CLEFMA-an anti-proliferative curcuminoid from structure-activity relationship studies on 3,5-bis(benzylidene)-4-piperidones.
CLEFMA-an anti-proliferative curcuminoid from structure-activity relationship studies on 3,5-bis(benzylidene)-4-piperidones.
复制标题
DOI：
10.1016/j.bmc.2010.06.055
复制
发表时间：
2010-08-15
影响因子：
3.5
通讯作者：
Awasthi, Vibhudutta
中科院分区：
文献类型：
--
作者：
Lagisetty, Pallavi;Vilekar, Prachi;Sahoo, Kaustuv;Anant, Shrikant;Awasthi, Vibhudutta
3,5-双（苄基）-4-哌啶酮作为姜黄素的合成类似物，具有抗癌和抗炎作用。我们通过测试几种合成的3,5-双（苄基）-4-哌啶酮对肺腺癌H441细胞的抗增殖活性进行了构效关系研究。与先导化合物1,5 -双（2-氟苯二烯）-4-哌酮相比，有5个化合物的IC50 < 30 μM，有16个化合物的IC50 < 50 μM，细胞杀伤效果降低。在此基础上，我们合成了4-[3,5-二（2-氯苄基-4-氧-哌替啶-1-酰基）-4-氧-2-丁烯酸]（29或CLEFMA）作为1的新型类似物。CLEFMA对H441细胞的抗增殖活性进行了评估，发现其效力比化合物1强几倍。我们在流式细胞术中没有发现凋亡细胞群，并且通过缺乏caspase切割证实了没有凋亡。h441细胞电镜显示CLEFMA和化合物1诱导细胞自噬死亡，这种自噬死亡被特异性自噬抑制剂3-甲基腺嘌呤抑制。结果表明，强效的新型姜黄素CLEFMA为细胞凋亡抵抗性癌症的细胞死亡提供了一种替代模式。
3,5-bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anticancer and anti-inflammatory properties. We performed structure-activity relationship studies, by testing several synthesized 3,5-bis(benzylidene)-4-piperidones for anti-proliferative activity in lung adenocarcinoma H441 cells. Compared to the lead compound 1, or 3,5-bis(2-fluorobenzylidene)-4-piperidone, five compounds were found to be more potent (IC50 < 30 μM), and sixteen compounds possessed reduced cell-killing efficacy (IC50 > 50 μM). Based on the observations, we synthesized 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (29 or CLEFMA) as a novel analog of 1. CLEFMA was evaluated for anti-proliferative activity in H441 cells, and was found to be several folds more potent than compound 1. We did not find apoptotic cell population in flow cytometry, and the absence of apoptosis was confirmed by the lack of caspase cleavage. The electron microscopy of H441cells indicated that CLEFMA and compound 1 induce autophagic cell death that was inhibited by specific autophagy inhibitor 3-methyladenine. The results suggest that the potent and novel curcuminoid, CLEFMA, offers an alternative mode of cell death in apoptosis-resistant cancers.
登录
查看更多内容
影响因子：
2.3
作者：
Adams, BK;Cai, JY;Shoji, M
通讯作者：
Shoji, M
影响因子：
3.5
作者：
Adams, BK;Ferstl, EM;Shoji, M
通讯作者：
Shoji, M
影响因子：
3.6
作者：
Kasinski, Andrea L.;Du, Yuhong;Fu, Haian
通讯作者：
Fu, Haian
影响因子：
37.3
作者：
Landais I;Hiddingh S;McCarroll M;Yang C;Sun A;Turker MS;Snyder JP;Hoatlin ME
通讯作者：
Hoatlin ME
影响因子：
6.7
作者：
Dimmock, JR;Padmanilyam, MP;Stables, JP
通讯作者：
Stables, JP