Synthesis and self-assembly of chemotherapeutic cisplatin analogues
The discovery of cisplatin (cis-diamminedichloroplatinum(II)) is regarded as a medical revolution in cancer therapy. Following studies have shown activity against cancers of the head, lung, ovarian, testicular, and cervical. The reaction mechanism of cisplatin is established on the intrastrand cross linking by the formation of covalent bonds with the N7 of the purine bases which causes an irregular effect impeding the normal transcription and DNA replication mechanisms of the cell. Only cisplatin and carboplatin (cis-diamimine-1,1’-cyclobutane dicarboxylate platinum) are clinically used as antitumor agents today. Carboplatin is an analogue of cisplatin and is used more often because it has a reduced amount of side effects. Analogues of cisplatin having heterocyclic compounds with aromatic N-containing ligands have shown very promising antitumor properties in vitro and in vivo in cisplatin resistant model systems. Heterocyclic compounds function as DNA intercalating agents which insert between the base pairs of the double helix unwinding it disrupting the normal function of DNA and leads to interference with gene transcriptions, gene expression, carcinogenesis, mutagenesis and cell death. This research focuses on the design and synthesis of amphiphilic molecules having a lipid hydrophobic chain containing ester functional groups and a hydrophilic head which has a platinum coordinated bond with aromatic N-containing heterocyclic compounds such as bipyridine and biquinoline to form cisplatin analogues. Amphiphilic cisplatin analogues emulsify to make micelles that project the Pt-Cl groups on the surface of the micelle. These platinum micelles may be used as alkylating-like agents, intercalating agents and as drug delivery systems that encapsulate anticancer drugs. The action of over expressed esterases will cleave the ester group found in the lipid chain and micelles. The micelles of platinum biquinoline and platinum bipyridine will disassemble by the action of the esterases releasing the anticancer drugs, the Pt-Cl will bind to the DNA and the heterocyclic rings will intercalate in the DNA disrupting the DNA structure leading to cell death.
Gonzalez Esparza, Gabriel Angel, "Synthesis and self-assembly of chemotherapeutic cisplatin analogues" (2010). ETD Collection for University of Texas, El Paso. AAI1477786.