TY - JOUR
T1 - Tumor-Targeted Delivery of 6-Diazo-5-oxo- l -norleucine (DON) Using Substituted Acetylated Lysine Prodrugs
AU - Tenora, Lukáš
AU - Alt, Jesse
AU - Dash, Ranjeet P.
AU - Gadiano, Alexandra J.
AU - Novotná, Kateřina
AU - Veeravalli, Vijayabhaskar
AU - Lam, Jenny
AU - Kirkpatrick, Quinn R.
AU - Lemberg, Kathryn M.
AU - Majer, Pavel
AU - Rais, Rana
AU - Slusher, Barbara S.
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/4/11
Y1 - 2019/4/11
N2 - 6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by its biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON's toxicity, we synthesized a series of tumor-targeted DON prodrugs designed to circulate inert in plasma and preferentially activate over DON in tumor. Our best prodrug 6 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate) showed stability in plasma, liver, and intestinal homogenates yet was readily cleaved to DON in P493B lymphoma cells, exhibiting a 55-fold enhanced tumor cell-to-plasma ratio versus that of DON and resulting in a dose-dependent inhibition of cell proliferation. Using carboxylesterase 1 knockout mice that were shown to mimic human prodrug metabolism, systemic administration of 6 delivered 11-fold higher DON exposure to tumor (target tissue; AUC0-t = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC0-t = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.
AB - 6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by its biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON's toxicity, we synthesized a series of tumor-targeted DON prodrugs designed to circulate inert in plasma and preferentially activate over DON in tumor. Our best prodrug 6 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate) showed stability in plasma, liver, and intestinal homogenates yet was readily cleaved to DON in P493B lymphoma cells, exhibiting a 55-fold enhanced tumor cell-to-plasma ratio versus that of DON and resulting in a dose-dependent inhibition of cell proliferation. Using carboxylesterase 1 knockout mice that were shown to mimic human prodrug metabolism, systemic administration of 6 delivered 11-fold higher DON exposure to tumor (target tissue; AUC0-t = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC0-t = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.
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U2 - 10.1021/acs.jmedchem.8b02009
DO - 10.1021/acs.jmedchem.8b02009
M3 - Article
C2 - 30892035
AN - SCOPUS:85064226564
SN - 0022-2623
VL - 62
SP - 3524
EP - 3538
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 7
ER -