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 (IC50 = 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. Computational ADMET analyses further supported the experimental findings. These findings identify 7a and 7c as potent and selective HDAC6 inhibitors with antiproliferative activity in hematologic tumor cells, highlighting benzodioxol-benzyl hydroxamate hybrids as promising scaffolds for anticancer drug development.