Increasing the levels of antiapoptotic Bcl-2 proteins is an important way that cancer cells utilize to get out of apoptosis, underscoring their significance as promising targets for anticancer therapies. Lately, a primary compound bearing thiazolidine-2,4-dione was discovered to exhibit comparable Mcl-1 inhibitory activity in comparison to WL-276. Herein, thirty-nine thiazolidine-2,4-dione analogs were yielded through incorporating different biphenyl moieties (R), amino acid side chains (R) and sulfonamides (R) on . The findings indicated that certain compounds exhibited favorable inhibitory effects against Bcl-2/Mcl-1, while demonstrating limited or negligible binding affinity towards Bcl-xL. In particular, compounds and exhibited greater Bcl-2/Mcl-1 inhibition compared to AT-101, WL-276 and . Moreover, they demonstrated notable antiproliferative effects and significantly induced apoptosis in U937 cells. The western blot and co-immunoprecipitation assays confirmed that could induce alterations in the expression of apoptosis-associated proteins to result in apoptosis through on-target Bcl-2 and Mcl-1 inhibition. In addition, exhibited favorable stability profiles in both rat plasma and rat liver microsomes. In total, could be used as a promising compound to discover Bcl-2/Mcl-1 dual inhibitors with favorable therapeutic properties.

中文翻译：

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噻唑烷-2,4-二酮衍生物作为 Bcl-2/Mcl-1 双重抑制剂的发现和开发


提高抗凋亡 Bcl-2 蛋白的水平是癌细胞摆脱凋亡的重要途径，强调了它们作为抗癌治疗有希望的靶标的重要性。最近，发现带有 thiazolidine-2,4-dione 的主要化合物与 WL-276 相比表现出相当的 Mcl-1 抑制活性。在此，通过在 上掺入不同的联苯部分（R）、氨基酸侧链（R）和磺酰胺（R），得到了 39 种噻唑烷-2,4-二酮类似物。研究结果表明，某些化合物对 Bcl-2/Mcl-1 表现出良好的抑制作用，同时对 Bcl-xL 的结合亲和力有限或可忽略不计。特别是，与 AT-101、WL-276 和 相比，化合物 和 表现出更强的 Bcl-2/Mcl-1 抑制作用。此外，它们在 U937 细胞中表现出显着的抗增殖作用并显着诱导细胞凋亡。蛋白质印迹和免疫共沉淀测定证实，可以诱导细胞凋亡相关蛋白表达的改变，从而通过靶向 Bcl-2 和 Mcl-1 抑制而导致细胞凋亡。此外，在大鼠血浆和大鼠肝微粒体中均表现出良好的稳定性。总的来说，它可以作为一种有前途的化合物来发现具有良好治疗特性的 Bcl-2/Mcl-1 双重抑制剂。