α-(异吲哚啉酮-2-基)戊二酰亚胺含氟类似物的合成与白血病细胞K562抑制活性
收稿日期: 2014-12-01
修回日期: 2014-12-25
网络出版日期: 2015-01-14
基金资助
上海市科学技术委员会(No.13142201001)资助项目.
Synthesis and Leukemia Cell Line K562 Inhibitory Activities of α-(Fluoro-substituted isoindolinone-2-yl)glutarimide Analogues
Received date: 2014-12-01
Revised date: 2014-12-25
Online published: 2015-01-14
Supported by
Project supported by the Science and Technology Commission of Shanghai Municipality (No.13142201001).
以L-谷氨酰胺为原料, 经氨基保护、缩合闭环、氨基脱保护得中间体3-氨基-2,6-哌啶二酮盐酸盐(4), 另以不同的2-甲基-硝基苯甲酸甲酯为原料, 经硝基还原、Balz-Schiemann反应、硝化反应、溴化反应得一系列2-溴甲基苯甲酸甲酯衍生物9a~9d和12a~12b; 4与不同的2-溴甲基苯甲酸甲酯衍生物在弱碱下反应得到了一系列新的α-(异吲哚啉酮-2-基)戊二酰亚胺含氟类似物10a~10d, 13a~13b和15; 13a和13b经硝基还原得两个目标化合物14a和14b. 合成化合物的结构经1H NMR和HRMS确证. 用噻唑蓝(MTT)法测试了7个目标化合物对白血病细胞株K562的抑制活性, 结果表明, 化合物10a对K562细胞的抑制作用与来那度胺相当; 化合物15对K562细胞具有较强的抑制作用, 在25 μg/mL浓度下抑制率达99%.
关键词： α-(异吲哚啉酮-2-基)戊二酰亚胺; 合成; 白血病; 抑制活性
陈衍炽 , 任玉杰 . α-(异吲哚啉酮-2-基)戊二酰亚胺含氟类似物的合成与白血病细胞K562抑制活性[J]. 有机化学, 2015 , 35(5) : 1123 -1130 . DOI: 10.6023/cjoc201412001
A series of α-(fluoro-substituted isoindolinone-2-yl)glutarimide analogues 10a~10d, 13a~13b and 15 were synthesized from 3-amino-piperidine-2,6-dione hydrochloride (4) and different methyl 2-bromomethylbenzoate derivatives under alkaline condition, respectively. Furthermore, target compounds 14a and 14b were obtained via nitro reduction of 13a and 13b, respectively. The intermediate 4 was synthesized via amino-protection, cyclization and amino-deprotection using L-glutamine as the starting material. Different methyl 2-bromomethylbenzoate derivatives 9a~9d and 12a~12b were readily available via nitro reduction, Balz-Schiemann reaction, nitration reaction and bromination reaction strategies of nitro-substituted 2-methyl benzoic acid methyl esters. The structures of all compounds have been confirmed by 1H NMR and HRMS spectra. The inhibitory activity against leukemia cell line K562 of seven target compounds was evaluated by thiazolyl blue tetrazolium bromide (MTT) method. The results indicated that the inhibitory activity to K562 cells of compound 10a was comparable with lenalidomide. Compound 15 exhibited strong inhibitory effect against K562 cells and with an inhibition rate of 99% at the concentration of 25 μg/mL.
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