Open AccessTumor-Targeted Delivery of 6-Diazo-5-oxo-l -norleucine (DON) Using Substituted Acetylated Lysine Prodrugs
Author(s) -
Lukáš Tenora,
Jesse Alt,
Ranjeet Prasad Dash,
Alexandra J. Gadiano,
Kateřiovotná,
Vijayabhaskar Veeravalli,
Jenny Lam,
Quinn R. Kirkpatrick,
Kathryn M. Lemberg,
Pavel Majer,
Rana Rais,
Barbara S. Slusher
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b02009
Subject(s) - prodrug , chemistry , pharmacology , toxicity , glutamine , pharmacokinetics , biochemistry , amino acid , biology , organic chemistry
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; AUC 0- t = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC 0- t = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.