Bringmann Gerhard, Gampe Christian M, Reichert Yanina, Bruhn Torsten, Faber Johan H, Mikyna Martin, Reichert Matthias, Leippe Matthias, Brun Reto, Gelhaus Christoph
Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany.
J Med Chem. 2007 Nov 29;50(24):6104-15. doi: 10.1021/jm061464w. Epub 2007 Nov 9.
The naphthylisoquinoline (NIQ) alkaloids from tropical Ancistrocladaceae and Dioncophyllaceae plants show high antiplasmodial activities in vitro and in vivo, even against chloroquine-resistant strains of the malaria pathogen. For the directed optimization of these activities, an investigation of the mode of action seems most rewarding. We have therefore embarked on the identification of the respective target protein in Plasmodium falciparum. For this purpose, we have developed a flexible pathway for the synthesis of a chemically divergent series of photoactive and fluorescent derivatives of such alkaloids and succeeded in preparing the first functionalized NIQ derivatives, 10, 12, and 35, suited for fluorescence and photoaffinity labeling experiments. Pharmacological investigations ensured that the modified alkaloid derivatives retained their antiplasmodial activity. The work may pave the way for a further improvement of the activity of these natural products and will thus increase their pharmacological potential as a valuable lead structure against the widespread tropical disease malaria.
来自热带钩枝藤科和双钩叶科植物的萘基异喹啉（NIQ）生物碱在体外和体内均表现出较高的抗疟活性，甚至对疟原虫的氯喹抗性菌株也有效。为了有针对性地优化这些活性，研究其作用模式似乎最有价值。因此，我们着手鉴定恶性疟原虫中的相应靶蛋白。为此，我们开发了一条灵活的途径，用于合成这类生物碱的一系列化学性质不同的光活性和荧光衍生物，并成功制备了首批适用于荧光和光亲和标记实验的功能化NIQ衍生物10、12和35。药理学研究确保了修饰后的生物碱衍生物保留其抗疟活性。这项工作可能为进一步提高这些天然产物的活性铺平道路，从而增加它们作为对抗广泛流行的热带疾病疟疾的有价值先导结构的药理潜力。
