Design, synthesis and biological evaluation of novel nitric oxide donors with antioxidative activity.

Reactive oxygen species (ROS) are the primary cause of organic nitrate drug tolerance and endothelial dysfunction. In order to scavenge the ROS and maintain the therapeutic effect of nitrates, we designed and synthesized ten new types of dual-acting nitrate molecules by combining NIT-type nitroxides and 5-ISMN. These included two types of novel epimeric nitroxide-nitrate conjugates (15(S) and 15(R)), which had pharmacophore connections. We also synthesized 8 NIT radicals without 5-ISMN in order to compare the activities of these novel nitric oxide donors. Several dual-acting nitroxide-based nitrate conjugates showed the ability to release NO and cause anti-oxidant effects in human umbilical vein endothelial cells. Among these conjugates, 15(S) showed the most prominent pro-vasodilative effect. In angiotensin II infusion-induced hypertensive mice, 15(S) treatment for 4 weeks decreased both the systolic and diastolic blood pressures and ameliorated the vascular endothelial and smooth muscle functions of isolated thoracic aortas. In addition, the vascular structure of the mice was restored and their vascular oxidative stress was decreased. The results suggest that these novel nitric oxide donors can be used as potential drugs in the treatment of vascular diseases. Therefore, the strategy of using a combination of antioxidants and NO-donors can be a promising way to develop novel organic nitrate drugs for future use in combating disease.