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

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

  • ACS Omega. 2026 Jan 28;11(5):8415-8430. doi: 10.1021/acsomega.5c11286.
Lara Gimenez Borges 1,  Thais Nascimento de Oliveira Alves 1,  Sandra Valeria Vassiliades 1,  Jorge Antonio Elias Godoy Carlos 2,  Karoline de Barros Waitman 1,  Sebastian Hilscher 3,  Mike Schutkowski 3,  Wolfgang Sippl 3,  Maurício Temotheo Tavares 4 5,  Monica Franco Zannini Junqueira Toledo 1,  Letícia Veras Costa-Lotufo 2,  Thales Kronenberger 6 7 8,  João Agostinho Machado-Neto 2,  Roberto Parise-Filho 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
  • 2 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
  • 3 Faculty of Biosciences, Martin-Luther-University of Halle-Wittenberg, Halle/Saale 06120, Germany.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 6 Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen 72076, Germany.
  • 7 German Center for Infection Research (DZIF), Tübingen 72076, Germany.
  • 8 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland.
PMID: 41696207 DOI: 10.1021/acsomega.5c11286
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.

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