Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.
Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.
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DOI：
10.1021/jm401377v
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发表时间：
2014-02-13
影响因子：
7.3
通讯作者：
Hurley TD
中科院分区：
文献类型：
--
作者：
Kimble-Hill AC;Parajuli B;Chen CH;Mochly-Rosen D;Hurley TD
乙醛脱氢酶(ALDH)参与多种代谢途径，并在多种癌症疾病中发挥作用。我们的实验室对开发新型和选择性的ALDH抑制剂感兴趣。我们期待着最近发表的进一步工作，开发一类使用类似的吲哚-2，3-二酮的同工酶选择性抑制剂，这些抑制剂对ALDH1A1、ALDH2和ALDH3A1表现出不同的抑制作用。动力学和X射线结晶学数据表明，这些抑制剂与醛结合是竞争的，与活性部位的半胱氨酸残基形成直接相互作用。选择性是精确的，因为这些化合物似乎直接与ALDH3A1中的催化亲核试剂Cys243相互作用，而不是在ALDH2中。在ALDH2中，3-酮基被相邻的Cys301/303包围。令人惊讶的是，相互作用的方向取决于基本吲哚环结构上取代的性质，并与观察到的每个ALDH同工酶的构效关系很好地相关。
Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure–activity relationships for each ALDH isoenzyme.
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DOI：
10.1111/j.1530-0277.2009.01031.x
发表时间：
2009-11
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Arolfo MP;Overstreet DH;Yao L;Fan P;Lawrence AJ;Tao G;Keung WM;Vallee BL;Olive MF;Gass JT;Rubin E;Anni H;Hodge CW;Besheer J;Zablocki J;Leung K;Blackburn BK;Lange LG;Diamond I
通讯作者：
Diamond I
影响因子：
3
作者：
Moreb, Jan S.;Muhoczy, Dagmara;Zucali, James R.
通讯作者：
Zucali, James R.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Khanna, May;Chen, Che-Hong;Hurley, Thomas D.
通讯作者：
Hurley, Thomas D.
影响因子：
11.4
作者：
Cheung, A. M. S.;Wan, T. S. K.;Leung, A. Y. H.
通讯作者：
Leung, A. Y. H.