TY - JOUR
T1 - Discovery of 6-Diazo-5-oxo- l -norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys
T2 - A Potential Treatment for Glioblastoma
AU - Rais, Rana
AU - Jančařík, Andrej
AU - Tenora, Lukáš
AU - Nedelcovych, Michael
AU - Alt, Jesse
AU - Englert, Judson
AU - Rojas, Camilo
AU - Le, Anne
AU - Elgogary, Amira
AU - Tan, Jessica
AU - Monincová, Lenka
AU - Pate, Kelly
AU - Adams, Robert
AU - Ferraris, Dana
AU - Powell, Jonathan
AU - Majer, Pavel
AU - Slusher, Barbara S.
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/9/22
Y1 - 2016/9/22
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.6b01069
DO - 10.1021/acs.jmedchem.6b01069
M3 - Article
C2 - 27560860
AN - SCOPUS:84988729972
SN - 0022-2623
VL - 59
SP - 8621
EP - 8633
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 18
ER -