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Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex  1a  as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels  in cellulo  and activates HIF-1α mediated gene expression, including  VEGF ,  GLUT1 , and  EPO . In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e.  HSP-90 ,  VEGFR-1 ,  SDF-1 ,  SCF , and  Tie-2 ) are increased in the wound tissue of  1a -treated diabetic mice (including,  db / db , HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

A small molecule HIF-1α stabilizer that accelerates diabetic wound healing