菲并吲哚里西啶生物碱（±）-安托非宁、（±）-脱氧佩尔古拉里宁及其脱氢类似物的全合成及其细胞毒性活性评估
Total synthesis of phenanthroindolizidine alkaloids (+/-)-antofine, (+/-)-deoxypergularinine, and their dehydro congeners and evaluation of their cytotoxic activity.
作者信息
Su Chung-Ren, Damu Amooru G, Chiang Po-Cheng, Bastow Kenneth F, Morris-Natschke Susan L, Lee Kuo-Hsiung, Wu Tian-Shung
机构信息
Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC.
出版信息
Bioorg Med Chem. 2008 Jun 1;16(11):6233-41. doi: 10.1016/j.bmc.2008.04.032. Epub 2008 Apr 18.
Abstract
Due to their limited natural abundance and significant biochemical effects, we synthesized the alkaloids (+/-)-antofine (1a), (+/-)-deoxypergularinine (1b), and their dehydro congeners (2 and 3) starting from the corresponding phenanthrene-9-carboxaldehydes. We also evaluated their in vitro cytotoxic activity. Compounds 1a and 1b showed significant potency against various human tumor cell lines, including a drug-resistant variant, with EC(50) values ranging from 0.16 to 16ng/mL. Structure-activity correlations of these alkaloids and some of their synthetic intermediates were also ascertained. The non-planar structure between the two major moieties, phenanthrene and indolizidine, plays a crucial role in the cytotoxic activity of phenanthroindolizidines. Increasing the planarity and rigidity of the indolizidine moiety significantly reduced potency. A methoxy group at the 2-position (1a) was more favorable for cytotoxic activity than a hydrogen atom (1b).
摘要
由于它们天然丰度有限且具有显著的生化效应，我们从相应的菲-9-甲醛出发合成了生物碱(±)-安托非宁(1a)、(±)-脱氧佩尔古拉里宁(1b)及其脱氢类似物(2和3)。我们还评估了它们的体外细胞毒性活性。化合物1a和1b对包括耐药变体在内的多种人类肿瘤细胞系显示出显著的活性，其半数有效浓度(EC50)值在0.16至16 ng/mL之间。还确定了这些生物碱及其一些合成中间体的构效关系。菲和中氮茚这两个主要部分之间的非平面结构在菲并中氮茚的细胞毒性活性中起关键作用。增加中氮茚部分的平面性和刚性会显著降低活性。2位上的甲氧基(1a)比氢原子(1b)对细胞毒性活性更有利。
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