Design of dual-action & selective Histone
Deacetylase enzyme inhibitors

Abstract

Carcinogenesis cannot be explained only by genetic alterations. Epigenetic processes such as histone modification via (de)acetylation play a key role in gene expression, where overexpression of histone deacetylase (HDAC) enzymes, can result in aberrant transcription of
key genes regulating important cellular functions such as cell proliferation, cell‐cycle regulation and apoptosis. Herein we report the synthesis of novel organometallic HDAC inhibitors based upon copper(II) and ruthenium(II), with a view to designing new anticancer agents. An emerging area in the field of HDAC inhibitors is the design of dual-action inhibitors, focussing on the inclusion of copper(II) into the design to harness the DNA targeting and therapeutic effects of copper(II) generally, in addition to the potency of drugs inhibiting HDAC enzymes. In this study a novel copper(II) complex, dichloro(N20-hydroxy-N11-(1,10-phenanthrolin-5-yl)octanediamide)copper(II), was synthesised, inhibiting HDAC activity by 50% in-vitro at a lower concentration than clinically approved vorinostat (SAHA), attributing an IC50 = 0.32 ± 0.02 µM, compared to SAHA’s IC50 = 0.70 ± 0.05 µM.

There is a growing body of evidence to suggest that enhanced potency of HDAC inhibitors lies in the design of inhibitors that selectivity inhibit particular HDAC enzymes within the family of 11 zinc-dependent HDACs. The ability of selective recognition using organometallics has been realised through the design of piano stool ruthenium complexes, where variation in the capping arene leads to differences in HDAC isoform selectivity. We report the synthesis of 11 novel
ruthenium(II) piano stool complexes which are awaiting a series of HDAC selectivity assays to determine their superior potency.

Overall, this study illustrates the crucial importance of HDAC inhibitors in oncology, the
tuneability of such complexes, and the remaining potential of these inhibitors in the design of dual-action and enzyme-selective analogues.