b-Annulated 1,4-dihydropyridines as Notch inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Gomez-Galeno, Jorge E.¹  Hurtado, Cecilia^2,3  Cheng, Jiongjia¹  Yardimci, Ceren¹  Mercola, Mark^2,3  Cashman, John R.¹ 

[1] Human BioMol Res Inst, 5310 Eastgate Mall, San Diego, CA 92121 USA

[2] Stanford Univ, Cardiovasc Inst, 300 Pasteur Dr,MC-5501, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Med, 300 Pasteur Dr,MC-5501, Stanford, CA 94305 USA

关键词: Notch;    Dihydropyridines;    Notch signaling;    Colorectal cancer;   

DOI  :  10.1016/j.bmcl.2018.09.002

来源: Elsevier

【 摘 要 】

The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal cancer, pancreatic cancer, breast cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 ( 1) is an inhibitor of the Notch pathway with an EC50 approximate to 2.5 mu M prompted us to screen a library of related analogs. After structure activity studies were conducted, racemic compound 7 was identified with an EC50 = 0.36 mu M. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50 = 0.13 mu M, or about 20-fold the potency of 1.

【 授权许可】

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