DataSheet1_Discovery of 2-(4-Acrylamidophenyl)-Quinoline-4-Carboxylic Acid Derivatives as Potent SIRT3 Inhibitors.PDF

In discovery of novel SIRT3 inhibitors for the treatment of cancer, a series of 2-(4-acrylamidophenyl)-quinoline-4-carboxylic acid derivatives were designed and synthesized. Among the derived compounds, molecule P6 exhibited SIRT3 inhibitory selectivity with IC50 value of 7.2 µM over SIRT1 (32.6 µM) and SIRT2 (33.5 µM). molecular docking analysis revealed a specific binding pattern of P6 in the active site of SIRT3 compared with the bindings in the active site of SIRT1 and SIRT2. In the antiproliferative and colony forming assay, molecule P6 showed potent inhibitory activity against a group of MLLr leukemic cell lines. Further analysis revealed that induction of G0/G1 phase cell cycle arrest and cell differentiation, but not apoptosis, makes contributions to the anticancer effects of P6. Collectively, a potent SIRT3 inhibitor (P6) was discovered as a lead compound for the leukemic differentiation therapy.

本研究旨在开发用于癌症治疗的新型沉默信息调节因子3（SIRT3）抑制剂，设计并合成了一系列2-(4-丙烯酰胺基苯基)-喹啉-4-羧酸衍生物。在所获得的衍生物中，化合物P6展现出对SIRT3的选择性抑制活性，其针对SIRT3的半数抑制浓度（IC50）为7.2 μM，对SIRT1与SIRT2的IC50分别为32.6 μM与33.5 μM。分子对接分析结果显示，相较于P6在SIRT1、SIRT2活性位点的结合模式，其在SIRT3活性位点中呈现出特异性结合构象。在抗增殖与集落形成实验中，P6对一系列MLL重排（MLLr）型白血病细胞系展现出强效抑制活性。进一步机制分析表明，P6的抗癌活性源于其诱导细胞周期阻滞于G0/G1期并促进细胞分化，而非引发细胞凋亡。综上，本研究发现了一种强效SIRT3抑制剂P6，可作为白血病分化治疗的先导化合物。