Naman C Benjamin, Gupta Gaurav, Varikuti Sanjay, Chai Heebyung, Doskotch Raymond W, Satoskar Abhay R, Kinghorn A Douglas
†Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
‡Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio 43210, United States.
J Nat Prod. 2015 Mar 27;78(3):552-6. doi: 10.1021/np501028u. Epub 2015 Jan 28.
Screening of a plant-derived natural product library led to the observation of in vitro antileishmanial activity by three bisbenzyltetrahydroisoquinoline alkaloids (1-3) that were purified previously from Thalictrum alpinum. A spectroscopic study of the active compounds was conducted to confirm their identities. Of the compounds tested, northalrugosidine (1) showed the most potent in vitro activity against Leishmania donovani promastigotes (0.28 μM) and the highest selectivity (29.3-fold) versus its general cytotoxicity against HT-29 human colon adenocarcinoma cells. Northalrugosidine was tested in vivo using a murine model of visceral leishmaniasis, resulting in the observation of a dose-dependent reduction of the parasitic burden in the liver and spleen without overt toxicity effects at 2.8, 5.6, and 11.1 mg/kg per animal when administered intravenously. This represents the first report of a bisbenzyltetrahydroisoquinoline alkaloid with in vivo efficacy against visceral leishmaniasis.
对一个植物来源的天然产物文库进行筛选后发现，之前从高山唐松草中纯化得到的三种双苄基四氢异喹啉生物碱（1 - 3）具有体外抗利什曼原虫活性。对这些活性化合物进行了光谱研究以确认其结构。在所测试的化合物中，去甲鲁戈辛（1）对杜氏利什曼原虫前鞭毛体显示出最强的体外活性（0.28 μM），并且相对于其对HT - 29人结肠腺癌细胞的一般细胞毒性，具有最高的选择性（29.3倍）。使用内脏利什曼病小鼠模型对去甲鲁戈辛进行了体内试验，结果观察到，当以每只动物2.8、5.6和11.1 mg/kg的剂量静脉给药时，肝脏和脾脏中的寄生虫负荷呈剂量依赖性降低，且无明显毒性作用。这是关于一种双苄基四氢异喹啉生物碱对内脏利什曼病具有体内疗效的首次报道。
