Design, synthesis and activity of novel 2,6-disubstituted purine derivatives, potential small molecule inhibitors of signal transducer and activator of transcription 3.
Eur J Med Chem
; 179: 218-232, 2019 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-31254923
ABSTRACT
Sustained activation of STAT3 is closely related to the cancer development, but the inhibitors for STAT3 overexpression are still in the clinical research stage. In this study, a series of 2,6-disubstituted purine derivatives were designed and synthesized, and their biological activities, as small molecule inhibitors of STAT3, were assessed. Compound PD26-TL07 exhibited remarkable antiproliferative activity against three cancer cell lines (IC50 values for HCT-116, SW480 and MDA-MB-231 were 1.77⯱â¯0.35, 1.51⯱â¯0.19, and 1.25⯱â¯0.38⯵M, respectively). Moreover, detailed biological assays revealed that PD26-TL07 could effectively inhibited STAT3 phosphorylation, and had little inhibition to others'. The newly discovered PD26-TL07 displayed an expecting anticancer effect both in vitro and in vivo. The molecular docking models revealed that PD26-TL07 could bind to the SH2 domain of STAT3. Three additional compounds (PD26-BZ01, PD26-TL03 and PD26-AS06) were also able to inhibit this phosphorylation. This study described novel 2,6-disubstituted purine derivatives as potent anticancer agents targeting STAT3.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Purinas
/
Desenho de Fármacos
/
Fator de Transcrição STAT3
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Bibliotecas de Moléculas Pequenas
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China