Discovery of Indenopyrazolesas a New Class of HypoxiaInducible Factor (HIF)-1 Inhibitors

摘要

The indenopyrazole framework was investigated as a new class of HIF-1α inhibitors. Indenopyrazole >2l was found to most strongly inhibit the hypoxia-induced HIF-1α transcriptional activity (IC50 = 0.014 μM) among all of the known compounds having relatively simple structures, unlike manassantins. Indenopyrazole >2l suppressed HIF-1α transcriptional activity without affecting both HIF-1α protein accumulation and HIF-1α/HIF-1β heterodimerization in nuclei under the hypoxic conditions, suggesting that >2l probably affected the transcriptional pathway induced by the HIF-1α/HIF-1β heterodimer.