Development of HDACi Derivatives with Coordination Sites to Connect Pt

Cancer remains the leading cause of death worldwide. Due to the constant evolution of cancer, it is crucial for scientists to search for better treatment by developing new anticancer drug with higher potency, lower side-effect, and overcoming cross resistance. One promising approach involves concurrently targeting two biological sites, such as histone deacetylases (HDACs) and DNA. Incorporation of HDAC inhibitors onto a platinum (Pt) core as a non-leaving group may improve the potency and selectivity of both anticancer drugs and maintain the synergistic effect. The synthesis of HDACi derivatives involves connecting three parts, protein-recognition, linker and zinc-bonding domains, in a stepwise fashion. One or two amine groups were installed onto the aromatic ring in the protein recognition domain to build monodentate or bidental coordination sites to incorporate Pt. All organic precursors and derivatives were successfully synthesized and fully characterized using mass spectrometry and NMR spectroscopy. The purity was confirmed by analytical HPLC. Molecular docking studies revealed strong binding affinity of the inhibitors towards the HDAC enzymes. Future study is focusing on the metalation and bioactivities of the HDACi derivatives and Pt complexes.