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.

治疗性血管生成是一种针对后肢缺血（HLI）的潜在治疗策略；然而，目前尚无能够在临床水平上诱导其发生的具有小分子特性的药物。通过激活骨骼肌中的低氧诱导因子-1（HIF-1）通路，可诱导血管生成因子的分泌，因此，该策略被视为一种吸引人的治疗性血管生成方法。以天然糖苷化合物淫羊藿苷为引导，我们进行了一项构效关系（SAR）研究，旨在开发一种更有效且可药物化的血管生成剂。我们发现了一种新型糖苷骨架化合物（C-30），其在增强HIF-1α蛋白积累和刺激骨骼肌细胞的旁分泌功能方面优于淫羊藿苷。进而，这一发现显著提升了血管内皮细胞和平滑肌细胞的血管生成潜力，并随后在糖尿病和非糖尿病HLI小鼠中诱导成熟、功能性的血管形成。综上所述，本研究为治疗HLI提供了一种新颖且具有前景的小分子治疗策略。