Synthesis and Characterization of Telmisartan‐Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia. (6th May 2020)

• Record Type: Journal Article
• Authors: Schoepf, Anna M.; Salcher, Stefan; Hohn, Verena; Veider, Florina; Obexer, Petra; Gust, Ronald
• Is Part Of: ChemMedChem. Volume 15:Number 12(2020)
• Page Start: 1067
• Page End: 1077
• Publication Date: 2020-05-06
• Subjects: chronic myeloid leukemia -- imatinib resistance -- peroxisome proliferator-activated receptor gamma -- sensitizers -- structure-activity relationship; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000092
• Languages: English
• ISSNs: 1860-7179

Abstract

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 (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‐CO2 CH3 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 ). Abstract : Heterocyclic compounds with carbazole, benzimidazole, or indole core were synthesized as sensitizers to imatinib treatment in resistant chronic myelogenous leukemia cells. The benzimidazole derivatives were clearly more potent as cell death modulators than the respective carbazoles or indoles. These results are important for the further development of effective sensitizers to circumvent tyrosine kinase inhibitor resistance.