Design, Synthesis and Biological Study of Novel NO-Donor-Caffeic Acid Hybrids as Potential Anti-Atherosclerotic Drug Candidates

Nian-Guang      Li; Rong      Wang; Yu-Ping      Tang; Zhi-Hao      Shi; Bao-Quan      Li; Wei      Li; Jian-Ping      Yang; Zhen-Jiang      Wang; Shu-Lin      Song; Li-Hua      Qian; Li-Juan      Yao; Jun-Zuan      Xia; Jia      Xu; Feng      Feng; Da-Wei      Qian; Jin-Ao      Duan

Abstract

Novel NO-donor-caffeic acid hybrids with antioxidant, nitric oxide release and vasodilator properties were designed and synthesized through a symbiotic approach using caffeic acid and three different NO-donating groups such as nitric ester, 4-hydroxyl-3-phenylfuroxan and 4-hydroxymethyl-3-phenylsulfonylfuroxan. The antioxidant activities of these hybrid products were assessed by DPPH assay and by detecting the TBARS produced in the ferrous salt/ascorbate induced autoxidation of lipids which were present in microsomial membranes of rat hepatocytes. The nitric oxide release activities were assessed by indirect evaluation of the produced nitrite. The vasodilator activities were determined through an in vitro vascular relaxation assay (organ bath) using PGF2α-precontracted porcine pulmonary arteries. The results showed that the target phenylsulfonylfuroxan 12, especially 12a while keeping the antioxidant activity, showed more NO release activity and vasodilating activity than isosorbide dinitrate (ISDN). Thus 12a may be considered as a novel potent anti-atherosclerosiss drug candidate.

Keywords: Atherosclerosis, Nitric oxide donor, Caffeic acid, Antioxidant activity, Nitric oxide release, Vasodilator activity, LDL, Acid Hybrids, Anti-Atherosclerotic, Moiety, reactive oxygen species (ROS), vasodilation, isoproterenol (ISO), myocardial infarction, dibromoalkanes, lipid autooxidation