Coumarin derivatives from Ainsliaea fragrans and their anticoagulant activity.

Liang Lei,Yang Zhang,Zeng-Wei Luo,Hong-Ping Song,Yan He,Jian-Ping Wang,Si-Si Peng,Geng Zhang,Rong Fang,Yong-Bo Xue,Guang-Min Yao,Yong-Hui Zhang,Jin-Wen Zhang,Zhong Liu

doi:10.1038/srep13544

Abstract

Coumarin derivatives are an important class of C6–C3 plant metabolites that show a variety of bioactivities. Currently, most clinical anticoagulant agents are coumarins, such as warfarin, dicoumarol and acenocoumarol, and patients taking these drugs must be monitored for adverse reactions. In a search for safe and effective anticoagulant compounds from Chinese herbal medicine, a screening procedure on the whole plant of Ainsliaea fragrans was performed. The phytochemical investigation of this plant afforded five new coumarin derivatives, including a pair of natural 4-hydroxycoumarin enantiomers (1), a pair of coumarin enantiomers with a rare polycyclic pyrano[3-2c] carbon skeleton (2) and a 7-hydroxycoumarin derivative (3), together with 5 known biogenetically related compounds (4–8). Enantioseparation of 1 and 2 produced optically pure compounds 1a, 1b, 2a and 2b. The absolute configurations of the new compounds were confirmed by single-crystal X-ray diffraction analysis. In addition, we evaluated the anticoagulant activity of all isolates via activated partial thromboplastin time (APTT), thrombin time (TT) and prothrombin time (PT) assays in vitro and in vivo. Of note, compound 3 displayed potent anticoagulant activity and no significant hepatic or renal toxicity, which could make it a promising agent for further preclinical evaluation for preventing abnormal blood clotting.

Highlights

Coumarins are a well-known class of secondary metabolites in plants[1,2,3] and fungi[4,5,6] Owing to their structural features, coumarins are an important type of substrate in the areas of natural product modification and synthetic chemistry[7,8,9]
In order to search for novel, highly efficient anticoagulant compounds with low toxicity from Chinese herbal medicine, a study was conducted on extracts of Ainsliaea fragrans Champ (Compositae)
This study is focused on identifying the structure of coumarin derivatives from Ainsliaea fragrans and investigating the anticoagulant activity of these isolates in vitro and in vivo

Summary

Introduction

Coumarins are a well-known class of secondary metabolites in plants[1,2,3] and fungi[4,5,6] Owing to their structural features, coumarins are an important type of substrate in the areas of natural product modification and synthetic chemistry[7,8,9]. Among the various coumarin derivatives, 4-hydroxycoumarins, which have a special enol moiety, have shown high activity in chemical synthesis and can act as potent metal ligands and starting material[10,11]. The C3-substituted 4-hydroxycoumarins in particular have attractive biological activities[12], especially anticoagulant activity. Coumarins are widely used in the clinic for antithrombotic therapy; for example, warfarin, which used to be a rodenticide, is used as an anticoagulant[13,14]. In order to search for novel, highly efficient anticoagulant compounds with low toxicity from Chinese herbal medicine, a study was conducted on extracts of Ainsliaea fragrans Champ (Compositae). We report five new coumarin derivatives and five other known, biogenetically related coumarin derivatives isolated from this plant. Two pairs of new natural C3-substituted 4-hydroxycoumarin enantiomers 1 and 2 were enantioseparated successfully. A preliminary assay was carried out to evaluate the anticoagulant activity of all of the isolates

Methods

Results

Conclusion