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

doi:10.1021/acs.jmedchem.1c01726

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

J Med Chem. 2022 Feb 10;65(3):2208-2224. doi: 10.1021/acs.jmedchem.1c01726. Epub 2022 Jan 10.

Authors

Samir Mehndiratta^{1

2

3}, Bin Qian¹, Jian-Ying Chuang³, Jing-Ping Liou^{2

4}, Jean C Shih^{1

5

6

2}

Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, United States.
² School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
³ The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
⁴ TMU Research Center of Drug Discovery, Taipei Medical University, Taipei 110, Taiwan.
⁵ Department of Integrative Anatomical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States.
⁶ USC-Taiwan Center for Translational Research, Los Angeles, California 90089, United States.

PMID: 35005974
DOI: 10.1021/acs.jmedchem.1c01726

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Glioma / drug therapy
Glioma / mortality
Histone Deacetylases / chemistry*
Histone Deacetylases / metabolism
Histones / metabolism
Humans
Hydroxamic Acids / chemistry*
Hydroxamic Acids / metabolism
Hydroxamic Acids / pharmacology
Hydroxamic Acids / therapeutic use
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Kaplan-Meier Estimate
Male
Mice
Mice, Inbred C57BL
Monoamine Oxidase / chemistry*
Monoamine Oxidase / metabolism
Pargyline / analogs & derivatives
Pargyline / chemistry
Propylamines / chemistry
Structure-Activity Relationship
Transplantation, Heterologous

Substances

Enzyme Inhibitors
Histones
Hydroxamic Acids
Isoenzymes
Propylamines
propargylamine
Pargyline
Monoamine Oxidase
Histone Deacetylases