Synthesis and cytotoxicity of 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole (amino-seco-CBI-TMI) and related 5-alkylamino analogues:: New DNA minor groove alkylating agents
Synthesis and cytotoxicity of 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole (amino-seco-CBI-TMI) and related 5-alkylamino analogues:: New DNA minor groove alkylating agents
复制标题
DOI：
10.1021/jo981395w
复制
发表时间：
1998-12-11
影响因子：
3.6
通讯作者：
Denny, WA
中科院分区：
文献类型：
--
作者：
Atwell, GJ;Tercel, M;Denny, WA
首次报道了含5-氮基的Seco-CBI-TMI烷化剂的合成。以1-羟基萘-2-羧酸为原料，经15步反应合成了母体5-氨基化合物。5-氨基化合物的还原烷基化反应得到相应的5-甲氨基和5-二甲氨基类似物，而通过手性高效液相色谱拆分中间体可以制备5-氨基类似物的R和S对映体。用X射线结晶学确定了其绝对构型。在细胞系实验中，S对映体的细胞毒性约为R对映体的65倍。5-氨基和5-甲氨基化合物的体外细胞毒性与已知的5-羟基类似物(0.2-0.5 nm)相当，而5-二甲氨基衍生物的细胞毒性约为其10倍。5-氨基和5-甲氨基类似物的高势使它们对形成相对稳定的胺基前药很有兴趣。
The first synthesis of seco-CBI-TMI alkylating agents with 5-nitrogen substituents is reported. The parent 5-amino compound was prepared in a 15-step synthesis from 1-hydroxynaphthalene-2-carboxylic acid. Reductive alkylation of the 5-amino compound gave the corresponding 5-methylamino and 5-dimethylamino analogues, while resolution of an intermediate by chiral HPLC allowed preparation of the R and S enantiomers of the 5-amino analogue. Absolute configuration was assigned by X-ray crystallography. The S enantiomer was about 65-fold more cytotoxic than the R enantiomer in cell line assays. The 5-amino and 5-methylamino compounds had in vitro cytotoxicities comparable to that of the known 5-hydroxy analogue (0.2-0.5 nM), while the 5-dimethylamino derivative was about 10-fold less potent. The high potencies of the 5-amino and 5-methylamino analogues make them of interest for the formation of relatively stable amine-based prodrugs.