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Synthesis and Biological Evaluation of Diaryl‐Substituted Carboranes as Inhibitors of Hypoxia Inducible Factor (HIF)‐1 Transcriptional Activity
Author(s) -
Minegishi Hidemitsu,
Matsukawa Takuya,
Nakamura Hiroyuki
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200502
Subject(s) - hypoxia (environmental) , chemistry , hela , chromosomal translocation , transcriptional activity , messenger rna , microbiology and biotechnology , biochemistry , stereochemistry , gene expression , oxygen , gene , biology , cell , organic chemistry
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 μ M , 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.