稠合四环噻嗪烷-4-酮衍生物的合成及其抗肿瘤活性  

Synthesis of the Fused Tetracyclic Thiazinan-4-one Derivatives and Their Anti-tumor Activitiy

作　　者：牛丽萍 邢顺凯 李小六 陈华 Niu Liping;Xing Shunkai;Li Xiaoliu;Chen Hua(Key Laboratory of Chemical Biology of Hebei Province,College of Chemistry and Environmental Science,Hebei University,Baoding 071002)

机构地区：[1]河北大学化学与环境科学学院河北省化学生物学重点实验室

出　　处：《有机化学》2019年第3期771-777,共7页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.21372060);河北省自然科学基金重点(No.B2016201031)资助项目~~

摘　　要：以叔丁氧羰基(Boc)保护的脯氨醛 1、氨基酸酯盐酸盐 2a^2d 和巯基水杨酸 3a^3b 为原料,三组分一锅法得到苯并噻嗪烷-4-酮中间体.酸性条件下脱除Boc,分子内酰胺缩合制备稠合四环噻嗪烷-4-酮衍生物6~11.新生成手性碳(1-C)的构型通过 H-1 和 H-2 的偶合常数及 X-ray 单晶衍射确定.测试了化合物抗 Hela 和 A549 的肿瘤细胞增殖活性.结果表明,部分化合物具有中等的抗 Hela 细胞活性,其中(13aR,13bR)-1,2,3,13b-四氢苯并[e]吡咯并[2',1':3,4]吡嗪并[2,1-b][1,3]噻嗪-5,8(6H,13aH)-二酮(6b)的 IC50 值为 9.50 μmol/L.所有化合物对 A549 的细胞没有抑制活性.The benzothiazin-4-one intermediates were prepared by the one-pot three-components condensation from the N-Boc-L-prolinal 1, amino acid ethyl/methyl ester hydrochlorides 2a^2d, and mercaptobenzoic acids 3a^3b. After removal of Boc, the target novel fused tetracyclic thiazinan-4-one derivatives 6~11 were afforded by the intramolecular cy-clo-amidation reaction. The absolute configurations of the newly generated chiral carbon (1-C) were determined by the cou-pling constants of H-1 and H-2 and the X-ray crystallographic structures. The tetracyclic alkaloids were examined for their anti-proliferative activity against Hela and A549 tumor cells. The results showed that some compounds could moderately in-hibit the growth of Hela cells, and among them,(13aR,13bR)-1,2,3,13b-tetrahydrobenzo[e]pyrrolo[2',1':3,4]pyrazino[2,1- b][1,3]thiazine-5,8(6H,13aH)-dione (6b) was the best one with the IC50 value of 9.50 μmol/L. However, all the compounds showed no anti-tumor activity against A549.

关 键 词：稠合衍生物 噻嗪烷-4-酮 三组分缩合 酰胺环缩合 抗肿瘤活性 

分 类 号：TQ463[化学工程—制药化工]