Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents.
Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents.
复制标题
DOI：
10.1016/j.bmc.2013.11.046
复制
发表时间：
2014-01-01
影响因子：
3.5
通讯作者：
Romo D
中科院分区：
文献类型：
--
作者：
Low WK;Li J;Zhu M;Kommaraju SS;Shah-Mittal J;Hull K;Liu JO;Romo D
合成了一系列用于结构/活性关系（SAR）研究的帕丁胺A（1）衍生物，并基于关于这些翻译抑制剂的作用机制的当前信息重新评估了上一代类似物的选择。新一代衍生物中的结构修饰集中在对先前描述的简化的、去甲基的、去氨基的苯丙氨酸A（DMDAPatA，2）的C19-C22 Z，E-二烯和三烯基侧链的改变。测试衍生物在细胞培养中的抗增殖活性和在体外对哺乳动物帽依赖性翻译的抑制。活性高度依赖于大环内酯的刚性和构象以及侧链的功能性。唯一耐受性良好的取代是用其他叔胺基团取代2侧链上的N，N-二甲基氨基。SAR报告表明，该网站可能会在未来的研究中进行修改，以提高血清稳定性，细胞类型的特异性，和/或对快速增殖的细胞的特异性。
A series of pateamine A (1) derivatives were synthesized for structure/activity relationship (SAR) studies and a selection of previous generation analogs were re-evaluated based on current information regarding the mechanism of action of these translation inhibitors. Structural modifications in the new generation of derivatives focused on alternations to the C19-C22 Z, E-diene and the trienyl side chain of the previously described simplified, des-methyl, des-amino pateamine A (DMDAPatA, 2). Derivatives were tested for anti-proliferative activity in cell culture and for inhibition of mammalian cap-dependent translation in vitro. Activity was highly dependent on the rigidity and conformation of the macrolide and the functionality of the side chain. The only well tolerated substitutions were replacement of the N,N-dimethyl amino group found on the side chain of 2 with other tertiary amine groups. SAR reported here suggests that this site may be modified in future studies to improve serum stability, cell-type specificity, and/or specificity towards rapidly proliferating cells.
登录
查看更多内容
影响因子：
5.7
作者：
Kuznetsov G;Xu Q;Rudolph-Owen L;Tendyke K;Liu J;Towle M;Zhao N;Marsh J;Agoulnik S;Twine N;Parent L;Chen Z;Shie JL;Jiang Y;Zhang H;Du H;Boivin R;Wang Y;Romo D;Littlefield BA
通讯作者：
Littlefield BA
DOI：
10.1073/pnas.0504249102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Bordeleau, ME;Matthews, J;Pelletier, J
通讯作者：
Pelletier, J
影响因子：
7.2
作者：
Hood, KA;West, LM;Miller, JH
通讯作者：
Miller, JH
影响因子：
3.5
作者：
Grimmler, M;Otter, S;Fischer, U
通讯作者：
Fischer, U
影响因子：
16.6
作者：
Di Marco, Sergio;Cammas, Anne;Gallouzi, Imed Eddine
通讯作者：
Gallouzi, Imed Eddine