Design, Synthesis and Biological Evaluation of Nitrate Derivatives of Sauropunol A and B as Potent Vasodilatory Agents

Lu Lu; Xuemin Rao; Rigang Cong; Chenxi Zhang; Zhimei Wang; Jinyi Xu; Genzoh Tanabe; Osamu Muraoka; Xiaoming Wu; Weijia Xie

Design, Synthesis and Biological Evaluation of Nitrate Derivatives of Sauropunol A and B as Potent Vasodilatory Agents

2019

A group of nitrate derivatives of naturally occurring sauropunol A and B were designed and synthesized. Nitric oxide (NO) releasing capacity and vasodilatory capacity studies were performed to explore the structure-activity relationship of resulted nitrates. Biological evaluation of these compounds revealed that most of the synthesized mononitrate derivatives demonstrated superior releasing capacity than isosorbide mononitrate (ISMN), and 2MNS-6 even demonstrated stronger NO releasing capacity than isosorbide dinitrate (ISDN). Two dinitrates, DNS-1 and DNS-2, showed higher NO releasing capacity than ISDN. Evaluation of inhibitory activities to the contractions in mesenteric artery rings revealed that 2MNS-8 and DNS-2 showed stronger vasorelaxation activities than ISDN. High level of NO and soluble guanylyl cyclase (sGC) may be essential for the potent vasodilatory effect of DNS-2. The vasodilatory effects of DNS-2 may result from cellular signal transduction of NO-sGC-cGMP. DNS-2 was found to be the most potent sauropunol-derived nitrate vasodilatory agent for further pharmaceutical investigation against cardiovascular diseases.

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