菲并吲哚里西啶生物碱作为潜在抗肿瘤药物的构效关系研究。
Structure-activity studies of phenanthroindolizidine alkaloids as potential antitumor agents.
作者信息
Gao Wenli, Bussom Scott, Grill Susan P, Gullen Elizabeth A, Hu You-Cai, Huang Xueshi, Zhong Sanbao, Kaczmarek Conrad, Gutierrez Julio, Francis Samson, Baker David C, Yu Shishan, Cheng Yung-Chi
机构信息
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
出版信息
Bioorg Med Chem Lett. 2007 Aug 1;17(15):4338-42. doi: 10.1016/j.bmcl.2007.05.021. Epub 2007 May 16.
Five phenanthroindolizidine alkaloids (PA) were chemically synthesized and seven were isolated from Tylophora atrofolliculata. To facilitate future drug design of phenanthroindolizidine alkaloids as potential antitumor agents, we have explored the structure-activity relationships (SAR) of this class of compounds. We demonstrated that DCB-3503 and tylophorinidine (PA-7) were among the most active compounds against tumor growth both in vitro and in vivo. In the hepatocellular carcinoma cell line HepG2, the GI(50)s of DCB-3503 and PA-7 were 35+/-5 nM and 11+/-5 nM, respectively. DCB-3503 and PA-7 significantly inhibited HepG2 tumor growth in nude mice at a dose of 9 mg/kg given by intraperitoneal (ip) injections twice a day every third day for a total of four cycles (P<0.05 for DCB-3503 and P<0.01 for PA-7). Their potent antitumor activities correlated with their potent NF-kappaB-inhibitory effects and their cyclin D1 down-regulatory effects.
化学合成了五种菲并吲哚里西啶生物碱（PA），并从暗色叶娃儿藤中分离出七种。为便于将来将菲并吲哚里西啶生物碱作为潜在抗肿瘤药物进行药物设计，我们探索了这类化合物的构效关系（SAR）。我们证明，DCB - 3503和娃儿藤定碱（PA - 7）是体外和体内对肿瘤生长最具活性的化合物之一。在肝癌细胞系HepG2中，DCB - 3503和PA - 7的半数生长抑制浓度（GI(50)）分别为35±5 nM和11±5 nM。DCB - 3503和PA - 7以9 mg/kg的剂量腹腔注射，每三天每天两次，共四个周期，显著抑制裸鼠体内HepG2肿瘤生长（DCB - 3503的P<0.05，PA - 7的P<0.01）。它们的强效抗肿瘤活性与其强效的核因子κB（NF-κB）抑制作用和细胞周期蛋白D1下调作用相关。
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