Design,Synthesis And Activities Of Metal Anticancer Complexes Based On Pt/Fe

Classical platinum drugs,represented by cisplatin,are widely used in cancer treatment,and the cure rate for testicular cancer is as high as 90%.However,the side effects and resistance restrict their developments seriously.The Pt drugs based on classical structure-activity relationship will produce similar cellular activity like cisplatin,and can not overcome the shortcomings of cisplatin.It is significant to develop non-classical platinum drugs to break the mode of traditional Pt?II?drugs.In this study,the lipophilic anticancer drug chlorambucil was chemically bonded to Pt?IV?prodrug to improve uptake by regulating lipophilicity,decrease the pre-target resistance of Pt?II?drugs,damage DNA dually,and improve anticancer activity synergistically?Part I:Design,synthesis and anticancer activities of Pt?IV?prodrugs based on chlorambucil?.Apart from the Pt drugs,non-platinum metal complexes have attracted widespread attention from researchers due to their unique biological properties.Based on the development of new Pt?IV?prodrugs,the endogenous metal elemental Fe was used to replace exogenous Pt,in order to design and synthesize new Fe complexes with high efficiency and low toxicity?Part 2:Design,synthesis and anticancer activities of Fe complexes based on thiazolidinone ligands?.Objective:In this work,we designed and synthesized non-classical Pt/Fe complexes based on the latest advances in metal anticancer drugs to develop novel metal antitumor drugs with high efficiency and low toxicity.Methods:?1?Design,synthesis and anticancer activities of Pt?IV?prodrugs based on chlorambucil:First,cisplatin was oxidized to tetravalent hydroxyplatinum with H₂O₂.In the presence of TBTU,the carboxyl group of chlorambucil is condensed with tetravalent hydroxyplatinum to form a novel monosubstituted/disubstituted Pt?IV?prodrug.IR,¹H-/¹³C-NMR,ESI-MS,HPLC and CV was used to characterize the structure and physicochemical properties of prodrugs.HPLC was used to simulate the release of prodrugs in the presence of reducing substances in vivo.The antitumor activity and molecular mechanism of prodrugs were investigated at the cellular level by means of MTT assay,ICP-MS,comet assay,Hoechst 33342 staining and scratch assay.The in vivo anti-tumor activity and toxicity of prodrugs were examined at the MDA-MB-231 tumor-bearing mice and H&E staining.?2?Design,synthesis and anticancer activities of Fe complexes based on thiazolidinone ligands:Fe complex crystals were obtained based on three thiazolidinone ligands with different substituents.Their structures were characterized by IR,elemental analysis,X-ray single crystal diffraction.Nuclease properties were studied by UV,Fluorescence Spectroscopy and Agarose Gel Electrophoresis.Tumor cell selectivity,growth and invasion inhibition,and molecular mechanism were studied by flow cytometry,MTT assay,ICP-MS,western blot and scratch assay.Results:?1?Design,synthesis and anticancer activities of Pt?IV?prodrugs based on chlorambucil:Two Pt?IV?prodrugs were obtained successfully,including CLB-Pt and CLB-Pt-CLB,and characterized by various means?purity>95%?.CLB-Pt-CLB would release chlorambucil and cisplatin in the presence of ascorbic acid and glutathione.Both prodrugs significantly inhibited the growth of A549,HeLa and MCF-7 cells,and better than monotherapy and combination.Especially,CLB-Pt-CLB showed strong killing effect in triple-negative breast cancer cells MDA-MB-231,up to 21-fold of that of cisplatin.Compared with cisplatin,CLB-Pt-CLB can accumulate in tumor cells in a large amount,enhance DNA damage and induce cell death.In the MDA-MB-231 xenograft tumor model,CLB-Pt-CLB presented good tumor inhibition similar to cisplatin.Different from the systemic toxicity of cisplatin,CLB-Pt-CLB had almost no observable tissue toxicity.?2?Design,synthesis and anticancer activities of Fe complexes based on thiazolidinone ligands:Three crystals were obtained successfully,and all three?complex 1-3?have good DNA binding and cleavage activities.3 had the strongest effect on HeLa cells,followed by 2 and 1.Compared with cisplatin,the tumor selectivity of iron complexes was significantly enhanced,especially for 3,which was up to 13.94-fold,partly due to the high amount of 3 in HeLa compared with LO2.Complex 1-3 caused G1 arrest in HeLa cells,down-regulated CyclinD1 effectively,and inhibited invasion and metastasis.Conclusion:Two Pt?IV?prodrugs based on chlorambucil and three Fe complex crystals based on thiazolidinone ligands were designed and synthesized successfully.The toxicity of CLB-Pt-CLB and 3 was lower than that of cisplatin.Especially,CLB-Pt-CLB improved the efficacy greatly,which provided valuable information for the development of new metal drugs with high-efficiency and low-toxic.Moreover,chlorambucil and cisplatin are clinical drugs approved by FDA.The mechanism is clear and the safety is relatively high.The preparation of prodrugs was simple and effective,and easy to realize industrial production with wide application prospect.