Platinum-based anticancer drugs, such as cisplatin, carboplatin, and oxaliplatin, have been approved for world-wide clinical use for decades. Nearly 50% of all cancer therapies involve the use of them as stand-alone treatments or in combination with other medication. Despite the enormous success, their widespread application and efficacy are hindered by either cross-resistance or toxic side effects, including nephrotoxicity and neurotoxicity. The need to overcome these drawbacks has stimulated research for new Pt-based drugs. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are a pair of important enzymes in epigenetic regulation. They work in harmony to acetylate and deacetylate histone lysine residues, which result in a more relaxed or a more condensed chromatin structure, respectively. HDAC has been found to be overexpressed in some cancer cells, which condenses the chromatin structure of tumor suppressor genes, cell-cycle inhibitor genes and apoptosis inducer genes. Marmion research group has demonstrated that the use of HDAC inhibitors (HDACi) in conjunction with Pt drugs transformed their anti-cancer activity. We approached the design from a different direction by installing HDACi on the platinum (II) center as a non-leaving group ligand. When the bifunctional drug reaches the cancer cell, a synergistic effect could be maintained as the relaxed chromatin structure makes DNA more susceptible to be attacked by the Pt core. Twelve new HDACi have been synthesized and fully characterized by MS, various nuclear NMR, HPLC analysis, as well as X-ray crystallography. The IC50 value of HDAC inhibition and cell viability study on HCT-116, A549 and HeLa cell lines were comparable with SAHA and cisplatin. Biostudy of the new Pt complexes with A2780 and A2780cis cancer cell lines are under investigation.

Design, synthesis, and biostudy of bifunctional platinum complexes: Anti-cancer activity through DNA binding and HDAC inhibition

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.