Structure activity study of S-trityl-cysteamine dimethylaminopyridine derivatives as SIRT2 inhibitors: Improvement of SIRT2 binding and inhibition.
Structure activity study of S-trityl-cysteamine dimethylaminopyridine derivatives as SIRT2 inhibitors: Improvement of SIRT2 binding and inhibition.
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DOI：
10.1016/j.bmcl.2020.127458
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发表时间：
2020-08
影响因子：
2.7
通讯作者：
Mohamed O. Radwan;Halil I. Ciftci;T. Ali;Ryoko Koga;Hiroshi Tateishi;Akiko Nakata;A. Ito;Minoru Yoshida;M. Fujita;M. Otsuka
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文献类型：
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作者：
Mohamed O. Radwan;Halil I. Ciftci;T. Ali;Ryoko Koga;Hiroshi Tateishi;Akiko Nakata;A. Ito;Minoru Yoshida;M. Fujita;M. Otsuka
沉默调节蛋白是一类高度保守的依赖于烟酰胺腺嘌呤二核苷酸（NAD+）的赖氨酸脱酰酶。在地球仪的大量报道中，Sirtuins的多效性人类同种型2（SIRT 2）参与了癌症的发病机制。因此，SIRT 2调节被认为是一种有前途的药物干预方法。以前，我们证实了S-三苯甲基-L-半胱氨酸（STLC）-修饰的二甲基氨基吡啶化学实体命名为STC 4具有显著的SIRT 2抑制能力;这与传统的应用STLC支架作为驱动蛋白-5抑制剂是分开的。SIRT 2和STC 4的相互作用分子对接研究显示，SIRT 2的Asn 168和STC 4的甲酯之间的相互作用似乎阻碍STC 4到达蛋白质的选择性口袋，不像强SIRT 2或SirReal 2。为了提高其活性，本文中，我们利用缺少甲酯的S-三苯甲基半胱胺药效团。共合成了9个化合物，得到3个具有生物活性的SIRT 2抑制剂，其中STCY 1和STCY 6的抑制活性高于STC 4。这些化合物对不同的癌细胞系具有显著的抗增殖活性。分子对接研究揭示了先导化合物STCY 1通过吡啶环上的氮与SIRT 2蛋白质的Ala 135相互作用进入SIRT 2选择性口袋的可能结合模式。研究结果表明，活性化合物是构建更有效的生物制剂的有效中间体。
Sirtuin proteins are a highly conserved class of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylases. The pleiotropic human isoform 2 of Sirtuins (SIRT2) has been engaged in the pathogenesis of cancer in a plethora of reports around the globe. Thus, SIRT2 modulation is deemed as a promising approach for pharmaceutical intervention. Previously, we reportedS-Trityl-l-Cysteine (STLC)-ornamented dimethylaminopyridine chemical entity namedSTC4with a significant SIRT2 inhibitory capacity; this was separate from the conventional application ofSTLCscaffold as a kinesin-5 inhibitor. An interactive molecular docking study of SIRT2 andSTC4showed interaction between Asn168 of SIRT2 and the methyl ester ofSTC4, that appears to hinderSTC4to reach the selective pocket of the protein unlike strong SIRT2 inhibitorSirReal2. To improve its activity, herein, we utilizedS-trityl cysteamine pharmacophore lacking the methyl ester. Nine compounds were synthesized and assayed affording three biopertinent SIRT2 inhibitors, and two of them,STCY1andSTCY6showed higher inhibitory activity thanSTC4. These compounds have pronounced anti-proliferative activities against different cancer cell lines. A molecular docking study was executed to shed light on the supposed binding mode of the lead compound,STCY1, into the selective pocket of SIRT2 by interaction of the nitrogen of pyridine ring of the compound and Ala135 of the protein. The outcome of the study exposes that the active compounds are effective intermediates to construct more potent biological agents.