title: Design, Synthesis and Biological Evaluation of Novel HIF1α Inhibitors.
abstract: Elevated levels of hypoxia inducible factor-1 (HIF1) are linked to tumor metastasis, angiogenesis, poor patient prognosis and response to chemotherapy. HIF1α is a master regulator of the hypoxic response, including in cancer cells, through transcriptional activation of several target genes. Previously, we identified compound CJ-3k with high anti-HIF1α activity based on the structure of a well-known HIF1α inhibitor, YC-1. In this study, the CJ-3k scaffold was systematically modified to explore the structure-activity relationships. Fifty-three new CJ-3k analogs were synthesized and screened for their anti-HIF-1α activity in a luciferase-transfected human breast cancer cell line (MDA-MB-231). Some of these new analogs have a significantly greater activity than that of CJ-3k and hold potential for development as new therapeutic agents for the treatment of cancer.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Georgina N
authors.initials: GN
authors.lastname: Masoud
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, U.S.A. Department of Pharmaceutical Sciences, School of Pharmacy, South College, Knoxville, TN, U.S.A.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Duane
authors.initials: D
authors.lastname: Miller
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, U.S.A. wli@uthsc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: HIF-1α inhibitors; Hypoxia; benzimidazoles; breast cancer