Synthesis and Biological Evaluation of Diaryl-Substituted Carboranes as Inhibitors of Hypoxia Inducible Factor (HIF)-1 Transcriptional Activity

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 IC50 values of 3.2 and 2.2 mu M, respectively. Compounds 1 and 2 similarly suppressed hypoxia-induced HIF-1a accumulation in a concentration-dependent manner without affecting the expression level of HIF-1a mRNA. The hypoxia-induced accumulation and translocation of HIF-1a 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-1a protein under hypoxic conditions.