Synthesis and Biological Evaluation of New Madecassic Acid Derivatives Targeting ERK Cascade Signaling.
Synthesis and Biological Evaluation of New Madecassic Acid Derivatives Targeting ERK Cascade Signaling.
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DOI：
10.3389/fchem.2018.00434
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发表时间：
2018
影响因子：
5.5
通讯作者：
Salvador JAR
中科院分区：
文献类型：
--
作者：
Valdeira ASC;Ritt DA;Morrison DK;McMahon JB;Gustafson KR;Salvador JAR
在本研究中，合成了一系列新的羟基积雪草酸衍生物，并对美国国家癌症研究所的60人癌细胞系面板进行了筛选。其中，化合物5、12和17显示出针对80%的具有纳摩尔范围内的B-RafV 600 E突变的肿瘤细胞的有效和高度差异的抗增殖活性。结构-活性分析显示，含有在C-23处被2-呋喃甲酰基取代的α，β-不饱和醛的5元A环似乎对产生这种特定的生长抑制特征至关重要。这些化合物的细胞毒性模式的计算机模拟分析鉴定了两种高度相关的临床批准的药物，其具有已知的B-RafV 600 E抑制活性。后续分析显示，通过降低细胞Raf蛋白水平抑制ERK信号通路是这些化合物的关键作用机制。特别地，17是抑制B-RafV 600 E突变细胞系的肿瘤生长的最有效的化合物，并且在测试的化合物中显示Raf蛋白水平的最高降低。总之，这项研究表明，羟基积雪草酸结构的修饰可以提供对具有临床相关B-RafV 600 E突变的细胞系具有有效抗癌活性的分子，其中化合物17被鉴定为开发新抗癌药物的有希望的先导。
In the present study, a series of novel madecassic acid derivatives was synthesized and screened against the National Cancer Institute's 60 human cancer cell line panel. Among them, compounds 5, 12, and 17 displayed potent and highly differential antiproliferative activity against 80% of the tumor cells harboring the B-RafV600E mutation within the nanomolar range. Structure-activity analysis revealed that a 5-membered A ring containing an α,β-unsaturated aldehyde substituted at C-23 with a 2-furoyl group seems to be crucial to produce this particular growth inhibition signature. In silico analysis of the cytotoxicity pattern of these compounds identified two highly correlated clinically approved drugs with known B-RafV600E inhibitory activity. Follow-up analysis revealed inhibition of the ERK signaling pathway through the reduction of cellular Raf protein levels is a key mechanism of action of these compounds. In particular, 17 was the most potent compound in suppressing tumor growth of B-RafV600E-mutant cell lines and displayed the highest reduction of Raf protein levels among the tested compounds. Taken together, this study revealed that modifications of madecassic acid structure can provide molecules with potent anticancer activity against cell lines harboring the clinically relevant B-RafV600E mutation, with compound 17 identified as a promising lead for the development of new anticancer drugs.
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基于NCI-60人类肿瘤细胞板的分子谱，黄素脱氢酶抑制剂二苯基二苯和DI-2-噻二乙烯二元的作用机理。
影响因子：
5.8
作者：
Doroshow, James H.;Juhasz, Agnes;Ge, Yun;Holbeck, Susan;Lu, Jiamo;Antony, Smitha;Wu, Yongzhong;Jiang, Guojian;Roy, Krishnendu
通讯作者：
Roy, Krishnendu
影响因子：
3.7
作者：
Patil KS;Basak I;Pal R;Ho HP;Alves G;Chang EJ;Larsen JP;Møller SG
通讯作者：
Møller SG
影响因子：
5.9
作者：
Hsu YM;Hung YC;Hu L;Lee YJ;Yin MC
通讯作者：
Yin MC
影响因子：
5.8
作者：
Fitzpatrick, Leo R.;Stonesifer, Elizabeth;Liby, Karen T.
通讯作者：
Liby, Karen T.
影响因子：
7.3
作者：
Dong Y;Shi Q;Liu YN;Wang X;Bastow KF;Lee KH
通讯作者：
Lee KH