title: Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma.
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.
authors: Rana
authors: R
authors: Rais
authors: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, v.v.i. , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors: Andrej
authors: A
authors: Jančařík
authors: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, v.v.i. , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors: Lukáš
authors: L
authors: Tenora
authors: Michael
authors: M
authors: Nedelcovych
authors: Jesse
authors: J
authors: Alt
authors: Judson
authors: J
authors: Englert
authors: Camilo
authors: C
authors: Rojas
authors: Anne
authors: A
authors: Le
authors: Amira
authors: A
authors: Elgogary
authors: Jessica
authors: J
authors: Tan
authors: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, v.v.i. , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors: Lenka
authors: L
authors: Monincová
authors: Kelly
authors: K
authors: Pate
authors: Robert
authors: R
authors: Adams
authors: Department of Chemistry, McDaniel College , Westminster, Maryland 21157, United States.
authors: Dana
authors: D
authors: Ferraris
authors: Jonathan
authors: J
authors: Powell
authors: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, v.v.i. , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors: Pavel
authors: P
authors: Majer
authors: Barbara S
authors: BS
authors: Slusher
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000134:cerebrospinal fluid* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003980:Diazooxonorleucine / Q000134:cerebrospinal fluid* / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003980:Diazooxonorleucine; D005973:Glutamine