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Research and Development of the New Antiviral Drugs by Remodeling of the New Diterpenoid Isolated from Sea Algae

海藻新二萜改造研发新型抗病毒药物

基本信息

批准号：
15590097
负责人：
IWASHIMA Makoto
金额：
$ 2.18万
依托单位：
University of Toyama (2005)Toyama Medical and Pharmaceutical University (2003-2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

In the screening study for investigation of a new antiviral compound, the authors found the chromene derivative 1 from the brown alga Sargassum micracanthum along with some known plastoquinones. More careful isolation revealed compound 1 possessing a strong antiviral activity against HSV,HIV and HCMV to be an artifact, converted from the known plastoquinones in the isolation process ; however, these plastoquinones did not show antiviral effect even for HSV-1. The authors started to find much more active compound similar to 1 by SAR method, including the remodeling of chromene 1,polymer-supported derivatives and the analogs of 1 hybridized with some delivery peptides. Totally twelve analogs were synthesized from the plastoquinones and commercially available simple compounds. According to the bioassay of them, four chromenes converted from the known plastoquinones showed strong antiviral activity against HSV-1,HSV-2,HCMV, Influenza and HIV as much as that of 1. Moderate antiviral activity against HSV was observed from the remaining eight compounds in vitro. According to the data, the chromene structure is the crucial for expressing the antiviral activity. These chromenes might be inhibited reverse-transcriptase (RT) and some chemokine receptor such as CCR5 in the primitive analysis of HIV infection. The activity of polymer-supported chromenes were still under investigation. In addition, the author continued to find the new bioactive compounds from algae. Four new antioxidative plastoquinones related the above-mentioned ones were isolated from S.micracanthum. Unfortunately, these new compounds did not exhibit antiviral effect. From the other brown algae related S.micracanthum, a lot of known compounds were obtained such as antioxidative carotenoids (a kind of fucoxanthine), cytotoxic terpenoids and fatty acid derivatives (glycerides and oxylipins). These results were already published, and see the references and patent.

在研究新型抗病毒化合物的筛选研究中，作者发现了来自褐藻马尾藻的色烯衍生物 1 以及一些已知的质体醌。更仔细的分离表明，对 HSV、HIV 和 HCMV 具有强抗病毒活性的化合物 1 是一种人工产物，是在分离过程中由已知的质体醌转化而来的；然而，这些质体醌甚至对 HSV-1 也没有表现出抗病毒作用。作者开始通过SAR方法寻找活性更高的类似于1的化合物，包括色烯1的重构、聚合物支持的衍生物以及与一些递送肽杂交的1的类似物。由质体醌和市售简单化合物合成了总共十二种类似物。根据它们的生物测定，由已知质体醌转化的四种色烯对HSV-1、HSV-2、HCMV、流感和HIV表现出与1一样强的抗病毒活性。其余八种化合物在体外观察到对HSV的中等抗病毒活性。数据显示，色烯结构对于表达抗病毒活性至关重要。在 HIV 感染的原始分析中，这些色烯可能会抑制逆转录酶 (RT) 和一些趋化因子受体（例如 CCR5）。聚合物支持的色烯的活性仍在研究中。此外，作者还继续从藻类中寻找新的生物活性化合物。从S.micracanthum 中分离出四种与上述相关的新的抗氧化质体醌。不幸的是，这些新化合物没有表现出抗病毒作用。从其他褐藻相关的S.micracanthum中，获得了许多已知的化合物，如抗氧化类胡萝卜素（一种岩藻黄质）、细胞毒性萜类化合物和脂肪酸衍生物（甘油酯和氧脂素）。这些结果已经发表，请参阅参考文献和专利。