Establishing a noncanonical zinc-binding group as a selective histone deacetylase inhibitor and possible novel anticancer agent.

HDAC inhibitors, which have been proven to be effective for some cancers, have potential as treatments for Non-small cell lung cancer (NSCLC). Building on the core structure of the highly selective HDAC6 inhibitor J22352, we modified various zinc-binding groups of this inhibitor. The resulting compounds 1-8 were designed and synthesized to explore potential derivatives and assess their effects on NSCLC bioactivity. Notably, compounds 2, 7, and 8 selectively inhibited HDAC6, with IC50 values of 865.4, 145.0, and 11.9 nM, respectively. Additionally, a significant synergistic interaction was observed when benzamide 6 and ethyl hydrazine 7 were combined with the chemotherapy drug etoposide. The combination index of benzamide 6 (10 μM) with etoposide (10 μM) was 0.22, in contrast to 0.01 for ethyl hydrazine 7 (30 μM) with etoposide (10 μM). Encouragingly, ethyl hydrazine 7 also demonstrated superior bioavailability (149 %) after oral administration.