期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 22, 页码 9589-9606出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3008536
关键词
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资金
- CNRS
- Canceropole Grand Ouest axis Valorisation des produits de la mer
- Association de Recherche contre le Cancer
- Program Hubert Curien Volubilis
- Canceropole Grand-Ouest
- Association pour la Recherche sur le Cancer [ARC-1092, 5098]
- Ligue Nationale contre le Cancer (Comae Grand-Ouest)
- Institut National du Cancer project GLIOMER
The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number-of-diverse structures have been reported to inhibit CDKs and GSK-3 beta. in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates: for further development as anticancer agents.
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