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 journalArticlepeer-review

11 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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