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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/LTAUSA18166" target="_blank" >LTAUSA18166: Nádorově cílená proléčiva glutaminových antagonistů</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

—

Svazek periodika

62

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

3524-3538

Kód UT WoS článku

000464768300023

EID výsledku v databázi Scopus

2-s2.0-85064226564