| Literature DB >> 27560860 |
Rana Rais, Andrej Jančařík1, Lukáš Tenora1, Michael Nedelcovych, Jesse Alt, Judson Englert, Camilo Rojas, Anne Le, Amira Elgogary, Jessica Tan, Lenka Monincová1, Kelly Pate, Robert Adams, Dana Ferraris2, Jonathan Powell, Pavel Majer1, Barbara S Slusher.
Abstract
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 DON's 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 DON's 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.Entities:
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Year: 2016 PMID： 27560860 DOI： 10.1021/acs.jmedchem.6b01069
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446