title: Development of hypoxia-inducible factor (HIF)-1α inhibitors: effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia.
abstract: A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI(50)) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC(50): 1.9 ± 0.4 and 1.4 ± 0.2 μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC(50): 6.80 ± 0.25 μM) and this inhibition activity was higher than that of ETB (IC(50): 10.9 ± 0.63 μM).
authors.affiliation: Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Tokyo 171-8588, Japan. hiroyuki.nakamura@gakushuin.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yasui
authors.forename: Minako
authors.initials: M
authors.lastname: Maruyama
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Minegishi
authors.forename: Hyun Seung
authors.initials: HS
authors.lastname: Ban
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000693:Anaerobiosis / Q000502:physiology; D000818:Animals; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001896:Boron Compounds / Q000737:chemistry*; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D013552:Swine; D019772:Topotecan / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D016227:Benzoquinones; D001896:Boron Compounds; D001897:Boronic Acids; D004791:Enzyme Inhibitors; C549649:GN 26361; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D019772:Topotecan