B-Annulated 1,4-dihydropyridines As Notch Inhibitors

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2018 Sep 12

PMID 30201292

Citations 5

Authors

Jorge E Gomez-Galeno

Cecilia Hurtado

Jiongjia Cheng

Ceren Yardimci

Mark Mercola

John R Cashman

Affiliations

Soon will be listed here.

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.

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