Synthesis and Characterization of Telmisartan-Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia.

Synthesis and Characterization of Telmisartan-Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia. ChemMedChem. 2020 Apr 16;: Authors: Gust R, Schoepf AM, Salcher S, Hohn V, Veider F, Obexer P Abstract 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-1 H -benzo[ d ]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid 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-CO 2 CH 3  derivatives, only the ester of the lead ( 2b ) slightly activated PPARγ. Sensitizing effects were observed for the non-cytotoxic  2b  (80% cell death), and to a lesser extent for the lead ( 3b ) or the 5-Br substituted ester of the be...
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research