Design, Synthesis, and Characterization of HDACi Derivatives with Special Stereochemistry

In designing new therapeutic candidates, it is crucial to consider stereochemistry, as diastereomers and enantiomers of chiral drugs could present distinct affinities toward various biomolecules including the targeted ones, which, in turn, affects a drug’s bioactivity and pharmacology. Among the many families of anti-cancer drugs, some platinum (Pt) agents have been modified to contain chiral ligands such as trans-1(R),2(R)-diaminocyclohexane (DACH) in oxaliplatin. Chirality of the diamine ligands has sparked unique interest in the biological activity of the Pt complexes. Research has shown the R,R-DACH-Pt isomer have better antitumor activity as compared to its S,S-enantiomer counterpart. To incorporate chirality into our ligand designs, previously synthesized histone deacetylase inhibitors (HDACi) were modified to contain S,S-, R,S-, R,R-, or S,R-DACH fragments in the protein surface recognition (cap) domain. The general synthesis scheme of the HDACi derivatives includes a substitution reaction to connect the phenyl group on the cap domain to the linker, an amine-aldehyde condensation and reduction to build the chiral fragments onto the cap, followed by a nucleophilic addition-elimination reaction for the formation of the zinc binding group, and lastly a Boc deprotection to yield the chiral HDACi. Through metalation process, Pt center was installed onto the diaminocyclohexane moiety of the HDACi ligand, resulting in the final HDACi-Pt complex with great stability. The precursors, HDACi ligands, and Pt complexes have been characterized via ESI-LTQ Mass Spectrometry and 600 MHz JEOL nuclear magnetic resonance spectrometry. Addition of the HDACi derivatives on the Pt center, as non-leaving group ligands, could allow two anticancer drugs to reach the cell nucleus at the same time, and potentially alter the reactivity of the bifunctional Pt complexes.