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

研究成果: 雜誌貢獻文章同行評審

1 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)2208-2224
頁數17
期刊Journal of Medicinal Chemistry
65
發行號3
DOIs
出版狀態已發佈 - 2月 2022

ASJC Scopus subject areas

  • 分子醫學
  • 藥物發現

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