Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as SIRT2 inhibitors. SAR analyses with new synthesized derivatives revealed a number of new potent SIRT2 inhibitors, among which 28e is the most potent inhibitor with an IC₅₀ value of 42 nM. The selectivity analyses found that 28e has a very good selectivity to SIRT2 over SIRT1 and SIRT3. In cellular assays, 28e showed a potent ability to inhibit human breast cancer cell line MCF-7 and increase the acetylation of α-tubulin in a dose-dependent manner. This study will aid further efforts to develop highly potent and selective SIRT2 inhibitors for the treatment of cancer and other related diseases.

中文翻译：

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发现2-（（4,6-二甲基嘧啶-2-基）硫基）-N-苯基乙酰胺衍生物作为新型有效的选择性人Sirtuin 2抑制剂

人Sirtuin 2（SIRT2）在多种生物过程中发挥关键作用，例如细胞周期调节，自噬，免疫和炎症反应。SIRT2的失调被认为是导致多种人类疾病（包括癌症）的一个主要方面。当前期望开发新的有效的和选择性的SIRT2抑制剂，其可以提供治疗相关疾病的新策略。在这里，基于结构的优化方法导致了新的2-（（（4,6-二甲基嘧啶-2-基）硫基）-N-苯基乙酰胺衍生物作为SIRT2抑制剂。使用新合成衍生物进行的SAR分析揭示了许多新的有效SIRT2抑制剂，其中28e是最有效的IC ₅₀抑制剂。值为42 nM。选择性分析发现28e对SIRT2的选择性优于SIRT1和SIRT3。在细胞测定中，28e显示出抑制人乳腺癌细胞系MCF-7并以剂量依赖性方式增加α-微管蛋白乙酰化的有效能力。这项研究将有助于进一步努力，开发出用于治疗癌症和其他相关疾病的高效和选择性SIRT2抑制剂。