PMID- 34939794 OWN - NLM STAT- MEDLINE DCOM- 20220207 LR - 20220207 IS - 1520-4804 (Electronic) IS - 0022-2623 (Linking) VI - 65 IP - 1 DP - 2022 Jan 13 TI - Discovery of Salidroside-Derivated Glycoside Analogues as Novel Angiogenesis Agents to Treat Diabetic Hind Limb Ischemia. PG - 135-162 LID - 10.1021/acs.jmedchem.1c00947 [doi] AB - 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-1alpha 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. FAU - Liu, Caiping AU - Liu C AUID- ORCID: 0000-0002-6365-2108 AD - Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing 400044, China. FAU - Han, Jingxuan AU - Han J AUID- ORCID: 0000-0001-5901-4464 AD - Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China. FAU - Marcelina, Olivia AU - Marcelina O AUID- ORCID: 0000-0003-0941-3314 AD - Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China. FAU - Nugrahaningrum, Dyah Ari AU - Nugrahaningrum DA AD - Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China. FAU - Huang, Song AU - Huang S AD - Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Zou, Meijuan AU - Zou M AD - Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Wang, Guixue AU - Wang G AUID- ORCID: 0000-0002-9192-8757 AD - Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing 400044, China. FAU - Miyagishi, Makoto AU - Miyagishi M AD - Molecular Composite Medicine Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8566, Japan. FAU - He, Yun AU - He Y AUID- ORCID: 0000-0002-5322-7300 AD - School of Pharmaceutical Science, Chongqing University, Chongqing 400044, China. FAU - Wu, Shourong AU - Wu S AUID- ORCID: 0000-0001-9650-5465 AD - Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing 400044, China. FAU - Kasim, Vivi AU - Kasim V AUID- ORCID: 0000-0001-9182-8230 AD - Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China. AD - State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing 400044, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211223 PL - United States TA - J Med Chem JT - Journal of medicinal chemistry JID - 9716531 RN - 0 (Angiogenesis Inducing Agents) RN - 0 (Glucosides) RN - 0 (Glycosides) RN - 0 (Phenols) RN - M983H6N1S9 (rhodioloside) SB - IM MH - Angiogenesis Inducing Agents/chemistry/*pharmacology MH - Animals MH - Diabetes Mellitus, Experimental/*complications MH - Glucosides/*chemistry MH - Glycosides/*chemistry MH - Hindlimb/*blood supply MH - Ischemia/*drug therapy/etiology/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neovascularization, Pathologic/*drug therapy/pathology MH - Phenols/*chemistry MH - Rats MH - Rats, Sprague-Dawley EDAT- 2021/12/24 06:00 MHDA- 2022/02/08 06:00 CRDT- 2021/12/23 12:17 PHST- 2021/12/24 06:00 [pubmed] PHST- 2022/02/08 06:00 [medline] PHST- 2021/12/23 12:17 [entrez] AID - 10.1021/acs.jmedchem.1c00947 [doi] PST - ppublish SO - J Med Chem. 2022 Jan 13;65(1):135-162. doi: 10.1021/acs.jmedchem.1c00947. Epub 2021 Dec 23.