Syntheses and biological evaluation of polyamine/transition metal complexes as potential antitumor agents.

摘要

The antitumor agents, cisplatin and carboplatin exhibit broad spectrum activity against epithelial cancers, testicular and ovarian cancers, and cancers of the lung, head and neck, esophagus, bladder, cervix, and endometrium. Cisplatin forms a variety of stable bifunctional adducts with DNA that blocks replication and inhibits transcription, and treated cells undergo apoptosis characterized by cell volume reduction and chromatin condensation. Unfortunately, cisplatin, and to a lesser degree carboplatin, have substantial renal, neurologic, and emetogenic toxicities. In addition, resistance to these agents develops by three mechanisms, including reduction in cellular import, enhanced cytoplasmic detoxification and enhanced repair of DNA adducts. We reasoned that polyamine complexes of platinum would exhibit improved cellular import through use of the polyamine transport system, and would be more selectively targeted to cancer cells. Moreover a better association between the drug and the primary target DNA could be expected due to electrostatic interactions between them than simple uncharged metal compounds such as cisplatin. Water solubility of these metal complexes would also be improved due to the polycationic polyamine segment.; It has been observed that metal compounds containing rhenium, rhodium and ruthenium also bind to DNA in a manner similar to platinum analogues. Thus, to address the problems associated with cisplatin therapy, we have synthesized a series of platinum, rhenium, ruthenium and rhodium polyamine complexes as potential antitumor agents. In comparison to cisplatin, several complexes out of these displayed an enhanced antitumoral efficacy against human non small cell lung carcinoma cell lines and a quite few complexes exhibited remarkable inhibitory effects in human breast cancer cell line. These complexes may serve as interesting options for future clinical therapy for these diseases. They may also serve as useful tools in tumor imaging or as probes of the DNA conformation and DNA cleavage agents.; In this dissertation, the details of the synthetic pathways, preliminary biological evaluations and mechanistic studies of these complexes as antitumor agents have been reported.