Polynuclear platinum(II) complexes are promising chemotypes for the development of new anticancer agents with distinct mechanisms of action when compared to cisplatin-derived mononuclear complexes. Triplatin BBR3464 is a successful polynuclear Pt(II) complex, the only non-cisplatin analog to reach Phase II human clinical trials. However, pharmacokinetic issues derived from thiol nucleophilic attack of proteins to BBR3464 resulted in the blockage of further trials. Substitution-inert polynuclear complexes with amino substituents were designed to solve this issue. The amino-substituted complexes presented a unique mode of binding to DNA, the "phosphate clamps" and presented cytotoxicity over a panel of cancer cell lines. In this project, we intend to improve the original Ph.D. project in development in Brazil by including "anticancer applications of metal complexes with sulfonamides", since recent results of our copper(II)-sulfonamide complexes have shown their promising activities over several cancer cell lines, including sulfonamide-dependent cytotoxicity degrees. Since platinum(II)-sulfonamide complexes were also part of our project in Brazil, we are envisaging the substitution of chloride ions from Triplatin BBR3464 by sulfonamides for the development of new active molecules. The sulfonamides of this project were chosen based on their already reported biological activities and because they are scaffolds of anticancer sulfonamides in clinical use. Biophysical experiments will be performed in order to investigate the interactions of the synthesized molecules with possible targets. Cytotoxicity experiments are suggested to investigate the activity of the new polynuclear platinum-sulfonamide complexes and establish any possible structure-activity relationships that may guide the development of new drugs.
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