N-Methylpropargylamine-Conjugated Hydroxamic Acids as Dual Inhibitors of Monoamine Oxidase A and Histone Deacetylase for Glioma Treatment

Samir Mehndiratta, Bin Qian, Jian Ying Chuang, Jing Ping Liou, Jean C. Shih

Research output: Contribution to journalArticlepeer-review

Abstract

Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine oxidase A (MAO A) plays a role in glioma development, and MAO A inhibitors reduce glioma growth. Histone deacetylase (HDAC) inhibition has emerged as a promising therapy for various malignancies including gliomas. We have synthesized and evaluated N-methylpropargylamine-conjugated hydroxamic acids as dual inhibitors of MAO A and HDAC. Compounds display potent MAO A inhibition with IC50 from 0.03 to <0.0001 μM and inhibit HDAC isoforms and cell growth in the micromolar to nanomolar IC50 range. These selective MAO A inhibitors increase histone H3 and α-tubulin acetylation and induce cell death via nonapoptotic mechanisms. Treatment with 15 reduced tumor size, reduced MAO A activity in brain and tumor tissues, and prolonged the survival. This first report on dual inhibitors of MAO A and HDAC establishes the basis of translational research for an improved treatment of glioma.

Original languageEnglish
Pages (from-to)2208-2224
Number of pages17
JournalJournal of Medicinal Chemistry
Volume65
Issue number3
DOIs
Publication statusPublished - Feb 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'N-Methylpropargylamine-Conjugated Hydroxamic Acids as Dual Inhibitors of Monoamine Oxidase A and Histone Deacetylase for Glioma Treatment'. Together they form a unique fingerprint.

Cite this