| Cancer is the leading cause of death in global,which seriously threatens human health.Platinum-based metal drugs including cisplatin and its analogs have been widely used as anticancer agents in the clinic.However,the clinical application of platinum-based metal anticancer drugs has been greatly limited due to serious side effects,such as nephrotoxicity,ototoxicity and neurotoxicity,as well as inherent and acquired drug resistance.To overcome the shortages from the classical platinum drugs and increase the anticancer activity,extensive efforts have been devoted to develop the next generation of novel platinum-based anticancer drugs,especially the strategies based on the DNA damage repair mechanism of action of cisplatin.The main contents of this thesis are focused on the design and synthesis of new platinum complexes and investigate the mechanism of their avoidance of drug resistance.DNA damage repair mechanism is the main cause of platinum drug resistance.Therefore,avoiding DNA damage repair is conducive to overcoming drug resistance and improving the anti-tumor effect.Herein,two novel cationic monofunctional platinum(Ⅱ)complexes bearing DNA targeting moiety,cis-[Pt(NP)(NH3)2Cl]NO3,{PNP,NP=N-(2-ethylpyridine)-1,8-naphthalimide} and cis-[Pt(NPBr)(NH3)2Cl]NO3,{PNPBr,NPBr=4-Bromine-N-(2-ethylpyridine)-1,8-naphthalimide} were prepared and characterized.PNP was superior to PNPBr and cisplatin in vitro anti-proliferation activities,especially for MCF-7 cells.PNP also showed potent in vivo anticancer potency with low systemic toxicity.PNP bind to DNA with covalent and noncovalent double DNA-binder effectively.Importantly,expect for entering the nucleus,resulting in a significant DNA damage and remarkable DNA damage repair inhibition,PNP also distributed in mitochondria,inducing the mtDNA damage and affecting the downstream transcriptional level of mitochondria encoded genes.Besides,PNP disturbed the physiological processes of mitochondria and induce cell apoptosis with caspase-dependent pathways.Taken together,PNP can enhance DNA damage and avoid DNA damage repair,which has the potential to overcome cancer resistance and improve the anti-tumor activity.Based on previous experimental work on the monofunctional platinum complex,Mono-Pt,by our group,in this part,the role of mitochondria in inducing autophagic cell death were further investigated to explain the unique antitumor effects of Mono-Pt that without DNA damaging.Mono-Pt exhibited better inhibition against cisplatin-resistant ovarian cancer cells(Caov-3),and its toxicity to human normal renal epithelial cells was significantly weaker than that of cisplatin.Besides accumulates in the nucleus,it also enters in mitochondria.Mechanism studies show that Mono-Pt disrupted the oxidative respiration in mitochondria,which stimulated the increase of mitochondrial reactive oxygen species,decreased the generation of ATP,and affected energy metabolism.Further studies have shown that Mono-Pt down-regulates the expression of mRNA and protein levels of some of the downstream electron transport chain-related proteins encoded by mtDNA.Although Mono-Pt did not interact with nuclear DNA,it affects the energy metabolism of mitochondria.Mono-Pt may partially participate in the occurrence of autophagic cell death,which may provide a potential strategy to overcome the resistance of platinum complex through new mechanism.The growth and subsequent metastasis of tumors require blood vessels to supply nutrients and oxygen,and further to provide a transport route for metastasizing tumor cells.Triple-negative breast cancer(TNBC)is the most aggressive variant of breast cancers accompanied by poor prognosis owing to its high propensity for metastasis Platinum drugs are widely used in the clinical treatment of breast cancer.However,cancer cells are easily resistant to them and platinum drugs are ineffective in the treatment of post-operative metastasis.At present,there is no effective drug to treat TNBC.In this study,a Pt(Ⅳ)prodrug(PDMA)by combining a DNA damaging agent cisplatin with a vascular-disrupting agent was designed.PDMA exhibited higher cellular Pt accumulation,superior antitumor efficacy over cisplatin and displayed low toxicity in vivo;PDMA can be reduced to Pt(Ⅱ)active species and axial tumor vascular blockers through intracellular reductive species.On the one hand,the Pt(Ⅱ)species can interact with intracellular DNA to enhance the double-stranded damage effect of DNA,on the other hand,it can destroy tumor vascular network and inhibit angiogenesis,thus inhibiting the migration of cancer cells.Overall,as an attractive platinum-based prodrug with anti-metastatic and anti-angiogenic activities,PDMA is expected to overcome the resistance of cisplatin through enhancing drug uptake and further inhibit the metastasis of cancer cells by blocking the nutritional supply of tumor vesselsIn summary,different strategies were applied to study novel platinum complexes.Novel DNA-targeting monofunctional platinum complexes were designed and their anti-tumor mechanism was investigated,illuminating that introducing DNA-targeting and pyridine group could improve the cytotoxicsity and avoid the DNA damage repair to overcome drug resistance of tumors.Further study on the mechanism of the monofunctional platinum complexes reported by our group,revealing that mitochondria as the alternative targets in cells besides nuclear DNA,could participate in inducing autophagic cell death by avoiding the interaction with DNA and disrupting the mitochondrial dysfunction,ultimately overcome the drug resistance of cancer cells;in view of the problems of drug resistance,toxicity and side effects of traditional platinum drugs and their inability to inhibit the metastasis of tumors,a Pt(Ⅳ)prodrug was prepared by combining cisplatin and tumor vascular disrupting agents to defeat breast cancer through disrupting vasculature and inhibiting metastasis,so as to improve the therapeutic effect of cisplatin and overcome drug-resistant problems. |
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