Synthesis and bioactivity evaluation of ferrocene-based hydroxamic acids as selective histone deacetylase 6 inhibitors

Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes and emerges as a promising target for treating cancer and neurodegenerative diseases. Benefited from the unique sandwich conformation of ferrocene, a series of ferrocene-based hydroxamic acids have been developed as novel HDAC6 inhibitors in this paper, especially the two ansa-ferrocenyl complexes with IC50s at the nanomolar level. [3]-Ferrocenophane hydroxamic acid analog II-5 displays the most potent inhibitory activity on HDAC6 and establishes remark-able selectivity towards other HDAC isoforms. Compound II-5 dose-dependently induces accumulation of acet-ylated alpha-tubulin while having a negligible effect on the level of acetylated Histone H3, confirming its isoform selectivity. Further biological evaluation of II-5 on cancer cells corroborates its antiproliferative effect, which mainly contributed to the induction of cellular apoptosis. It is worth noting that compound II-5 demonstrates an optimal profile on human plasma stability. These results strengthen ferrocene's unique role in developing se-lective protein inhibitors and indicate that compound II-5 may be a suitable lead for further evaluation and development for treating HDAC6-associated disorders and diseases.

Automated summary

This paper develops a series of ferrocene-based hydroxamic acids as novel HDAC6 inhibitors. The two ansa-ferrocenyl complexes show the most potent inhibition activity at the nanomolar level. Compound II-5 displays the highest inhibitory activity on HDAC6 and selective towards other HDAC isoforms. It induces cellular apoptosis in cancer cells and demonstrates optimal human plasma stability, making it a suitable lead for further evaluation and development in treating HDAC6-associated disorders and diseases.