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

Abstract

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.

Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy

“…Administration of chetomin suppressed the growth of xenografts in mice 64. Indenopyrazole 21, a compound containing the indenopyrazole framework, was found to strongly inhibit HIF-1α transcriptional activity without affecting HIF-1α protein accumulation and HIF-1 heterodimerization 65. YC-1, an antiplatelet aggregation agent, was shown to dissociate the binding of HIFα T-CAD to p300 co-activator, leading to the repression of HIF transcriptional activity; YC-1 could also impair HIFα protein accumulation 2666.…”

ortho-Carboranylphenoxyacetanilides as inhibitors of hypoxia-inducible factor (HIF)-1 transcriptional activity and heat shock protein (HSP) 60 chaperon activity

“…1 HSPs are classified into six families according to their molecular weights: HSP100, HSP90, HSP70, HSP60, HSP40, and small HSPs (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), with several members in each family. 2 HSP60 is a family of sequence-related proteins of $60 kDa and typically reside in the mitochondria.…”

“…[15][16][17] We have developed various HIF-1 inhibitors, including YC-1 derivatives, 18 orthocarboranylphenoxyacetanilides, 19,20 diaryl-ortho-carboranes, 21,22 and indenopyrazoles. 23 We recently identified HSP60 as a primarily target of ortho-carboranylphenoxyacetanilide (GN26361), a HIF-1a inhibitor (Fig. 1).…”

Synthesis and evaluation of N -(benzofuran-5-yl)aromaticsulfonamide derivatives as novel HIF-1 inhibitors that possess anti-angiogenic potential

“…2a). Compared with little expression in normoxia, HIF-1α protein level was greatly boosted under hypoxia, [33][34] which can be reduced by 7q in a concentration-dependent manner in MCF-7 cells (Fig. 2b-c).…”