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

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.

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

“…Another interesting idea is based on the high activity of one of the isoforms of monoamine oxidases (MAO), MAO-B in GBM [131]. Monoamine oxidase-B is located on the outer mitochondrial membrane, it is normally highly expressed by astrocytes and oxidizes various amines and other molecules.…”

Pharmacokinetics of Selegiline in a Rabbit Model

“…Lifespan was prolonged [9][10][11][12], the cognitive function [13] and sexual activity of rats were definitely improved by chronic treatments of selegiline, which were reported in a number of in vivo studies [14][15][16]. Nowadays, these effects are summarized as senolytic [17]. According to Kitani et al [9] the lifespan-prolongating effect of selegiline can be explained by its upregulating effect in the dopaminergic brain areas of several animal species (mice, rats, hamsters and dogs) on the activity of anti-oxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD).…”

Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

“…A full description of the synthesis and characterization of MP-MUS has been recently published by our laboratory ( Sharpe et al, 2015 ). The synthetic route taken for the synthesis of MP-MUS that was used in our initial work is found in Supplemental Experimental Procedure 2.…”

“…Based on the high levels of MAOB in the mitochondria of glioma cells, MP-MUS is expected to have increased specificity for glioblastoma cells. We have recently shown that MP-MUS is a MAOB specific substrate and that the oxidized product, P + -MUS, is indeed toxic toward cultured glioblastoma cells, but not normal human astrocytes ( Sharpe et al, 2015 ).…”