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

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          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.

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          Author and article information

          Journal
          J. Med. Chem.
          Journal of medicinal chemistry
          American Chemical Society (ACS)
          1520-4804
          0022-2623
          Sep 22 2016
          : 59
          : 18
          Affiliations
          [1 ] Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, v.v.i. , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
          [2 ] Department of Chemistry, McDaniel College , Westminster, Maryland 21157, United States.
          Article
          10.1021/acs.jmedchem.6b01069
          27560860
          4d674615-464a-4bcb-97c5-90dbb9304f3e
          History

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