Cited by 138Glioma Diagnosis and TreatmentAmino Acid Enzymes and MetabolismSynthesis and biological activity

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, Anne +9 more·2016·Journal of Medicinal Chemistry

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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Crossref · 10.1021/acs.jmedchem.6b01069

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47 of 47 references verified0 citation errors · 0 not checkable

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  • DON was identified as a potential anti-cancer glutamine antagonist more than half a century ago, but its lack of substrate specificity caused too much off-target toxicity.

    “6-Diazo-5-oxo-l-norleucine (DON) was identified as a potential anti-cancer glutamine antagonist more than a half century ago201, but its lack of substrate specificity provided too much off-target toxicity202.”

    From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [202]

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Authors
Rais, R., Jančařík, A., Tenora, L., Nedelcovych, M., Alt, J., Englert, J., Rojas, C., Le, A., Elgogary, A., Tan, J., Monincová, L., Pate, K., Adams, R., Ferraris, D., Powell, J., Majer, P., & Slusher, B. S.
Affiliations
  • Johns Hopkins University (US)
  • Czech Academy of Sciences (CZ)
  • McDaniel College (US)
Corresponding author
  • Majer, Pavel
  • Slusher, Barbara S.
Venue
Journal of Medicinal Chemistry
Published
2016-09-06
Volume
59
Issue
18
Pages
8621-8633
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W2516129687
Cited by
138
References
47
Citations by year
2026: 11 · 2025: 16 · 2024: 20 · 2023: 22 · 2022: 14 · 2021: 18 · 2020: 7 · 2019: 14 · 2018: 11 · 2017: 5
FWCI
7.26
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • ASEP (submittedVersion, public-domain)
Funders
  • Ústav organické chemie a biochemie AV CR, v.v.i. (RVO 61388963)
  • Maryland Technology Development Corporation
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
6-diazo-5-oxo-L-norleucine, prodrugs, glioblastoma, brain drug delivery, cerebrospinal fluid, plasma stability, antitumor efficacy, systemic toxicity
MeSH terms
Animals, Haplorhini, Antimetabolites, Antineoplastic, Brain Neoplasms, Diazooxonorleucine, Female, Glioblastoma, Glutamine, Humans, Mice, Nude, Prodrugs, Mice

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