4'-((2-Propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid derived from telmisartan was identified as lead for the design of cell death modulators. In this study, we evaluated the efficacy of telmisartan itself and other sartans in combination with imatinib against K562-resistant cells. The findings were directly used to further optimize the lead structure. Telmisartan and candesartan cilexetil represented the most effective sartans, thus the influence of carboxyl/methyl carboxylate groups at positions 7 (compounds 6, 7) or 4 (compounds 12-14) at the benzimidazole core was studied. Additionally, according to the results of a former structure-activity study, telmisartan was transformed to the related amide (1). Telmisartan amide 1, as well as the esters 6 and 12 markedly sensitized the resistant CML cells to imatinib treatment. Correlation with their potency to activate PPARγ is not given. Candesartan cilexetil, telmisartan and 1 showed the profile of partial agonists at PPARγ with EC50 values of 4.2, 4.3 and 9.1 μM, respectively, while 6 and 12 caused only marginal intrinsic activation at 10 μM (Amax = 22% and 13%). However, the repression of the STAT5 phosphorylation relates with the possibility to sensitize K562-resistant CML cells to imatinib treatment. It is worth mentioning that all compounds were per se non-cytotoxic at relevant concentrations.

中文翻译：

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非细胞毒性细胞死亡调节剂的鉴定和开发：沙坦及其衍生物对PPARγ活化和对伊马替尼耐药的慢性粒细胞白血病细胞生长的影响。

替米沙坦衍生的4'-（（2-丙基-1H-苯并[d]咪唑-1-基）甲基）-[1,1'-联苯] -2-羧酸被确定为细胞死亡设计的先导调制器。在这项研究中，我们评估了替米沙坦本身和其他沙坦与伊马替尼联合对K562耐药细胞的疗效。这些发现直接用于进一步优化引线结构。替米沙坦和坎地沙坦西酯是最有效的萨尔坦，因此研究了苯并咪唑核心位置7（化合物6、7）或4（化合物12-14）的羧基/羧酸甲酯基团的影响。此外，根据以前的结构活性研究的结果，替米沙坦被转化为相关的酰胺（1）。替米沙坦酰胺1，以及酯6和12明显使耐药的CML细胞对伊马替尼治疗敏感。没有给出它们激活PPARγ的能力的相关性。Candesartan cilexetil，telmisartan和1显示PPARγ处部分激动剂的分布，EC50值分别为4.2、4.3和9.1μM，而6和12仅在10μM时引起边缘内在活化（Amax = 22％和13％）。但是，STAT5磷酸化的抑制与使耐K562的CML细胞对伊马替尼治疗敏感的可能性有关。值得一提的是，所有化合物本身在相关浓度下均无细胞毒性。而6和12仅在10μM时引起边际固有激活（Amax = 22％和13％）。但是，STAT5磷酸化的抑制与使耐K562的CML细胞对伊马替尼治疗敏感的可能性有关。值得一提的是，所有化合物本身在相关浓度下均无细胞毒性。而6和12仅在10μM时引起边际固有激活（Amax = 22％和13％）。但是，STAT5磷酸化的抑制与使耐K562的CML细胞对伊马替尼治疗敏感的可能性有关。值得一提的是，所有化合物本身在相关浓度下均无细胞毒性。