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.

Luminescent metal complexes have found increasing use in multiple areas of science and technology, including in chemosensing, light-emitting devices and photochemistry. In particular, the use of cyclometalated iridium(III) complexes as chemosensors has received increasing attention in the recent literature. Phosphorescent metal complexes enjoy a number of advantages (e.g., long-lived phosphorescence, high quantum efficiency and modular syntheses) that render them as suitable alternatives to organic dyes for sensing a variety of analytes. This review describes recent examples of cyclometalated iridium(III) complexes that act as luminescent chemosensors for cations, anions or small molecules.

Targeting protein–protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI interfaces with organic small molecules has been found to be exceptionally challenging, and few candidates have been successfully developed into clinical drugs. Meanwhile, the striking array of distinctive properties exhibited by metal compounds renders them attractive scaffolds for the development of bioactive leads. Here, we report the identification of iridium(III) compounds as inhibitors of the H-Ras/Raf-1 PPI. The lead iridium(III) compound 1 exhibited potent inhibitory activity against the H-Ras/Raf-1 interaction and its signaling pathway in vitro and in vivo, and also directly engaged both H-Ras and Raf-1-RBD in cell lysates. Moreover, 1 repressed tumor growth in a mouse renal xenograft tumor model. Intriguingly, the Δ-enantiomer of 1 showed superior potency in the biological assays compared to Λ-1 or racemic 1. These compounds could potentially be used as starting scaffolds for the development of more potent Ras/Raf PPI inhibitors for the treatment of kidney cancer or other proliferative diseases.

A novel luminescent cyclometalated iridium(iii) complex 1 was synthesized and employed as a chemosensor for the detection of Al³⁺ ions. 1 displays a long lifetime luminescence that allow 1 to detect Al³⁺ ions in strong fluorescence media.