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

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

doi:10.3390/molecules24030583

Abstract

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.

Highlights

Nitric oxide has long been considered as a critical cellular signaling molecule related to different chemical and biological responses within the human body [1,2,3]
Natural products 1/2 previously synthesized by our group [32] were directly treated with nitric acid to give target 5-mononitrate derivatives 5MNS-1 and 5MNS-2 (Figure 2) [33]
In the study to verify the contributions of Nitric oxide (NO) and soluble guanylyl cyclase (sGC) on the vasodilatoy effect of DNS-2, the results showed that treatment with PTIO or ODQ did not affect contracted mesenteric artery rings whereas the introduction of DNS-2 alone remarkably vasodilated pre-contracted mesenteric artery rings

Summary

Introduction

Nitric oxide has long been considered as a critical cellular signaling molecule related to different chemical and biological responses within the human body [1,2,3]. As a common method for drug design, molecular hybridization was usually used to introduce NO-releasing part, known as NO donor, into an existing chemical entity. The resulting hybrid compounds usually present: (i) increased bioactivities compared to the parent compounds; (ii) new biological activities which were not observed in the parent compounds; (iii) less side effects than parent compounds [16,17,18,19,20]. NO donors have been used for many years in treatment of various clinical indications such as angina pectoris and coronary disease. Organic nitrate vasodilators such as gluceryl trinitrate (GTN), pentaerythritol tetranitrate (PETN), ISDN and ISMN are the oldest and the most successfully used NO

Methods

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Discussion

Conclusion