The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in cancer.

在许多肿瘤细胞中过度表达的抗凋亡蛋白 B 细胞淋巴瘤 2 (Bcl-2) 是潜在的小分子抗癌药物发现的一个有吸引力的目标。在此，设计、合成了一系列具有酰基磺酰胺骨架的新型衍生物，并通过生物等排置换的方式对其作为 Bcl-2 抑制剂进行了评估。其中，与阳性对照 ABT-199 相比，化合物24g对 RS4;11 细胞系表现出同等有效的抑制活性。此外，它显示出对 Bcl-2/Bcl-xL 抑制作用的选择性提高，其结果与血小板毒性研究一致。化合物24g的体外和体内药代动力学特性有一个显着改善的配置文件。总之，这些结果表明它是开发针对癌症中 Bcl-2 的新疗法的有希望的候选者。