Design and Synthesis of a MAO-B-Selectively Activated Prodrug Based on MPTP: A Mitochondria-Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas

作者：Sharpe Martyn A^*; Han Junyan; Baskin Alexandra M; Baskin David S

来源：ChemMedChem, 2015, 10(4): 621-628.

DOI：10.1002/cmdc.201402562

• DNA damage
• gliomas
• MAO-B
• MPTP
• prodrugs

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 75M, 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 150-180M 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.

• 出版日期2015-4