Capsaicin-Inspired Hydroxamate Hybrids as Selective HDAC6 Inhibitors with Antiproliferative Activity in Hematological Malignancies.

ABSTRACT: A series of capsaicin-inspired benzodioxol-benzyl-hydroxamate hybrids was synthesized in three steps with high purity (≥95%) and excellent yields (71-94%). Compounds 7a and 7c exhibited the strongest antiproliferative effects against Jurkat, Namalwa, and K-562 cells (IC₅₀ = 3.0-4.5 μM). Enzymatic assays revealed potent and selective HDAC6 inhibition in the nanomolar range (IC_{5 0} = 0.040 μM ± 0.011 for 7a and 0.007 μM ± 0.001 for 7c), with over 300- and 1600-fold selectivity versus HDAC1, respectively. Western blot confirmed target engagement through α-tubulin hyperacetylation, while molecular docking and dynamics studies supported stable bidentate zinc coordination and favorable hydrophobic interactions in the HDAC6 active site.

SUBMITTER: Gimenez Borges L 

PROVIDER: S-EPMC12903172 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature