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

SUBMITTER: Gomez-Galeno JE 

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

REPOSITORIES: biostudies-literature