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 - Funding Information:
This research was supported by NIH Grant R01CA193895 (to B.S.S. and R.R.), R01CA229451 (to B.S.S. and R.R.), R01NS103927 (to B.S.S. and R.R.), Bloomberg Kimmel Institute for Cancer Immunotherapy (to B.S.S. and R.R.), LTAUSA18166 by the Ministry of Education, Youth and Sports of the Czech Republic, program INTER-EXCEL- LENCE (to P.M.), and by the Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, v.v.i. (RVO 61388963).
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
VL - 62
SP - 3524
EP - 3538
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 7
ER -