Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN, U.S.A.
Department of Chemistry and Biochemistry, University of Minnesota, Duluth, MN, U.S.A.
Anticancer Res. 2024 Mar;44(3):911-919. doi: 10.21873/anticanres.16885.
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.
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 Cell death via apoptosis or necrosis by compound 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.
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 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 indicated that it was well tolerated at high concentrations in healthy mice. Additionally, compound showed higher growth inhibition in the MDA-MB-231 tumor xenograft mouse model compared to telmisartan.
Our study indicated that alkylamine derivatives of telmisartan exhibited good solubility and higher inhibition of cancer cell proliferation than telmisartan. Compound was found to be a good lead compound, with potential for development as an anticancer agent.
背景/目的：替米沙坦是一种血管紧张素 II 受体 1（AT1）拮抗剂，对实体瘤和血液癌细胞系具有抗癌特性。我们以替米沙坦为模板，开发了具有降低 AT1 活性但增强抗癌活性的烷基胺衍生物。
通过六氟磷酸苯并三唑四甲基脲鎓偶联反应合成候选化合物，然后通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴化物测定其抑制细胞增殖的作用，并用先导化合物进行集落形成测定 通过流式细胞术用 Annexin V 和碘化丙啶测定化合物诱导的细胞死亡是通过凋亡或坏死，在 ICR 小鼠中进行耐受性剂量测定，并在 MDA-MB-231 异种移植模型中测定肿瘤减少特性。
一些合成的候选物在三阴性乳腺癌细胞系 MDA-MB-231 和 4T1 中表现出良好的细胞增殖抑制作用，其半最大有效浓度为低微摩尔。化合物 对 AT1 的亲和力低于母体替米沙坦，抑制集落形成和细胞周期分析显示，细胞凋亡可能是导致细胞死亡的重要原因。在健康小鼠中进行的体内评估表明，化合物 在高浓度下具有良好的耐受性。此外，与替米沙坦相比，化合物 在 MDA-MB-231 肿瘤异种移植小鼠模型中表现出更高的生长抑制作用。
我们的研究表明，替米沙坦的烷基胺衍生物具有良好的溶解性和比替米沙坦更高的抑制癌细胞增殖作用。化合物 被认为是一种很好的先导化合物，具有开发为抗癌剂的潜力。
