Design and synthesis of a MAO-B-selectively activated prodrug based on MPTP: a mitochondria-targeting chemotherapeutic agent for treatment of human malignant gliomas

Martyn A. Sharpe, Junyan Han, Alexandra M. Baskin, David S. Baskin

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Malignant gliomas, including glioblastomas, are extremely difficult to treat. The median survival for glioblastoma patients with optimal therapeutic intervention is 15 months. We developed a novel MAO-B-selectively activated prodrug, N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propanamide (MP-MUS), for the treatment of gliomas based on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The design of neutral MP-MUS involved the use of a seeker molecule capable of binding to mitochondrial MAO-B, which is up-regulated ≥fourfold in glioma cells. Once the binding occurs, MP-MUS is converted into a positively charged moiety, P(+) -MUS, which accumulates inside mitochondria at a theoretical maximal value of 1000:1 gradient. The LD50 of MP-MUS against glioma cells is 75 μM, which is two- to threefold more potent than temozolomide, a primary drug for gliomas. Importantly, MP-MUS was found to be selectively toxic toward glioma cells. In the concentration range of 150-180 μM MP-MUS killed 90-95 % of glioma cells, but stimulated the growth of normal human astrocytes. Moreover, maturation of MP-MUS is highly dependent on MAO-B, and inhibition of MAO-B activity with selegiline protected human glioma cells from apoptosis.

Original languageEnglish (US)
Pages (from-to)621-628
Number of pages8
JournalChemMedChem
Volume10
Issue number4
DOIs
StatePublished - Apr 2015

Keywords

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Antineoplastic Agents
  • Drug Delivery Systems
  • Drug Design
  • Glioma
  • Humans
  • Mitochondria
  • Monoamine Oxidase
  • Monoamine Oxidase Inhibitors
  • Prodrugs
  • Selegiline

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

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