b-Annulated 1,4-dihydropyridines as Notch inhibitors |
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Authors: | Jorge E Gómez-Galeno Cecilia Hurtado Jiongjia Cheng Ceren Yardimci Mark Mercola John R Cashman |
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Institution: | 1. Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, United States;2. Cardiovascular Institute and Department of Medicine, Stanford University, 300 Pasteur Drive, MC-5501, Stanford, CA 94305, United States |
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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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Keywords: | QXRHCJQRPJNXHT-VWLOTQADSA-N Notch Dihydropyridines Notch signaling Colorectal cancer |
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