Discovery of Salidroside-Derivated Glycoside Analogues as Novel Angiogenesis Agents to Treat Diabetic Hind Limb Ischemia

Therapeutic angiogenesis
is a potential therapeutic strategy for
hind limb ischemia (HLI); however, currently, there are no small-molecule
drugs capable of inducing it at the clinical level. Activating the
hypoxia-inducible factor-1 (HIF-1) pathway in skeletal muscle induces
the secretion of angiogenic factors and thus is an attractive therapeutic
angiogenesis strategy. Using salidroside, a natural glycosidic compound
as a lead, we performed a structure–activity relationship (SAR)
study for developing a more effective and druggable angiogenesis agent.
We found a novel glycoside scaffold compound (C-30) with
better efficacy than salidroside in enhancing the accumulation of
the HIF-1α protein and stimulating the paracrine functions of
skeletal muscle cells. This in turn significantly increased the angiogenic
potential of vascular endothelial and smooth muscle cells and, subsequently,
induced the formation of mature, functional blood vessels in diabetic
and nondiabetic HLI mice. Together, this study offers a novel, promising
small-molecule-based therapeutic strategy for treating HLI.