期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 7, 页码 3524-3538出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b02009
关键词
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资金
- NIH [R01CA193895, R01CA229451, R01NS103927]
- Bloomberg Kimmel Institute for Cancer Immunotherapy
- Ministry of Education, Youth and Sports of the Czech Republic, program INTER-EXCEL-LENCE [LTAUSA18166]
- Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, v.v.i. [RVO 61388963]
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.
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