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

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 m...

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Published inJournal of medicinal chemistry Vol. 59; no. 18; pp. 8621 - 8633
Main Authors Rais, Rana, Jančařík, Andrej, Tenora, Lukáš, Nedelcovych, Michael, Alt, Jesse, Englert, Judson, Rojas, Camilo, Le, Anne, Elgogary, Amira, Tan, Jessica, Monincová, Lenka, Pate, Kelly, Adams, Robert, Ferraris, Dana, Powell, Jonathan, Majer, Pavel, Slusher, Barbara S
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 22.09.2016
Amer Chemical Soc
Subjects
Online AccessGet full text
ISSN0022-2623
1520-4804
DOI10.1021/acs.jmedchem.6b01069

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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.
AbstractList 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 DONs 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 DONs 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.
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.
Author Tenora, Lukás
Monincová, Lenka
Ferraris, Dana
Englert, Judson
Pate, Kelly
Rojas, Camilo
Tan, Jessica
Jančařík, Andrej
Elgogary, Amira
Powell, Jonathan
Alt, Jesse
Majer, Pavel
Rais, Rana
Le, Anne
Nedelcovych, Michael
Slusher, Barbara S
Adams, Robert
AuthorAffiliation Department of Chemistry
Pathology
Czech Academy of Sciences, v.v.i
Molecular and Comparative Pathobiology
Institute of Organic Chemistry and Biochemistry
McDaniel College
Johns Hopkins Drug Discovery
Oncology
Departments of Neurology
Johns Hopkins School of Medicine
AuthorAffiliation_xml – name: Pathology
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– name: Department of Chemistry
– name: Johns Hopkins School of Medicine
– name: Czech Academy of Sciences, v.v.i
– name: Johns Hopkins Drug Discovery
– name: Oncology
– name: Departments of Neurology
– name: McDaniel College
– name: Molecular and Comparative Pathobiology
Author_xml – sequence: 1
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/27560860$$D View this record in MEDLINE/PubMed
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Keywords SURVIVAL
DESIGN
CONCOMITANT
PROLIFERATION
HUMAN GLIOMA
RADIOTHERAPY
INHIBITOR
PHASE-I
GLUTAMINE-METABOLISM
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SSID ssj0003123
Score 2.5276563
Snippet 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...
Source Web of Science
SourceID pubmed
webofscience
crossref
acs
SourceType Index Database
Enrichment Source
Publisher
StartPage 8621
SubjectTerms Animals
Antimetabolites, Antineoplastic - cerebrospinal fluid
Antimetabolites, Antineoplastic - therapeutic use
Brain Neoplasms - drug therapy
Brain Neoplasms - metabolism
Chemistry, Medicinal
Diazooxonorleucine - cerebrospinal fluid
Diazooxonorleucine - therapeutic use
Female
Glioblastoma - drug therapy
Glioblastoma - metabolism
Glutamine - metabolism
Haplorhini
Humans
Life Sciences & Biomedicine
Mice
Mice, Nude
Pharmacology & Pharmacy
Prodrugs - pharmacokinetics
Prodrugs - therapeutic use
Science & Technology
Title Discovery of 6‑Diazo-5-oxo‑l‑norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma
URI http://dx.doi.org/10.1021/acs.jmedchem.6b01069
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https://www.ncbi.nlm.nih.gov/pubmed/27560860
Volume 59
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