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

## TL;DR

Researchers designed new compounds that selectively inhibit HDAC6, a protein linked to cancer, and showed they can stop the growth of blood cancer cells.

## Contribution

The paper introduces capsaicin-inspired hydroxamate hybrids as novel, selective HDAC6 inhibitors with strong antiproliferative effects in hematological malignancies.

## Key findings

- Compounds 7a and 7c showed strong antiproliferative activity against Jurkat, Namalwa, and K-562 cells with IC50 values of 3.0–4.5 μM.
- 7a and 7c inhibited HDAC6 with nanomolar potency and over 300- and 1600-fold selectivity over HDAC1.
- Molecular docking and Western blot confirmed HDAC6 inhibition and α-tubulin hyperacetylation, supporting their mechanism of action.

## 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 (IC5
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. 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.