Design, Synthesis and Bioactivity Evaluation of 4,6-Disubstituted Pyrido[3,2-d]pyrimidine Derivatives as Mnk and HDAC Inhibitors.
Molecules
; 25(18)2020 Sep 21.
Article
em En
| MEDLINE
| ID: mdl-32967084
ABSTRACT
Both HDACs and Mnks play important role in translating multiple oncogenic signaling pathways during oncogenesis. As HDAC and Mnk are highly expressed in a variety of tumors; thus simultaneous inhibit HDAC and Mnk can increase the inhibition of tumor cell proliferation and provide a new way of inhibiting tumor growth. Based on the previous work and the merge pharmacophore method; we designed and synthesized a series of 4,6-disubstituted pyrido[3,2-d]pyrimidine derivatives as HDAC and Mnk dual inhibitors. Among them; compound A12 displayed good HDAC and Mnk inhibitory activity. In vitro antiproliferative assay; compound A12 exhibited the best antiproliferative activity against human prostate cancer PC-3 cells. Docking study revealed that the pyrido[3,2-d]pyrimidine framework and hydroxamic acid motif of compound A12 were essential for maintaining the activity of HDAC and Mnk. These result indicated that A12 was a potent Mnk /HDAC inhibitor and will be further researched.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Desenho de Fármacos
/
Proteínas Serina-Treonina Quinases
/
Peptídeos e Proteínas de Sinalização Intracelular
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article