Tumor-Targeted Delivery of 6-Diazo-5-oxo-L-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00504477" target="_blank" >RIV/61388963:_____/19:00504477 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b02009" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b02009</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jmedchem.8b02009" target="_blank" >10.1021/acs.jmedchem.8b02009</a>

Result language
angličtina
Original language name
Tumor-Targeted Delivery of 6-Diazo-5-oxo-L-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry

Project
<a href="/en/project/LTAUSA18166" target="_blank" >LTAUSA18166: Tumor targeted prodrugs of glutamine antagonists</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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