Discovery of Indenopyrazoles as a New Class of Hypoxia Inducible Factor (HIF)-1 Inhibitors

The indenopyrazole framework was investigated as a new class of HIP-la inhibitors. Indenopyrazole 21 was found to most strongly inhibit the hypoxia-induced HIF-1 alpha transcriptional activity (IC50 = 0.014 mu M) among all of the known compounds having relatively simple structures, unlike manassantins. Indenopyrazole 21 suppressed HIP-la transcriptional activity without affecting both HIF-1 alpha protein accumulation and HIF-1 alpha HIF-1 beta heterodimerization in nuclei under the hypoxic conditions, suggesting that 21 probably affected the transcriptional pathway induced by the HIF-1 alpha/HIF-1 beta heterodimer.