O-propargylated tyrosine derivatives was designed, and these have been used in the construction of peptide motifs both (a) derived from phage display libraries and (b) found in natural products. The L-tyrosine derivative Y* (compound I, X=H, R=H) was incorporated into a peptide sequence, PTTIYY, which is known to prevent the inhibition of p53 by the AG-2 protein. Y* has been included as both the terminal and the internal tyrosine in the peptide sequence. ELISA assays were carried out to determine how the binding of PTTIYY* and PTTIY*Y to AG-2 compared to that of the un-marked PTTIYY sequence. The results of these assays allowed new conclusions to be drawn regarding the important binding features of the peptide and possible sites for further optimisation of the AG-2 binding properties of this peptide through ‘click’ functionalisation of the modified tyrosine. The binding of the peptides incorporating Y* was also assessed using MCF-7 breast cancer cell lysate, known to contain the AG-2 protein. These results confirmed those seen for the purified AG-2 ELISA. The related bromo-D-tyrosine derivative (compound I, X=Br, R=Me) has been prepared and employed towards the synthesis of a bisebromoamide derivative. Bisebromoamide is a newly discovered polypeptide, and a promising anti-cancer agent. The bisebromoamide derivative contains a thiazole unit (Tzl), two N-methylated amino acids, and an oxopropyl pyrrolidine (Opp) moiety, which is unique to bisebromoamide in natural products. The activity of this bisebromoamide derivative will be investigated via ‘click’-based affinity chromatography using a new supported linker recently developed within the Hulme group.
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Inman, Martyn William. "Catalytic processes in anti-cancer drug discovery." Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493304.
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The introduction (Chapter 1) reviews progress made in the last eight years in the field of multicomponent palladium-catalysed reactions, with particular attention paid to those processes which may be easily applied to the synthesis of compound libraries. The Results and Discussion (Chapters 2 to 7) provides an account of the author's work in the development of palladium-catalysed reactions of allene, and the application of such reactions to the synthesis of novel histone deacetylase inhibitors for the treatment of cancer.
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Dyer, Jolon Matthew. "Diels-Alder approaches to anti-cancer prodrugs." Thesis, University of Canterbury. Chemistry, 1998. http://hdl.handle.net/10092/6781.
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This thesis concerns the design and synthesis of compounds relevant to a new strategy for the synthesis of anti-cancer prodrugs. The focus of this strategy is Diels-Alder chemistry leading to oxygen or sulfur-bridged polycyclic adducts. Bridge cleavage of such adducts can result in the formation of polycyclic, aromatic compounds, a structure characteristic of anti-cancer drugs which act via intercalation.
Part A describes the design of a model system for the synthesis of Diels-Alder adducts as prodrugs. A range of isobenzofurans, along with a range of fumaramide and N-aryl maleimide derivatives, were synthesised, and these were reacted together in Diels-Alder fashion. The resulting adducts were bridge cleaved.
Part B describes the introduction of functional groups into Diels-Alder adducts. The functional groups investigated included alkylating and hydrogen-bonding substituents, introduced via N-aryl maleimide based dienophiles. A range of isobenzothiophenes was also synthesised, and these were used to generate sulphur-bridged Diels-Alder adducts, with the resulting increase in stability proving advantageous in some instances. A variety of functionalised adducts and their bridge cleaved derivatives were prepared. The biological properties of some showed promise as leads for the development of anti-cancer compounds.
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Kärkkäinen, Tiina Sinikka. "Synthesis of glycopeptide-based anti-cancer vaccines." Thesis, University of East Anglia, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273509.
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Cooper, Margaret S. "Anti-cancer peptides containing modified tyrosine residues." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246193.
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Soldevila, Barreda Joan Josep. "Design of catalytic organometallic anti-cancer drugs." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/63808/.
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This thesis is concerned with the design of organometallic half sandwich complexes which can catalyse the conversion of oxidised coenzyme nicotinamide adenine dinucleotide to its reduced form. The coenzyme pair NAD+/NADH is involved in many biological processes, such as regulation of the redox balance, and DNA repair. Disturbance of the NAD+/NADH ratio can lead to cell death. In particular, cancer cells are under constant oxidative stress and therefore might be more susceptible to changes in the NAD+/NADH levels. A series of neutral Ru(II) complexes of the type [(η6-arene)Ru(N,N’)(L)] (arene = p-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), benzene (bn); N,N’ = N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-toluensulfonamide (TsEn), or N-(2-aminoethyl)-4-methylensulfonamide (MsEn)) were synthesized and fully characterized. The complexes were shown by 1H-NMR to catalyse region-selectively the transfer hydrogenation of NAD+ to 1,4-NADH. Comparison of the turnover frequencies (TOF) for the complexes show a trend in which a decrease in catalytic activity with the arene ligand follows the order bn > bip > p-cym > hmb and TfEn > TsEn > MsEn. Complex [(η6-bn)Ru(TfEn)Cl] (12) was found to be the most active with a TOF of 10.4 h-1. The catalytic cycle for the transfer hydrogenation reaction was studied for complex [(p-cym)Ru(TsEn)Cl] (2). The monotosylate ethylenediamine Ru(II) complexes were used to carry out, for the first time, transfer hydrogenation reactions in cellulo (A2780 ovarian cancer cells) using formate as a hydride source. The antiproliferative activity of six complexes on co-administration with non-toxic doses of sodium formate were studied. A significant potentiation of the antiproliferative activity by formate was observed. The concentrations of NAD+ and NADH in cells showed an important reduction in the NAD+/NADH ratio. This study demonstrates that it may be possible to use catalytic transfer hydrogenation as a strategy for multi-targeted redox mechanisms of action for anticancer drugs. In order to compare the anticancer mechanism of the monotosylate ethylenediamine Ru(II) complexes with the corresponding ethylenediamine (en) complexes, DNA binding studies were carried out. The complexes were shown to bind to nucleobases only moderately strongly and no direct coordination to calf thymus DNA was observed. The complexes can destabilize DNA, but they display low affinity towards DNA, which suggests that DNA is probably not involved in the mechanism of these family of compounds. Interaction of complex [(p-cym)Ru(TsEn)] (2) with glutathione (GSH) was also studied. The complex undergoes ligand substitution. Two Ru(II) dimers were formed as the main products of the reaction: ([((p-cym)Ru)2(μ-GS)3] and [((p-cym)Ru)2(μ-GS)2]). These dimers share structural similitudes with other reported Ru(II) arene anticancer drugs, which suggests that they could be responsible for the moderate antiproliferactive activity of complex 2. A series of CpxRh(III) (CpX = CpXPhPh, CpXPh or Cp*) complexes containing en or TfEn were synthesised and fully characterised. The complexes were shown to catalyse regioselectively the transfer hydrogenation of NAD+ to 1,4-NADH with higher TOF than their Ru(II) analogues. Rh(III)-en compounds were shown to be more active than the Rh(III)-TfEn analogues. The nature of the Cpx ring was shown to influence significantly the catalytic activity of the complexes following the trend: CpXPhPh > CpXPh > Cp*. Complex [(CpXPhPh)Rh(en)Cl]+ (19) was the most active, with a TOF of 24.2 h-1. The catalytic cycle for the transfer hydrogenation reaction was studied using complex [(Cp*)Rh(en)Cl]+ (17) and compared to that of the Ru(II) analogues, and was found to be similar. Antiproliferative activity of the complexes in combination with formate, in A2780 cells, was investigated, but the potentiation due to the transfer hydrogenation was much lower than that obtained with Ru(II) compounds.
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Bennett, Ailsa. "Exploiting mitosis to improve anti-cancer strategies." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/exploiting-mitosis-to-improve-anticancer-strategies(b29182a1-2f37-47cb-8dc5-cbef76786dd2).html.
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Antimitotics are used in cancer chemotherapy for the treatment of cancers such as breast, ovarian, lung and prostate. Despite the success of agents such as Taxol, problems have emerged such as side effects, resistance and the lack of ability to predict patient responsiveness. As a result, a class of second-generation inhibitors have been developed with the aim to overcome or improve these issues. Such inhibitors target proteins and kinases involved in the control of mitosis and the cell cycle. However, these have yet to be clinically successful and therefore, this highlights the requirement for an increased understanding of the mitotic process and how antimitotics truly elicit their action. Reasons for the lack of efficacy may be due to the absence of biomarkers to stratify patients into those likely to respond to treatment. It may also be possible that other targets are required. Our understanding of the action of antimitotics is therefore paramount to improving cancer chemotherapy. By exploiting mitosis and understanding what happens when mitosis goes wrong, this thesis aims to explore new and improved methods of targeting, but also proposes to improve our understanding of the consequences of aberrant mitoses through the use of small molecule inhibitors. In the first case the thesis investigated the targeting of the spindle checkpoint protein Bub1 with 2OH-BNPP1, where previously inhibitors against the kinase were not acknowledged. However the inhibitor used was not effective in cells and therefore further experimentation was not possible. Secondly, to explore the consequences of mitotic perturbation, an assay to explore aneuploidy was established. To do this a Cenp-E inhibitor GSK923295 was synthesised, which was subsequently used in assays with the Mps1 inhibitor AZ3146 to generate aneuploidy progeny. The Cenp-E inhibitor was then used as an antimitotic agent in the final chapter to explore the mechanism of action of mitotic blockers and drivers often used in cell biology and clinical settings. Evidence suggests that the intrinsic apoptotic pathway is activated upon exposure to these agents. With focus on this pathway, the importance of Bcl-xL on cell survival was considered, revealing particular importance in the post-mitotic response. Ultimately, this thesis should contribute to devising new and improved anti-cancer strategies.
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Bire, Christophe. "Données récentes sur la vaccination anti-cancer." Paris 5, 1994. http://www.theses.fr/1994PA05P043.
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Oliva, Francisco. "The Anti-cancer Properties of Podophyllotoxin Analogues." Youngstown State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1579197212456721.
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Richardson, Monica Eilertsen. "Heterocyclic NO-donors as anti-cancer agents." Thesis, Keele University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.699674.
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Nitric oxide (NO) is involved in numerous biological processes including cancer, where this small diatomic radical can exert both pro- and anti-cancer effects. Two series of novel NO-donors were synthesised in this work, the first representing an extension to the S-nitrosothiols (RSNO) class, with the second utilising the popular 1,2,5-oxadiazole-2-oxide (furoxan) functionality. The oxathiazolylium-5-olates 39a, 39f, 39h-D, were successfully made via improved seven-step synthesis whilst a series of combretastatin-like furoxans 144a-c (NO-hybrids) were generated in a one-pot reaction. All compounds; including byproducts from failed alternative synthetic routes, had their cytotoxic activity evaluated. From this study NO-hybrid 144c showed the most promising biological profile when tested against eight different ovarian cancer cell lines.
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Ran, Yingqing. "Applications of liposomes on anti-cancer agents." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/290047.
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Toxicity is a major limitation in clinical use of most anticancer drugs. Liposomes, especially targeted long-circulating liposomes, provide the possibility of delivering drugs specifically to targeted cancer tissues, thus increasing anticancer activity and minimizing toxicity. 2-4'-Amino-3'-methylphenylbenzothiazole (AMPB), a potent anticancer drug, is inappropriate for traditional oral or parenteral formulations because of its severe dose-limiting hepatotoxicity. Several PEG-coated liposomal formulations were developed by using different drug/lipid ratios. Particle size and encapsulation efficiency of each formulation were investigated; the most stable liposomal formulation was selected for animal testing. The formulation with AMPB/egg phosphatidyl choline/cholesterol/1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-polyethylene glycol 2000, PEG2000-DSPE in a 1/5/5/1 molar ratio is the best formulation. This formulation contains 2 mg/ml AMPB with encapsulation efficiency above 95%, average particle size 120-150 nm. Daunorubicin is a well known anti cancer agent. To minimize its cardiotoxicity, targeted folate-PEG-liposomes were developed in this study. The pH-gradient loading method was used to increase the drug loading efficiency. Above 97% loading efficiency was reached by creating a 3 to 4 unit pH difference across the liposome membrane. The final folate-PEG-liposomml formulation contained 2.5 mg/ml daunorubicin HCI, with average particle size of 110∼120 nm, pH of ∼7.4, and a drug/lipid ratio 1/20 (w/w). The solvent, chloroform, commonly used for liposome preparation, is harmful to humans. Therefore, halothane, a commonly used inhalation anesthetic, was used in this study in place of chloroform to prepare liposomes. AMPB and several other proprietary anticancer agents were formulated in liposomes by using halothane and chloroform. No obvious differences in physicochemical properties were observed between halothane and chloroform mediated liposomes.
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Wong, Suk-yu. "Study of anti-cancer and anti-viral activities of lanthanide and vanadium complexes." View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36584599.
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Wong, Suk-yu, and 黃淑如. "Study of anti-cancer and anti-viral activities of lanthanide and vanadium complexes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37674547.
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Melo, Candice Soares de. "Anti-cancer and anti-malarial 4-aminoquinoline derivatives : synthesis and solid-state investigations." Master's thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/6334.
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Includes bibliographical references.The work presented in this thesis is two-fold: (i) development of single agents that provide inhibition of both the growth of malaria parasites and of tumour cells in vitro, and (ii) inclusion of these potential novel inhibitors in cyclodextrin host molecules in an attempt to render these dual drugs water-soluble. Of all the current clinically established antimalarials, the 4-aminoquinolines haveproven to be the most significant and efficacious for the treatment and prophylaxis of malaria. However, their efficacy has decreased by the spread of drug resistant strains of the causative agent Plasmodium Jalciparum. Future research into 4-aminoquinoline derivatives as antimalarial agents is still warranted and justified on the basis of several considerations. The quinoline moiety has also been shown to be a substructure in multi-drug resistance reversal agents against certain cancer cell lines and antitumour agents which have demonstrated the ability to act as differentiation-inducing agents. The strategy employed for this project was to hybridize chalcone moieties and their Mannich base derivatives with the 4-aminoquinoline moiety. This dual drug concept uses the basic structure of the chalcone scaffold, which has a wide range of known antimalarial and anticancer activities, and is hybridised with the 4-aminoquinoline moiety, in order to exert maximal biological activity and overcome or prevent drug resistance. Structural variation on the aromatic rings of the chalcone scaffold allowed preliminary structure-activity relationship studies to be undertaken.
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Studebaker, Adam Wade. "Targteing uracil exclusion mechanisms for development of anti-viral and anti-cancer therapies." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1056034774.
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Studebaker, Adam W. "Targeting uracil exclusion mechanisms for development of anti-viral and anti-cancer therapies." Connect to this title online, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1056034774.
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Thesis (Ph. D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xiii, 210 p.; also includes graphics (some col.). Includes bibliographical references (p. 174-210). Available online via OhioLINK's ETD Center
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O'Riley, Hannah Adele. "Mechanisms of the Anti-Metastatic and Cytotoxic Properties of Ruthenium Anti-Cancer Drugs." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13881.
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Despite significant advances in the treatment of primary tumours through radiotherapy, surgery and chemotherapy; treatment and prevention of metastasis remains problematic. The benefits that traditional Pt chemotherapies have had on patient outcomes have been hampered by drug resistance and severe patient side-effects. These disadvantages have spurred fresh research into other metal-based pharmaceuticals and Ru complexes have been identified as promising drugs for cancer therapy. In this work, the mechanism of action of NAMI-A, KP1019 and other Ru complexes were investigated. A series of RuII complexes containing neutral face-capping sulfur macrocycle ligands, 1,4,7-trithiacyclononane ([9]aneS3), and 1,4,7,10-tetrathiacyclododecane ([12]aneS4) were synthesized, characterized and investigated to determine the significance of the kinetically driven activity of Ru drugs. As these Ru complexes ([RuCl2([9]aneS3)(S-dmso)], [RuBr2([9]aneS3)(S-dmso)], and [RuCl([12]aneS4)(S-dmso)]Cl) have structural similarities, relationships between the kinetic rates of halido ligand substitution (determined by UV-vis spectroscopy) and in vitro activity were established. The ligand 1,4,7-trimethyltriazacyclononane (Me3tacn), is a neutral face capped ligand investigated in this work. The reactivity and biological activity of the RuII/III trimer complex [Ru3Br6(Me3tacn)2]Br was studied. Previous studies have shown that Ru complexes such as NAMI-A and KP1019 behave as pro-drugs, and that their interaction with blood serum proteins is essential to their activity. Structural properties of the adducts of Ru with various serum proteins were revealed with the use X-ray absorption spectroscopy. The nature of Ru interaction with serum proteins was investigated with gel electrophoresis X-ray fluorescence mapping. This work provided insight into the nature of the reactions that occur when Ru pro-drugs are administered intravenously, and the results of these interactions on anti-cancer activity.
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Butler, Gregory James. "Non-steroidal anti-inflammatory drugs and skin cancer /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19122.pdf.
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Bulmer, J. Todd. "Cellular responses to the anti-cancer drug, cisplatin /." *McMaster only, 2001.
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Zong, Jingyi. "The development of anti-cancer drug delivery systems." Thesis, Durham University, 2016. http://etheses.dur.ac.uk/11927/.
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Cancer is undoubtedly one of the main threats to global human health and as a result, despite significant advances in the field, new and improved cancer treatments are still in great need. Although chemotherapy (in combination with other therapies) is widely used to suppress the growth of tumours, many of the current anti-cancer drugs suffer from poor selectivity and consequently severe toxicity. In order to conquer these limitations, targeted drug delivery systems have been designed and studied with the primary aim of improving the accuracy of transporting anti-cancer drugs into cancer cells and tissue areas. The overall aim of the work presented in this thesis is to design new anti-cancer drug delivery systems using three different strategies. In Chapter 2, intelligent stimulus-responsive short elastin-like peptides (ELPs) and elastin-based side chain polymers (ESPs) were synthesised. The conformation and aggregation properties of these ELPs and ESPs were studied in different aqueous buffers (varying pH also) using ultraviolet-visible (UV-Vis) spectroscopy and circular dichroism (CD). Of the ELPs investigated, peptide 10 (N-acetylated VPGVG) was found to have the lowest transition temperature at pH 7 (i.e. 45oC). Amongst all the ESPs, PF100-GABA(VPGVG) (29) was proven to have the lowest transition temperature (47oC) which was most likely due to the fact that it had the highest molecular weight. In Chapter 3, gold nanoparticles (GNPs) were synthesised and functionalised with biomolecules including elastin-like peptides (ELPs), elastin-based side chain polymers (ESPs) and the pro-apoptotic peptide D-(KLAKLAK)2 (KLA). The hybrids materials, ELP-GNPs and ESP-GNPs were characterized by UV-Vis, CD and transmission electron microscopy (TEM). The hybrids showed the same temperature sensitive properties as the free ELPs and ESPs previously studied, confirming the successful functionalization of GNPs. The KLA-GNPs were found to have increased anti-cancer activity against HeLa cells compared to the free KLA. In Chapter 4, the pro-apoptotic KLA peptide was conjugated to a series of cell penetrating peptoids (CPPos) to prepare peptoid-peptide hybrids (CPPos-KLA). The anti-cancer, antimicrobial and cell penetrating properties of these peptoid-peptide hybrids were investigated. The results demonstrated an increasing trend in anti-cancer ability of CPPos-KLA hybrids (compared to free KLA) and KLA-CPPo6 (57) gave the lowest IC50 value (ca.8 μM) against HeLa cells.
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Oleschuk, Curtis. "Structure-activity studies of bioreductive anti-cancer agents." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0002/MQ32204.pdf.
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Faragalla, Jane Eliza. "Development of isoflavonoid-derived anti-prostatic cancer agents." Access electronically, 2005. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20060516.121728/index.html.
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Hill, Richard James. "Immunocompetent tumour model for anti-cancer adenovirus treatment." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414451.
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Hagan, Damien James. "The synthesis of novel anti-cancer acridine derivatives." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284428.
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Cook, Andrew James. "Metal catalysed approaches to novel anti-cancer agents." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411359.
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Manoharan, Gunasekar. "Anti-cancer effects of Momordica charantia in-vitro." Thesis, University of Central Lancashire, 2011. http://clok.uclan.ac.uk/2822/.
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A multitude of plants have been used extensively for the treatment of cancers throughout the world. In many parts of the world, especially in poor countries, this may be the only form of cancer therapy. Much research has been focused on the scientific evaluation of traditional anti-cancer drugs from the tropical plant; Momordica charantia (MC) is one of them and it has been used frequently as an anti-cancer agent. The green leaves, fruits, seeds and stems of M. charantia composed of many different proteins and steroids that are chemically active. These proteins are α and β momorcharins which possess anti-cancer and anti-HIV properties similar to crude water and methanol soluble extracts of M. charantia. This study investigated the anti cancer effect of either the crude water and methanol soluble extract of M. charantia, α and β and α, β momorcharins based on dose-dependent, time-dependent on the viability of 1321N1, Gos-3, U87-MG, Sk Mel, Corl -23, Weri Rb-1 and L6 cell lines employing different concentrations of each extract or drug. In addition, the study measured the effect of either temozolomide or vinblastine alone or combining each with either the crude water soluble extract of M. charantia or α β momorcharin measuring cell viability in the different cell lines. Furthermore, the present study investigated the cellular mechanism(s) via which the different anti-cancer agents were able to induce cell death measuring the activities of caspase - 3 and caspase - 9, the release of cytochrome c and intracellular free calcium concentrations [Ca 2+ ]i. The results have shown that the crude water soluble extract of M. charantia can evoke both time-course at (800 µg) and dose-dependent (200 µg - 800 µg) decreases in cell viability with maximal increases with 800 µg over a period of 24 hrs following incubation. Either the crude methanol soluble of M. charantia (200 µg - 800 µg), alpha or beta momorcharin (200 µM - 800 µM) had little or no effect on the viability of the different cell lines. In contrast, either alpha, beta momorcharin (200 µM - 800 µM), temozolomide (80 µM - 320 µM) or vinblastine (10 μg - 40 μg) can evoke significant (p < 0.05) decrease in cell viability, similar to the crude water soluble extract of M. charantia. The results also show that combining either temozolomide (240 µM) or vinblastine (40 μg) with either (800 µg) of the crude water- soluble extract of M. charantia or (800 µM) of alpha, beta momorcharin can result in significant decreases in cell viability for each cell line but these effects were neither additive or synergetic compared to the individual effect of temozolomide or vinblastine. The result of this study have also shown that either the crude water-soluble extract of M. charantia (800 µg) or (800 µM) of alpha, beta momorcharin can elicit marked and significant (p < 0.050) increases in the activities of caspase - 3 and caspase - 9 in all the cell lines. Similarly, both the crude water soluble extract of M. charantia and alpha, beta momorcharin can stimulate the release of cytochrome-c and elevated [Ca2+ ]i in the different cancer cell lines compared to untreated cell lines. Together, the results of the study have shown that either the crude water soluble extract of M. charantia or alpha, beta momorcharin can exert their anti-cancer effects (cell death) on cancer cell lines by increasing the activities of caspase - 3 and caspase - 9 and by releasing cytochrome-c and elevating [Ca2+ ]i in the cancer cells. These findings implicate the role of apoptosis and cellular Ca 2+ homeostasis in cancer cell death. Moreover, they confirm the beneficial use of extracts of M. charantia to treat cancers.
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Mehta, Shaveta. "Biomarkers of anti-angiogenic therapy in breast cancer." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:8b3869e3-fd60-450c-b165-0fe773681613.
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The hunt for biomarkers for anti-VEGF agent bevacizumab is ongoing since last decade with no success. Identifying robust biomarkers for stratifying patients and for monitoring response is important for the future use of bevacizumab in breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis and genome wide gene expression analysis are two promising approaches to understand the molecular mechanisms and search for biomarker of anti-angiogenic therapy. Firstly, with the retrospective pilot study, a close link between DCE-MRI findings and the molecular mechanisms assisting cancer survival and metastasis was established. Secondly, the prospective window of opportunity study conducted using single cycle of bevacizumab given before neoadjuvant chemotherapy and by performing detailed pharmacodynamic analyses with DCE-MRI and gene expression before and two weeks after bevacizumab had shown a wide variation in responses to bevacizmab both at genomic and imaging level. A close link between changes in DCE-MRI and the changes in gene expression profile was further established suggesting DCE-MRI has potential to serve as non-invasive biomarkers of antiangiogenic therapy. Tumours with high baseline values of forward transfer constant Ktrans showed the maximum response as assessed by DCE-MRI after bevacizumab. By performing biopsy after single cycle of bevacizumab, the changes in genes related to immune response, metabolism and cell signalling were observed that gives a useful insight into mechanisms governing response and resistance to bevacizumab. Also the certain gene expression changes observed with post bevacizumab biopsies, such as down regulation of endothelial cell specific molecule-1 (ESM1), cyclin E1 (CCNE1) and up regulation of pyruvate dehydrogenase kinase 1 (PDK1), cyclic GMP-inhibited phosphodiesterase B (PDE3B) could be helpful in decision-making about future therapy with bevacizumab at an early stage. This study has suggested that using bevacizumab in combination with other targeted agents could overcome resistance.
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Ghandhi, Laura Hester Dena. "Cobalt picolinamide complexes as potential anti-cancer agents." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/17618/.
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This thesis details the synthesis of cobalt picolinamide complexes with potential chemotherapeutic applications. The anti-cancer, anti-bacterial and anti-fungal activity of these complexes was probed, with lead complexes undergoing further mechanistic investigations. Three series of cobalt picolinamide complex were investigated: cobalt(III) trispicolinamide, cobalt(II) bis-picolinamide and cobalt(III) mixed ligand complexes. Cobalt tris-picolinamide complexes consist of a cobalt(III) ion surrounded by three picolinamide ligands, bound through the pyridyl and amide nitrogen atoms. A minor isomer with different ligand coordination was formed under certain reaction conditions, provided that an electron donating group is present as a substituent on the picolinamide ligand. The formation of cobalt bis-picolinamide complexes was also only successful when electron donating groups were present on the picolinamide ligand. These complexes contain a cobalt(II) ion with two picolinamide ligands and two axial thiocyanate ligands. The cis/trans orientation of the thiocyanate ligands varies dependent upon the position of the picolinamide ligand substituent. Mixed ligand complexes consist of a cobalt(III) ion with two picolinamide ligands and one β-diketonate or ferrocenyl β-diketonate ligand. Complexes were screened for their anti-cancer potential against a number of cell lines. Cobalt bis-picolinamide and mixed ligand complexes were non-toxic. Some cobalt tris-picolinamide complexes displayed cytotoxicity, with the minor isomer displaying greater activity than the analogous major isomer. The two lead complexes were active against cancer cells and cancer stem cells. The mechanism of action is proposed to be inhibition of cell proliferation through interruption of the cell cycle at M phase. The lead complexes did not undergo hydrolysis, in contrast to the mixed ligand complexes containing the ferrocenyl β-diketonate ligand. The lead complexes could also adsorb onto an artificial biomembrane surface, unlike the inactive complexes, implying a correlation between cytotoxicity and cellular uptake. Additionally, cobalt bis-picolinamide complexes displayed antifungal activity against C. albicans, with the thiocyanate ligands essential for activity.
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Chuang, Hsiao-Ching. "Mechanistic Validation of Potential Anti-Breast Cancer Therapeutics." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338213365.
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Sindi, Shaimaa Hesham. "Guanidine- Based HDAC-Inhibitors as Anti-Cancer Agents." University of Toledo / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1564676186975875.
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Shahi, Thakuri Pradip. "MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDS." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1574725861735168.
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Law, Ka Man. "Anti-cancer effect of ginsenosides on nasopharyngeal carcinoma." HKBU Institutional Repository, 2012. https://repository.hkbu.edu.hk/etd_ra/1383.
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Jagdev, Satinder P. K. "Anti-tumour effects of bisphosphonates in breast cancer." Thesis, University of Sheffield, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427201.
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Broughton, Laura J. "Characterisation of duramycin as an anti-cancer agent." Thesis, University of Hull, 2016. http://hydra.hull.ac.uk/resources/hull:15303.
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Duramycin is a relatively small (~2kDa) tetracyclic peptide that has a defined three-dimensional (3D) structure, this structure forms a stable binding pocket which specifically recognises the plasma membrane phospholipid phosphatidylethanolamine (PE). PE usually resides on the inner membrane layer though can become exposed on the outer membrane during physiological processes such as apoptotic cell death, cytokinesis and coagulation. Expression of cell surface PE has been observed on cancer cell lines, tumour endothelium and tumour-derived microparticles and observed in higher abundance in a variety of tumour xenografts compared to their normal tissue counterparts. There is a need in medical oncology for the development of novel, effective therapies and anti-cancer agents. A form of therapy that has gained interest is targeted anti-cancer therapy (TAT) which aims to bring about selective damage to tumour cells while limiting effect on surrounding normal tissue by utilising agents that recognise structures specific to tumours. Therefore, as duramycin had the potential to bind to PE exposed on cancer cell surfaces, it was theorised that it could be a promising targeted anti-cancer agent. Thus the aim of this project was to characterise duramycin’s anti-cancer properties and enhance its specificity to tumour cells. To achieve this a duramycin-porphyrin conjugate was developed as a novel photosensitiser and cancer cell lines were treated with photodynamic therapy (PDT). Duramycin was able to detect cell surface PE expression on cancer cell lines representing different cancer types including lymphoma, multiple myeloma and leukaemia and ovarian, pancreatic, breast and colon cancer. Duramycin was shown to have cytotoxic and anti-proliferative effects on cancer cell lines (ovarian and pancreatic), in both two-dimensional and 3D cell cultures, and a cytotoxic dose-dependent effect on a normal human endothelial cell line. Duramycin had been reported in the literature to have an effect on plasma membrane integrity and on a multitude of ion transport systems through the formation of membrane pores. Thus duramycin’s effect on cancer cell membranes was investigated along with a focus on whether the cytotoxic effect observed in the cancer cell lines was due to a form of calcium ion (Ca²⁺) overload. It was shown that duramycin treatment resulted in a concentration-dependent rise in intracellular Ca²⁺ concentration in cancer cell lines. The duramycin-porphyrin conjugate plus PDT light irradiation reduced cell proliferation of ovarian and pancreatic cancer cell lines in a dose-dependent manner and had a significantly enhanced effect over unconjugated duramycin and the free porphyrin. A preliminary investigation into the effect of duramycin-PDT treatment on tumour xenografts on the chorioallantoic membrane (CAM) of fertilised chicken eggs was undertaken with promising results. In summary, duramycin was shown to be an effective anti-cancer agent and was applicable to the PDT treatment of cancer in vitro and in a low level-in vivo tumour model and thus merits further studies.
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Shehata, Sara <1993>. "Synthesis of Anti-Metastatic Agent for Cancer Theraphy." Master's Degree Thesis, Università Ca' Foscari Venezia, 2018. http://hdl.handle.net/10579/13854.
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Breast cancer is the most common cancer in women worldwide and is the cause of millions of deaths around the world each year. The majority of breast cancer related mortalities are a result of metastatic disease involving the formation of secondary tumours where cancer cells have spread from the primary tumour to sites around the body. Among the most difficult to treat are those which belong to the basal-type, or triple-negative intrinsic molecular class as these lack the three key hormone receptors: oestrogen (ER), progesterone (PGR) and human epithelial receptor 2 (Her2) which are the targets of many of the existing, well-established targeted cancer therapeutics. Although there has been progress towards the discovery of a targeted drug for the treatment of metastatic, advanced breast cancer, to date there still remains limited options.
A current area of research interest in the treatment of metastatic disease has focused on the role in which chronic stress plays in tumour progression and the formation of metastases. Subsequently, a number of laboratory studies have shown that stress hormones play a crucial role in the progression of breast cancer and the formation of secondary tumours. It is now known that the action of stress is mediated through the stimulation of the β2-adrenergic receptor by the neurotransmitter and stress hormone norepinephrine. Furthermore, breast cancers have been found to express elevated levels of the β2-adrenergic receptor, and interestingly, the hard-to-treat basal-type (triple-negative) molecular class of breast cancers have been found to express the highest levels compared to other molecular classes.
Crucially, further studies have shown that the pro-metastatic influence of stress (via stimulation of the β2-adrenergic receptor) can be blocked by β-adrenoceptor antagonists such as Propranolol. Therefore, the retardation and potential inhibition of stress-induced breast cancer metastasis by blockade of the β2-adrenergic receptor is a potentially promising therapeutic target option.
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Guardia, Valenzuela Cristina 1990. "Cancer-associated fibroblasts and response to anti-HER2 monoclonal antibodies in breast cancer." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/668327.
Full textAbstract:
El cáncer de mama HER2-positivo es un subtipo muy agresivo. El desarrollo de terapias anti-diana HER2, particularmente el anticuerpo monoclonal (Mab) trastuzumab, supuso una mejora significativa en el pronóstico de esta enfermedad. De manera más reciente, otro Mab llamado pertuzumab, ha mejorado todavía más la eficiencia de trastuzumab. Aún y así, no todas las pacientes se beneficiarán de esta combinación de mAbs. Una proporción de estas pacientes no se beneficiarán de estas terapias anti-HER2, y fallecerán a causa de la presencia o el desarrollo de mecanismos de resistencia.
Los tumores consisten no únicamente de una población heterogénea de células tumorales; si no también del conocido como rnicroentorno tumoral (IME por sus siglas en inglés). En los últimos años, se ha evidenciado que los fibroblastos asociados al tumor (CAFs por sus siglas en inglés) (una población estroma! muy abundante dentro del TME), directamente promueven los procesos tutnorogénicos así cotno la resistencia a los fármacos. No obstante, al inicio de este proyecto de tesis doctoral, los estudios relativos sobre el papel de los CAFs en la resistencia a la terapia anti-HER2 eran escasos.
En resumen, este proyecto de tesis doctoral evidencia el papel de los fibroblastos asociado al tumor en la resistencia a la terapia anti-HER2 a través de la secreción de factores solubles que promueven la activación de mecanismos moleculares que promueven la supervivencia tumoral así como la resistencia terapéutica.HER2-positive breast cancer (BC) is an aggressive subtype of this disease. The development of anti-HER2 targeted therapies, particularly the monoclonal antibody (Mab) trastuzumab, significantly improved its otherwise poor prognosis. More recently, another Mab called pertuzumab, has further improved the efficacy of trastuzumab, yet no all patients benefit from the combination of the two Mabs. A proportion of HER2-breast cancer patients will not benefit from anti-HER2 agents, and will ultimately die as a consequence of innate or acquired drug resistance mechanisms. Tumours consist not only of heterogeneous populations of cancer cells, but also of the tumour microenvironment (TME). In recent years, increasing evidence has shown that cancer-associated fibroblasts (CAFs; an abundant stromal cell population within the TME), directly support tumorigenesis and promote therapy resistance. However, at the beginning of this PhD study, there was little published work on the role of CAFs on anti-HER2 targeted therapy resistance. The work presented in this doctoral thesis supported a role of CAFs in tumour resistance to anti-HER2 targeted therapies in HER2+ breast cancer through paracrine secretion of soluble molecules that ultimately will promote breast cancer survival and therapy resistance.
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Verghese, Jenson. "Investigations of Novel Mechanisms of Action for Anti-Bacterial and Anti-Cancer Agent Development." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/611.
Full textAbstract:
The development of drugs and therapeutic agents for combating infections and human malignancies continues to be a forefront area in both academic and industrial research. This is driven by the rapid emergence of multi-drug resistant bacterial strains and accumulating mutations in cancer targets that is quickly rendering our current arsenal of drugs ineffective for these therapies. Unless new drugs with novel mechanisms of action are identified and developed at a faster pace, we face a losing battle in managing these diseases. The first part of this work concerns with the natural product Simocyclinone D8 (SD8). Simocyclinone D8 is an angucyclinone antibiotic that inhibits DNA gyrase with a novel mechanism of action that has been termed competitive inhibition. Simocyclinone D8 was found to inhibit the growth of both Gram-(+ve) and Gram-(–ve) organisms and also inhibit a fluoroquinolone resistant mutant of DNA gyrase. Inspired by the structure and novel mechanism of action that SD8 displays, we synthesized analogues based on the co-crystal structure of SD8 with DNA gyrase. These compounds were found to inhibit DNA gyrase, albeit by a different mechanism of action than that of SD8. We also conducted studies towards the total chemical synthesis of SD8 and made three out of the four fragments in SD8 in decent yields. The second part of this work is focused on the development of a substrate-competitive covalent inhibitor for protein kinase B (AKT). AKT is a valid target for cancer research with two compounds currently in late stage clinical trials. Developing substrate- competitive inhibitors for kinases is a novel approach in targeting them, with very few examples in the literature. This mechanism has been postulated to overcome common resistance mutations that cancer targets harbor. A major drawback in this approach is the low binding affinity for peptide substrates by kinases. We circumvented this problem of affinity by utilizing a covalent mode of binding and synthesized a potent non-peptide active-site directed irreversible compound that inhibits AKT. Further studies on this compound are underway and are expected to yield a compound that can be used as a therapeutic agent or as a probe for AKT.