Identification and development of non-cytotoxic cell death modulators: Impact of sartans and derivatives on PPAR gamma activation and on growth of imatinib-resistant chronic myelogenous leukemia cells

摘要

4'4(2-Propyl-1H-benzoldlimidazol-1-yllmethyl)-[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 1(562-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 PPAR gamma is not given. Candesartan cilexetil, telmisartan and 1 showed the profile of partial agonists at PPAR gamma with EC50 values of 4.2, 4.3 and 9.1 mu M, respectively, while 6 and 12 caused only marginal intrinsic activation at 10 mu M (A(max) = 22% and 13%). However, the repression of the STATS phosphorylation relates with the possibility to sensitize 1(562-resistant CML cells to imatinib treatment. It is worth mentioning that all compounds were per se non-cytotoxic at relevant concentrations. (C) 2020 Elsevier Masson SAS. All rights reserved.