Synthesis And Mechanism Of Antitumor Of Platinum Complexes With Capable Of Anti-metastasis Or Tumor Cells Selectivity

Cisplatin,carboplatin and oxaliplatin are the most widely used chemotherapy drugs in clinic.Pt(Ⅱ)complexes exert anti-tumor activity by binding to DNA.Although these Pt(Ⅱ)complexes are successfully used in clinical practice,they also cause severe side effects,such as nephrotoxicity,ototoxicity,neurotoxicity,and lack activtity of anti-metastasis.Therefore,it is of practical significance to develop platinum drugs capable of anti-metastasis or tumor cells selectivity.The design of platinum drugs is related to the choice of ligands.Here we selected trans-retinoic acid(ATRA),nitric oxide donor and lipoic acid(LA)as ligands to design novel platinum complexes,and the research was carried out from two aspects of anti-metastasis and low toxicity:one is to design platinum complexes with dual functions of anti-proliferation and anti-metastasis;the other is to design platinum complexes with high antitumor activity and low toxicity.In this project,three new platinum complexes were designed and synthesized and their functions were investigated.Part one:A carboplatin analogue containing ATRA,Pt-ATRA was designed and synthesized.ATRA was linked to the leaving group of Pt-ATRA via ester bond.Upon entering in cells,Pt-ATRA released carboplatin analogue to induce apoptosis of cancer cells and ATRA to inhibit metastasis of cancer cells via intracellular hydrolysis.In vitro experiments showed that Pt-ATRA inhibited the proliferation of 4T1 cells,comparable to carboplatin,and inhibited the migration and invasion of 4T1 cells,comparable to ATRA.The in vivo antitumor and anti-metastasis effects were verified on 4T1 tumor bearing mice,and Pt-ATRA had little effect on the weight of mice.The mechanism of anti-metastasis may be related to the inhibition of stem genes in cancer stem cells.The preparation of Pt-ATRA provides a new lead compound for the development of anti-metastasis platinum drugs.Part two:A nitric oxide-releasing novle Pt(Ⅳ)complexes,Pt-furxoan was designed and sythesized.Pt-furoxan was prepared by incorporating two nitric oxide donors(furoxans)into the axial direction of oxoplatin.Pt-furoxan released NO in depend on sulfhydryl compounds,while the reduction of Pt(Ⅳ)moiety was mediated by ascorbic acid.The good release of NO in solution was detected by Griess method.The NO release in the cells was also verified by DAF-FM-DA probe,with aid of fluorescence microscope and flow cytometry.Pt-furoxan has stronger antitumor activity than cisplatin.The enhanced antitumor activity of Pt-furoxan was related to the increase of cellular uptake and the release of NO.The result of scratch test showed that Pt-furoxan could significantly inhibit the migration of 4T1 cells.The mechanism of anti-metastasis of Pt-furoxan was related to inhibition of the activity of MMP-2 and MMP-9,and inhibition of the adhesion of 4T1 to HUVECs.In vivo experiments,Pt-furoxan still showed strong anti-tumor effect.Even when the administered dose of Pt-furoxan was half of that of cisplatin,anti-tumor ability of Pt-furoxan was still stronger than that of cisplatin.Moreover,its systemic toxicity to mice was very little.It is more important that Pt-furoxan maintain the anti-metastasis effect in vivo experment.The development of Pt-furoxan provides a new strategy for the development of dual functional platinum complex with anti-proliferation and anti-metastasis.Part three:To overcome the low selectivity of platinum to tumor cells,lipoic acid was incorporated into the axial direction of oxoplatin to design and synthesize Pt-2LA.The accumulation of Pt-2LA in cells and mitochondria was studied.The results showed that the cellular uptake of Pt-2LA was 8.2 folds of that of cisplatin,while the accumulation in mitochondria of Pt-2LA was 14.6 folds of that of cisplatin,indicating that to a certain extent Pt-2LA could target mitochondria.The IC50 value of Pt-furoxan against tumor cells was over 10 times higher than that of cisplatin.Moreover the cytotoxicity of Pt-furoxan against tumor cells was significantly higher than that against normal cells,indicating that Pt-2LA exhibited good selection to cancer cells.Furthermore,a large amount of reactive oxygen species(ROS)could be released in tumor cells with treatment of Pt-2LA,but not in normal cells.The ROS released in cancer cells could contribute significantly to the cytotoxicity of Pt-2LA.The design and synthesis of Pt-2LA provides a new idea for the development of new platinum complexes with high efficiency and low toxicity.