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

Rana Rais, Andrej Jančařík, Lukáš Tenora, Michael Nedelcovych, Jesse Alt, Judson Englert, Camilo Rojas, Quy Hoa Le Thi, Amira Elgogary, Jessica Tan, Lenka Monincová, Kelly Pate, Robert John Adams, Dana Ferraris, Jonathan Powell, Pavel Majer, Barbara Slusher

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)8621-8633
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number18
DOIs
StatePublished - Sep 22 2016

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Diazooxonorleucine
Prodrugs
Glioblastoma
Haplorhini
Glutamine
Esters
Therapeutics
Imines
Amines
Cerebrospinal Fluid
Brain

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of 6-Diazo-5-oxo- l -norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys : A Potential Treatment for Glioblastoma. / Rais, Rana; Jančařík, Andrej; Tenora, Lukáš; Nedelcovych, Michael; Alt, Jesse; Englert, Judson; Rojas, Camilo; Le Thi, Quy Hoa; Elgogary, Amira; Tan, Jessica; Monincová, Lenka; Pate, Kelly; Adams, Robert John; Ferraris, Dana; Powell, Jonathan; Majer, Pavel; Slusher, Barbara.

In: Journal of Medicinal Chemistry, Vol. 59, No. 18, 22.09.2016, p. 8621-8633.

Research output: Contribution to journalArticle

Rais, Rana ; Jančařík, Andrej ; Tenora, Lukáš ; Nedelcovych, Michael ; Alt, Jesse ; Englert, Judson ; Rojas, Camilo ; Le Thi, Quy Hoa ; Elgogary, Amira ; Tan, Jessica ; Monincová, Lenka ; Pate, Kelly ; Adams, Robert John ; Ferraris, Dana ; Powell, Jonathan ; Majer, Pavel ; Slusher, Barbara. / Discovery of 6-Diazo-5-oxo- l -norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys : A Potential Treatment for Glioblastoma. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 18. pp. 8621-8633.
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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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