Synthesis and Biological Evaluation of Telmisartan Alkylamine Derivatives as Potential Anticancer Agents

Abstract

Background/aim: Telmisartan is an angiotensin II receptor type 1 (AT1) antagonist with anticancer properties against solid and hematological cancer cell lines. Using telmisartan as a template, we developed alkylamine derivatives with reduced AT1 activity but increased anticancer activity.

Materials and methods: Synthesis of candidate compounds was carried out via hexafluorophosphate benzotriazole tetramethyl uronium coupling reaction, then their inhibition of cell proliferation was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and colony-formation assay was carried out on the lead candidate compound 8 Cell death via apoptosis or necrosis by compound 8 was determined by flow cytometry using annexin V and propidium iodide, tolerability dosing was carried out in ICR mice, and tumor-reduction properties were determined in an MDA-MB-231 xenograft model.

Results: Some of the synthesized candidates exhibited good inhibition of cell proliferation with low micromolar half maximal effective concentrations in triple-negative breast cancer cell lines MDA-MB-231 and 4T1. Compound 8 exhibited lower affinity towards AT1 than parent telmisartan, inhibition of colony formation, and cell-cycle analysis revealed apoptosis as potentially important in causing cell death. In vivo evaluation with compound 8 indicated that it was well tolerated at high concentrations in healthy mice. Additionally, compound 8 showed higher growth inhibition in the MDA-MB-231 tumor xenograft mouse model compared to telmisartan.

Conclusion: Our study indicated that alkylamine derivatives of telmisartan exhibited good solubility and higher inhibition of cancer cell proliferation than telmisartan. Compound 8 was found to be a good lead compound, with potential for development as an anticancer agent.

Keywords: AT1 antagonist; MDA-MB-231; TNBC; alkylamine derivatives; telmisartan.