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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine
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Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine

机译：用亮氨酸和苯丙氨酸的新型O-苄基胺基抑制剂的合成和抗蒸馏酶活性

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Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells. Proteolytic degradation in cells is mainly ensured by proteasome and its inhibition by bortezomib showed benefit in clinical use for the treatment of multiple myeloma. We report here the library of antiproteasomal O-benzyl salicylamides built from leucine and phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM and U266 cancer cell lines, ranging from high micromolar to submicromolar GI(50) values. The most potent compounds (series 4 and 6) were further assayed for their inhibition of chymotrypsin-like protease activity of the 26S proteasome in U266 cells. The majority of compounds inhibited the proteasome in mid-nanomolar concentrations (IC50 ranging from 57 to 197 nM) and it correlated with cellular potency. In a cell based assay involving green fluorescence protein (GFP) fused to a short degron that is rapidly degraded by a proteasome the compounds induced accumulation of GFP, visualised and quantified by live-cell imaging. Levels of poly-ubiquitinated proteins in U266 cells treated by compound 4m were also analyzed by immunoblotting, revealing a typical high molecular mass smear of ubiquitin conjugates. Finally, apoptotic cell death in treated U266 cells was detected biochemically by measuring the activity of caspases 3 and 7 in lysates and by immunoblotting of caspase 7, its substrate poly(ADP-ribose)polymerase, and Mcl-1, which all together showed changes typical for apoptosis. All these observations were in agreement with expected cellular mechanism of action and confirmed proteasome targeting by prepared O-benzyl salicylamides. (C) 2017 Elsevier Masson SAS. All rights reserved.
机译：抑制蛋白质降解是抑制不受控制的癌细胞增殖的策略之一。细胞中的蛋白水解降解主要通过蛋白酶体确保蛋白酶，并通过硼替佐米的抑制在临床用途中的益处用于治疗多发性骨髓瘤。我们在此报道由亮氨酸和苯丙氨酸制造的抗汽油酶O-苄基水杨酸库。制备的化合物在K562，CEM和U266癌细胞系上显示出抗增殖活性，从高微摩拉到亚微粒摩尔GI（50）值。进一步测定最有效的化合物（系列4和6）以抑制U266细胞中26s蛋白酶体的胰凝乳蛋白样蛋白酶活性。大多数化合物抑制了中纳摩尔浓度的蛋白酶（IC50，范围为57至197nm），其与细胞效力相关。在基于细胞的测定中，涉及绿色荧光蛋白（GFP）与蛋白酶迅速降解的短乙型，化合物诱导GFP的积累，通过活细胞成像进行可视化和量化。通过免疫印迹还分析了化合物4M处理的U266细胞中的聚 - 泛耐蛋白水平，揭示了遍在蛋白缀合物的典型高分子质量涂片。最后，通过测量裂解物3和7中的裂解物3和7的活性来检测治疗的U266细胞中的凋亡细胞死亡，并通过Caspase 7的免疫印迹，其基质聚（ADP-核糖）聚合酶和MCL-1一起进行了变化典型的细胞凋亡。所有这些观察结果都与预期的组织机制一致，并通过制备的O-苄基酰胺靶向确认的蛋白酶体靶向。 （c）2017年Elsevier Masson SAS。版权所有。

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