Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 8, Pages 1776-1787Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.02.038
Keywords
Hypoxia-inducible factor (HIF); Cancer; Chemotherapy; Structure-activity relationship
Funding
- Japan Society for the Promotion of Science (JSPS)
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)
- Ministry of Health, Labour and Welfare of Japan (MHLW)
- Grants-in-Aid for Scientific Research [221S0001] Funding Source: KAKEN
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Hypoxia-inducible factor (HIF)-1 is well known as a promising target for cancer chemotherapy. By screening an in-house chemical library using a hypoxia-responsive luciferase reporter gene assay, we identified CLB-016 (1) containing 1-ethylpyrazole-3-carboxamide as a HIF-1 inhibitor (IC50 = 19.1 mu M). In a subsequent extensive structure-activity relationship (SAR) study, we developed compound 11Ae with an IC50 value of 8.1 mu M against HIF-1-driven luciferase activity. Compounds 1 and 11Ae were shown to significantly suppress the HIF-1-mediated hypoxia response, including carbonic anhydrase IX (CAIX) gene expression and migration of human sarcoma HT1080 cells. These results revealed 1-ethylpyrazole-3-carboxamide as a novel scaffold to develop promising anti-cancer drugs targeting the HIF-1 signaling pathway. (C) 2015 Elsevier Ltd. All rights reserved.
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