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 in | Journal of medicinal chemistry Vol. 59; no. 18; pp. 8621 - 8633 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
22.09.2016
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
ISSN | 0022-2623 1520-4804 |
DOI | 10.1021/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. |
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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 – name: Institute of Organic Chemistry and Biochemistry – 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 givenname: Rana surname: Rais fullname: Rais, Rana – sequence: 2 givenname: Andrej surname: Jančařík fullname: Jančařík, Andrej – sequence: 3 givenname: Lukáš surname: Tenora fullname: Tenora, Lukáš – sequence: 4 givenname: Michael surname: Nedelcovych fullname: Nedelcovych, Michael – sequence: 5 givenname: Jesse surname: Alt fullname: Alt, Jesse – sequence: 6 givenname: Judson surname: Englert fullname: Englert, Judson – sequence: 7 givenname: Camilo surname: Rojas fullname: Rojas, Camilo – sequence: 8 givenname: Anne surname: Le fullname: Le, Anne – sequence: 9 givenname: Amira surname: Elgogary fullname: Elgogary, Amira – sequence: 10 givenname: Jessica surname: Tan fullname: Tan, Jessica – sequence: 11 givenname: Lenka surname: Monincová fullname: Monincová, Lenka – sequence: 12 givenname: Kelly surname: Pate fullname: Pate, Kelly – sequence: 13 givenname: Robert surname: Adams fullname: Adams, Robert – sequence: 14 givenname: Dana surname: Ferraris fullname: Ferraris, Dana – sequence: 15 givenname: Jonathan surname: Powell fullname: Powell, Jonathan – sequence: 16 givenname: Pavel surname: Majer fullname: Majer, Pavel email: majer@uochb.cas.cz – sequence: 17 givenname: Barbara S surname: Slusher fullname: Slusher, Barbara S email: bslusher@jhmi.edu |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27560860$$D View this record in MEDLINE/PubMed |
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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... |
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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 |
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