Design, synthesis and biological evaluation of dehydroabietic acid derivative as potent vasodilatory agents

编号 020037201

推送时间 20221205

研究领域 林产化工 

年份 2022 

类型 期刊 

语种 英语

标题 Design, synthesis and biological evaluation of dehydroabietic acid derivative as potent vasodilatory agents

来源期刊 Bioorganic Chemistry

期 第372期

发表时间 20221201

关键词 Dehydroabietic acid;  Vasodilation;  Inflammation;  Endothelial nitric oxide synthasec;  GMP; 

摘要 Using dehydroabietic acid as the lead compound for structural modification, 25 dehydroabietic acid derivatives were synthesized. Among them, compound D1 not only showed the strongest relaxation effect on the aortic vascular ring in vitro (Emax = 99.5 +/- 2.1%, EC50 = 3.03 +/- 0.96 mu M), but also significantly reduced systolic and diastolic blood pressure in rats at a dose of 2.0 mg/kg in vivo. Next, the vascular protective effect of the best active D1 and its molecular mechanism were further investigated by HUVECs. The results showed that D1 induced endothelium-dependent diastole in the rat thoracic aorta in a concentration-dependent manner. Endothelium removal or aortic ring pretreatment with N-G-nitro-L-arginine methylester ((L)-NAME), 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), and tetraethylammonium (TEA) significantly inhibited D1-induced relaxation. In addition, wortmannin, KT5823, triciribine, diltiazem, BaCl2, 4-aminopyridine, indomethacin, propranolol, and atropine attenuated D1-induced vasorelaxation. D1 increased the phosphorylation of eNOS in HUVECs Furthermore, D1 attenuated the expression of TNF-alpha-induced cell adhesion molecules such as ICAM-1 and VCAM-1. However, this effect was attenuated by the eNOS inhibitors L-NAME and asymmetric dimethylarginine (ADMA). The findings suggest that D1-induced vasorelaxation through the PI3K/Akt/eNOS/NO/cGMP/PKG pathway by activating the K-Ca, K-ir and K-V channels or muscarinic and beta-adrenergic receptors, and inhibiting the L-type Ca2+ channels, which is closely related to the hypotensive action of the agent. Furthermore, D1 exhibits an inhibitory effect on vascular inflammation, which is associated with the observed vascular protective effects.

服务人员 尚玮姣

服务院士 宋湛谦

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