Discovery of 6-Diazo-5-oxo-L-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma

0464672 - ÚOCHB 2017 RIV US eng J - Journal Article
Rais, R. - Jančařík, Andrej - Tenora, Lukáš - Nedelcovych, M. - Alt, J. - Englert, J. - Rojas, C. - Le, A. - Elgogary, A. - Tan, J. - Monincová, Lenka - Pate, K. - Adams, R. - Ferraris, D. - Powell, J. - Majer, Pavel - Slusher, B. S.
Discovery of 6-Diazo-5-oxo-L-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma.
Journal of Medicinal Chemistry. Roč. 59, č. 18 (2016), s. 8621-8633. ISSN 0022-2623. E-ISSN 1520-4804
Institutional support: RVO:61388963
Keywords : phase I * glutamine metabolism * adjuvant temozolomide
Subject RIV: CC - Organic Chemistry
Impact factor: 6.259, year: 2016

The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DONs therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DONs amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.
Permanent Link: http://hdl.handle.net/11104/0263477