Design and synthesis of novel xyloketal derivatives and their vasorelaxing activities in rat thoracic aorta and angiogenic activities in zebrafish angiogenesis screen.
A novel series of xyloketal derivatives (1-21) were designed and prepared. The majority of the compounds demonstrated vasorelaxation action on 60 mM KCl-induced contractions rat isolated aortic rings in a concentration-dependent manner, and the action is mediated by both endothelium-independent and endothelium-dependent mechanisms. Compounds 9, 12, 13, 14, 15, and 19 showed higher vasorelaxation activities comparing with the lead compound 3. In addition, these derivatives had potential protective action against oxLDL-induced endothelial oxidative injury and enhanced NO production in HUVECs without toxic effects. The NO release was completely inhibited by eNOS inhibitor L-NAME. Furthermore, 3 significantly promoted the angiogenesis in zebrafish in a concentration-dependent manner at 0.1, 1, and 10 muM. Compounds 9, 12, 14, 16, 20, and 21 exhibited stronger angiogenic activities than 3. Therefore, xyloketal derivatives are unique compounds with multiple pharmacological properties and may have potential implications in the treatment of cardiovascular diseases.
Xu
Zhongliang
Z
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
Li
Yiying
Y
Xiang
Qi
Q
Pei
Zhong
Z
Liu
Xilin
X
Lu
Bingtai
B
Chen
Ling
L
Wang
Guanlei
G
Pang
Jiyan
J
Lin
Yongcheng
Y
D043925:Angiogenesis Inducing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015027:Zebrafish
D043925:Angiogenesis Inducing Agents; D008077:Lipoproteins, LDL; D011714:Pyrans; D014665:Vasodilator Agents; C099252:oxidized low density lipoprotein; C438053:xyloketal A; C515343:xyloketal B; D009569:Nitric Oxide