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

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2020 Apr 17

PMID 32298535

Citations 4

Authors

Anna M Schoepf

Stefan Salcher

Verena Hohn

Florina Veider

Petra Obexer

Ronald Gust

Affiliations

Soon will be listed here.

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-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-CO CH 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).

Citing Articles

Eradication of Therapy-Resistant Cancer Stem Cells by Novel Telmisartan Derivatives.

Schoepf A, Gebhart M, Federspiel M, Heidegger I, Puhr M, Hotze M J Med Chem. 2024; 68(1):287-306.

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Reaction Behavior of [1,3-Diethyl-4,5-diphenyl-1-imidazol-2-ylidene] Containing Gold(I/III) Complexes against Ingredients of the Cell Culture Medium and the Meaning on the Potential Use for Cancer Eradication Therapy.

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Cardiovascular Events throughout the Disease Course in Chronic Myeloid Leukaemia Patients Treated with Tyrosine Kinase Inhibitors-A Single-Centre Retrospective Study.

Varga A, Tilea I, Petra D, Tilinca M, Gliga M, Demian S J Clin Med. 2020; 9(10).

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

Schoepf A, Salcher S, Hohn V, Veider F, Obexer P, Gust R ChemMedChem. 2020; 15(12):1067-1077.

PMID: 32298535 PMC: 7318623. DOI: 10.1002/cmdc.202000092.

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