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

在一个新的抗病毒化合物的筛选研究中，作者发现了一个色烯衍生物1从棕色的微棘马尾藻和一些已知的质体醌。更仔细的分离揭示了对HSV、HIV和HCMV具有强抗病毒活性的化合物1是人工产物，在分离过程中由已知的质体醌转化而来;然而，这些质体醌甚至对HSV-1也不显示抗病毒作用。作者开始通过SAR方法寻找类似于1的活性更高的化合物，包括色烯1的改造、聚合物负载衍生物以及与一些递送肽杂交的1类似物。从质体醌和市售的简单化合物共合成了12个类似物。生物活性测定结果表明，由已知质体醌转化得到的4个色烯化合物对HSV-1、HSV-2、HCMV、流感病毒和HIV的抗病毒活性与1相当。从其余8个化合物在体外观察到对HSV的中等抗病毒活性。根据数据，色烯结构是表达抗病毒活性的关键。在HIV感染的初步分析中，这些色烯可能被逆转录酶（RT）和某些趋化因子受体如CCR 5所抑制。聚合物负载的色烯的活性仍在研究中。此外，作者还不断从藻类中发现新的生物活性化合物。从小棘链霉菌中分离得到4个与上述化合物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。从微棘链霉菌中分离得到了抗氧化类胡萝卜素（岩藻黄碱）、细胞毒性萜类化合物和脂肪酸衍生物（甘油酯和氧脂）等化合物。这些结果已经发表，参见参考文献和专利。

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.