New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator‐activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death‐modulating effects of the telmisartan‐derived lead 4′‐((2‐propyl‐1H ‐benzo[d ]imidazol‐1‐yl)methyl)‐[1,1′‐biphenyl]‐2‐carboxylic acid (3 b ) was investigated. Inspired by the pharmacodynamics of HYL‐6d and the selective PPARγ ligand VSP‐51, the benzimidazole was replaced by a carbazole or an indole core. The results indicate no correlation between PPARγ activation and sensitization of resistant CML cells to imatinib. The 2‐COOH derivatives of the carbazoles or indoles achieved low activity at PPARγ, while the benzimidazoles showed 60‐100 % activation. Among the 2‐CO₂CH₃ derivatives, only the ester of the lead (2 b ) slightly activated PPARγ. Sensitizing effects were further observed for this non‐cytotoxic 2 b (80 % cell death), and to a lesser extent for the lead 3 b or the 5‐Br‐substituted ester of the benzimidazoles (5 b ).

中文翻译：

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替米沙坦衍生的细胞死亡调节剂的合成和表征，以规避慢性粒细胞白血病的伊马替尼耐药性。

根除慢性粒细胞白血病 (CML) 中癌症干细胞的新策略包括伊马替尼与过氧化物酶体增殖物激活受体 γ (PPARγ) 配体的组合。最近，我们发现 PPARγ 部分激动剂替米沙坦是对伊马替尼治疗耐药的 K562 CML 细胞的有效敏化剂。在此，杂环核心对替米沙坦衍生铅 4'-((2-丙基-1 H-苯并[ d ]咪唑-1-基)甲基)-[1,1研究了'-联苯]-2-羧酸( 3 b )。受 HYL-6d 和选择性 PPARγ 配体 VSP-51 药效学的启发，苯并咪唑被咔唑或吲哚核心取代。结果表明 PPARγ 激活与耐药 CML 细胞对伊马替尼的敏感性之间没有相关性。咔唑或吲哚的 2-COOH 衍生物对 PPARγ 的活性较低，而苯并咪唑则显示出 60-100% 的活化率。在2-CO ₂ CH ₃衍生物中，只有铅的酯( 2b )轻微激活PPARγ。进一步观察到这种非细胞毒性2b 的致敏作用（80% 细胞死亡），以及较小程度的先导3b或苯并咪唑的 5-Br 取代酯 ( 5b )。