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
Affiliations
Lu Lu
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
Xuemin Rao
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
Rigang Cong
National Certified Enterprise Technology Center, Disha Pharmaceutical Group Co., Ltd., Weihai 264205, China
Chenxi Zhang
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
Zhimei Wang
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
Jinyi Xu
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
Genzoh Tanabe
Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
Osamu Muraoka
Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
Xiaoming Wu
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
Weijia Xie
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
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.
