Design Of Targeted Monofunctional Platinum(?)Drugs And Study Of Their Anticancer Mechanisms

Platinum drugs are important components of anti-tumor drugs and are the most widely used metal-based drugs in clinic.Clinic-used platinum drugs,such as cisplatin,carboplatin,oxaliplatin.can cause serious side effects,such as drug resistance and systemic toxicity,which limit their clinical applications.As a traditional chemotherapeutic drug,cisplatin contains no targeting group,leading to that it is easy to accumulate in highly metabolic tissues to cause systemic toxicity;cisplatin covalently binds to DNA to cause toxicity,which is easily repaired by DNA repair mechanism,which is the main cause of drug resistance.Therefore,the search for platinum-based drugs with targeting capacity and novel anti-tumor mechanisms will be beneficial to the wider clinical application of platinum anti-tumor drugs.In this paper,three targeted monofunctional platinum drugs were designed.In the first part,a melanin-targeted terpyridine platinum complex was designed to achieve melanoma targeting and the complex possesses good anti-metastasis effect.In the second part,a mitochondrial-targeting terpyridine platinum complex was designed,which destroys the intracellular redox homeostasis and inhibits the overall energy metabolism of cancer cells.In the third part,a mitochondrial-targeting monofunctional platinum labeled with fluorescence was designed.The potential targets of platinum drugs,such as mitochondrial DNA and proteins,are explored.This thesis has achieved the selective damage of tumor cells,organelles and biomacromolecules,and proposed new mechanisms of platinum drugs,which relieved the toxicity and drug resistance,and provided new ideas for the design of platinum drugs.Advanced melanoma is not sensitive to platinum-based chemotherapeutic drugs.and melanoma is prone to mutation and drug resistance in the late stage of treatment.Platinum drugs used in clinic do not possess tumor targeting ability,and do not have high therapeutic effect on melanoma.Therefore,the design of a platinum-based drug with a novel anti-tumor mechanism and melanoma targeting capacity may improve the therapeutic effect on advanced melanoma.To this end,we constructed melanoma-targeted terpyridine platinum BTP,which targeted melanoma by targeting melanin,and showed selective cytotoxicity to melanoma cells;tripyridine platinum inhibited thioredoxin reductase(TrxR)and destroyed the redox homeostasis in the cells.The experimental results showed that the induction of oxidative stress by TrxR had led to a good inhibitory effect on the migration process of melanoma,including matrix degradation,migration,re-adhesion,invasion.Therefore,BTP possesses the potential to treat advanced melanoma.The glycolytic process is an important way for cancer cells to acquire nutrients and energy.However,there is increasing evidence that both mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis,provide nutrients and energy for the development,growth and transformation of cancer cells.In addition,when a single energy pathway is inhibited,cancer cells switch to other energy pathways to produce energy and nutrients,namely metabolic flexibility,which is an important cause of drug resistance.To this end,we constructed a mitochondrial-targeting terpyridine platinum TTP,which diturbed the redox homeostasis of mitochondria and cells by inhibiting cellular and mitochondrial TrxR,thereby simultaneously inhibiting glycolysis and OXPHOS.This design,by affecting the redox homeostasis to regulate of energy metabolism,and to block the process of cancer cells to obtain energy and nutrients,had endowed new functions and targets on traditional chemotherapy drugs.Therefore,TTP can improve the anticancer efficiency potentially in clinical.It is generally believed that platinum drugs act on nuclear DNA and covalently bind to DNA to form Pt-DNA cross-linking products,thereby inducing cell death.However,cancer cells respond to DNA damage by initiating repair mechanisms,so patients often develop resistance to platinum drugs in the late stage of treatment.Exploring new targets for platinum drugs is an important way to address this shortcoming.To this end,we constructed a monofunctional platinum RBP with mitochondrial-targeting and fluorescent-labeling ability.Using confocal imaging,we found that RBP acted on mitochondrial DNA(mtDNA)and induced an increase in mtDNA copy number.In addition,we had found fluorescence-labeled protein bands on both gel and PVDF membranes.We then identified the potential target of RBP,protein S100-A6 by peptide mass fingerprinting(PMF),and verified RBP binding by immunofluorescence.Additionally,platinum atom in the molecule accounted for the binding to Protein S100-A6.Therefore,fluorescent RBP explores potential targets for platinum drugs and provides new ideas for the design of platinum-based drugs with a new mechanism of action in the future.In summary,this thesis studies the anti-tumor mechanism of monofunctional platinum complexes by constructing tumor,organelle and biomacromolecule-targeted platinum complexes,which achieve multiple control of selective tumor inhibition and energy metabolism suppression.The exploration of non-DNA targets could alleviate the side effects and drug resistance of platinum drugs.The work of this thesis has made a preliminary exploration of new targets and new mechanisms of platinum drugs,providing a new research sight into the realization of highly selective and effective treatment of cancer.