title: Synthesis and biological evaluation of diaryl-substituted carboranes as inhibitors of hypoxia inducible factor (HIF)-1 transcriptional activity.
abstract: Diaromatic-substituted ortho- and meta-carboranes were synthesized as mimics of manassantin A. Among the carboranes synthesized, compounds 1 and 2 showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity, with IC(50) values of 3.2 and 2.2 μM, respectively. Compounds 1 and 2 similarly suppressed hypoxia-induced HIF-1α accumulation in a concentration-dependent manner without affecting the expression level of HIF-1α mRNA. The hypoxia-induced accumulation and translocation of HIF-1α into nuclei were not observed in HeLa cells treated with compounds 1 and 2 by immunofluorescence analysis, revealing that the inhibition of hypoxia-induced HIF-1 transcriptional activity is induced by compounds 1 and 2 through a degradation pathway of the HIF-1α protein under hypoxic conditions.
authors.affiliation: Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Tokyo 171-8588, Japan.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Minegishi
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsukawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D001896:Boron Compounds / Q000737:chemistry* / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D017705:Lignans / Q000737:chemistry* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D001896:Boron Compounds; D051793:Hypoxia-Inducible Factor 1; D017705:Lignans; D012333:RNA, Messenger; C054895:manassantin A