Elrashedy Ahmed, Ibrahim Noha E, Abo-Salem Heba, Elaasser Mahmoud Mohamed, El-Sawy Eslam R
Department of the Chemistry of Natural and Microbial Products, Pharmaceutical and Drug Industries Institute, National Research Centre (NRC), 33 El-Behouth St., Dokki, Giza 12622, Egypt; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt.
Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 El-Behouth St. (former El-Tahrir St.), Dokki, Giza P.O.12622, Egypt.
Bioorg Chem. 2025 Aug;163:108677. doi: 10.1016/j.bioorg.2025.108677. Epub 2025 Jun 6.
Recently, the incidence of breast cancer has increased among postmenopausal women. This highlights the need for improved aromatase inhibitors with fewer side effects than those currently available. This study focuses on designing and evaluating potential aromatase inhibitors containing the 1,2,4-triazole/indole hybrid, given their proven impact in this respect. Accordingly, by exploiting the thiol and amine groups in 5-((1H-indole-3-yl)methyl)-4-amino-4H-1,2,4-triazole-3-thiol (2) to react with some reagents, new hybrid 1,2,4-triazole-indole compounds were obtained. A cytotoxicity (MTT) test was conducted to assess the anticancer activity of the newly synthesized compounds on the breast cancer cell line MCF-7. The results of the MTT assay indicated that compounds 4d and 5 exhibited significant cytotoxic activity against the MCF-7 cancer cell lines with IC values of 17.67 ± 0.34 and 17.01 ± 0.53 μM (respectively) compared with Cisplatin, which showed an IC value of 18.03 ± 0.71 μM. Molecular dynamics simulations were conducted to investigate the crystal structure of human placental aromatase cytochrome (AR) P450 for compounds 4d and 5. The results revealed that compound 5 exhibited significant interactions with key residues in the binding site, leading to a stable complex throughout the entire simulation. Depending on molecular dynamics data, compound 5 was selected for an in vitro aromatase inhibition study. Compound 5 inhibited aromatase with an IC value of 0.026 μM, which is approximately equivalent to the reference compound letrozole (IC 0.024 μM).
最近，绝经后女性乳腺癌的发病率有所上升。这凸显了研发副作用比现有药物更少的改良型芳香化酶抑制剂的必要性。鉴于含1,2,4 - 三唑/吲哚杂化物在这方面已被证实的作用，本研究着重于设计和评估这类潜在的芳香化酶抑制剂。因此，通过利用5 - ((1H - 吲哚 - 3 - 基)甲基)-4 - 氨基 - 4H - 1,2,4 - 三唑 - 3 - 硫醇(2)中的硫醇和胺基与一些试剂反应，得到了新的1,2,4 - 三唑 - 吲哚杂化物。进行了细胞毒性(MTT)试验，以评估新合成化合物对乳腺癌细胞系MCF - 7的抗癌活性。MTT分析结果表明，化合物4d和5对MCF - 7癌细胞系表现出显著的细胞毒性活性，IC值分别为17.67±0.34和17.01±0.53μM，而顺铂的IC值为18.03±0.71μM。进行了分子动力学模拟，以研究化合物4d和5与人胎盘芳香化酶细胞色素(AR)P450的晶体结构。结果显示，化合物5与结合位点的关键残基表现出显著的相互作用，在整个模拟过程中形成了稳定的复合物。根据分子动力学数据，选择化合物5进行体外芳香化酶抑制研究。化合物5抑制芳香化酶的IC值为0.026μM，与参考化合物来曲唑(IC 0.024μM)大致相当。
