Establishing a noncanonical zinc-binding group as a selective histone deacetylase inhibitor and possible novel anticancer agent.
Journal
Bioorganic chemistry
Journal Volume
165
Start Page
Article number 108917
ISSN
1090-2120
Date Issued
2025-10
Author(s)
Huang, Hsuan-Chun
Chen, Tse-Yu
Yeh, Tsung-Yu
Yu, Min-Hsuan
Wu, Sian-Siou
Li, Guang-Yi
Chen, Bo-Yu
Lin, Ching-Jung
Hsu, Jui-Ling
Abstract
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 IC 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.
Subjects
Benzamide
Ethyl hydrazine
Histone deacetylase (HDAC)
Non-hydroxamic acid histone deacetylase inhibitor (HDACi)
SDGs
Type
journal article