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B-Annulated 1,4-dihydropyridines as Notch inhibitors.


ABSTRACT: 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???2.5??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??M. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50?=?0.13??M, or about 20-fold the potency of 1.

SUBMITTER: Gomez-Galeno JE 

PROVIDER: S-EPMC6261437 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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b-Annulated 1,4-dihydropyridines as Notch inhibitors.

Gómez-Galeno Jorge E JE   Hurtado Cecilia C   Cheng Jiongjia J   Yardimci Ceren C   Mercola Mark M   Cashman John R JR  

Bioorganic & medicinal chemistry letters 20180905 20


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 ≈ 2.5 μM prompted us to sc  ...[more]

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