Modification of N-(6-(2-methoxy-3-(4-fluorophenylsulfonamido)pyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide as PI3Ks inhibitor by replacement of the acetamide group with alkylurea.
Bioorg Med Chem
; 23(17): 5662-71, 2015 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-26210161
ABSTRACT
N-(6-(2-Methoxy-3-(4-fluorophenylsulfonamido)pyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide exhibits remarkable anticancer effects and toxicity when orally administrated. In present study, alkylurea moiety replaced the acetamide group in the compound and a series of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)urea derivatives were synthesized. The antiproliferative activities of the synthesized compounds in vitro were evaluated against four human cancer cell lines. Several compounds with potent antiproliferative activities were tested for their acute oral toxicity and their inhibitory activity against PI3Ks and mTOR. The results indicate that the compound attached a alkylurea or 2-(dialkylamino)ethylurea moiety at the 2-position of [1,2,4]triazolo[1,5-a]pyridine can retain the antiproliferative activity and the inhibitory activity against PI3Ks and mTOR. In addition, their acute oral toxicity reduced dramatically. Moreover, the results also indicate that compound 1e can efficaciously inhibit tumor growth in a mice S180 model. These findings suggest that title compounds can serve as potent PI3K inhibitors and effective anticancer agents with low toxicity.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ureia
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Inibidores de Fosfoinositídeo-3 Quinase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article