Structural analysis and antitussive evaluation of five novel esters of verticinone and bile acids
Structural analysis and antitussive evaluation of five novel esters of verticinone and bile acids
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DOI：
10.1016/j.steroids.2008.12.007
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发表时间：
2009-04-01
期刊：
影响因子：
2.7
通讯作者：
Wu, Ji-zhou
中科院分区：
文献类型：
--
作者：
Zhang, Jiu-liang;Wang, Hui;Wu, Ji-zhou
蛇胆川贝散是一种中药复方制剂，由蛇胆（中文名“蛇胆”）和川贝母（中文名“川贝”）组成，是华人社区最流行的镇咳祛痰制剂。但由于蛇胆川贝散两种药材的短缺，特别是出于动物保护的考虑，其临床应用受到严格限制。此外，大多数中药复方存在基础药效物质不明确、质量控制困难等固有缺陷，阻碍了其进入国际医药市场。因此我们试图寻找射丹川贝散镇咳药的新替代品。为了获得一些具有更好生物活性和减弱毒性的新化合物，我们尝试通过酯键将两种药物结合起来。受药物发现“组合原理”的启发，我们合成了五种新型的维替西酮和胆汁酸的酯，这两种酯都是蛇胆川贝散的主要生物活性成分。然后我们评估了五种酯连接化合物的镇咳活性和急性毒性。相同剂量下，五种酯连接化合物比单一胆汁酸具有更强的镇咳活性和祛痰活性，并且与大约双摩尔剂量的单体维替西酮相比具有相当的镇咳活性和祛痰活性。尤其是胆酸-华替西酮酯在相同剂量下比单体华替西酮或胆酸具有更强的镇咳作用。进一步的急性毒性研究表明，小鼠腹腔注射5种酯联化合物的LD50值超过3.5 g/kg。基于药理学和急性毒性研究，五种酯连接化合物与单一维替西酮和单一胆汁酸相比具有协同药效作用且毒性减弱。 (C) 2008 Elsevier Inc. 保留所有权利。
Shedan-Chuanbei powder, a complex of traditional Chinese medicine preparation, which consists of Snake Bile (Chinese name "Shedan") and Fritillariae Cirrhosae (Chinese name "Chuanbei"), is the most popular antitussive and expectorant formulation in Chinese communities. However, the clinical application of Shedan-Chuanbei powder is now stringently limited because of the shortage of the two crude medicinal materials, especially for the sake of animal protection. In addition, the inherent defects of the most of the complex of traditional Chinese medicine such as the indistinct basal phartnacodynamic materials and the difficulties in quality control had blocked them heading into the international medicinal market. So we attempted to seek new substitute for Shedan-Chuanbei powder for antitussive drugs. In order to gain some new compounds with better bioactivity and attenuated toxicity, we tried to combine two kinds of drugs through ester bond. Enlightened with "combination principle" in drug discovery, we synthesized five novel esters of verticinone and bile acids, both of which are the major bioactive components in Shedan-Chuanbei powder. We then evaluated the antitussive activity and the acute toxicity of the five ester-linked compounds. The five ester-linked Compounds had much more potent antitussive activity and expectorant activity than single bile acids at the same doses, and had equivalent antitussive activity and expectorant activity in comparison with about double moles dose of the monomer verticinone. Especially, cholic acid-verticinone ester had much more potent antitussive effects than the monomer verticinone or cholic acid at the same dose. A further acute toxicity study showed that the LD50 values of the five ester-linked compounds exceeded 3.5 g/kg by intraperitoneal injection in mice. Based on the studies of pharmacology and acute toxicity, the five ester-linked compounds have synergic pharmacodynamic action and attenuated toxicity compared with single verticinone and single bile acids. (C) 2008 Elsevier Inc. All rights reserved.