Department of Biology, Faculty of Science and Letters, Manisa Celal Bayar University, 45140, Manisa, Turkey.
Department of Chemistry, Middle East Technical University, 06800, Ankara, Turkey.
Chem Biodivers. 2023 Nov;20(11):e202301228. doi: 10.1002/cbdv.202301228. Epub 2023 Nov 8.
The study aimed to investigate the in vitro inhibitory activities of spiro N-propargylic β-enaminones, SPEs 1-31, against BCa cells, to perform in silico molecular docking studies to understand the nature of the interaction between the compounds and the ERα, PR, EGFR, and Her2, and to determine the ADMET and drug-likeness properties. Cytotoxic activity was investigated via MTT assay. DNA fragmentation was evaluated via ELISA assay. Cell cycle distributions were investigated by flow cytometry. Expression levels of Bcl-2, Bax, p21 and Cyclin D1 were measured by qRT-PCR and western blot analysis. Molecular docking was done using Autodock/vina software. ADMET analysis was calculated using the ADMETlab 2.0 tool. SPEs 1, 22, and 28 showed selective cytotoxic activity against all BCa cells with SI values >2. SPEs induced apoptosis and caused significant changes in Bcl-2 and Bax levels. The cell cycle was arrested at the S phase and levels of p21 and Cyclin D1 were induced in all BCa cells. Molecular docking analysis revealed that SPE1, SPE22, and SPE28 showed high binding affinities with ERα, PR, EGFR, and Her2. ADMET analysis revealed that SPEs are drug-like compounds as they obey the five rules of Lipinsky and are not toxic. Therefore, these potential anticancer compounds should be further validated by in vivo studies for their appropriate function in human health with a safety profile, and a comprehensive drug interaction study should be performed.
本研究旨在研究螺环 N-丙炔基β-烯胺酮（SPEs）1-31 对 BCa 细胞的体外抑制活性，进行计算机分子对接研究，以了解化合物与 ERα、PR、EGFR 和 Her2 相互作用的性质，并确定 ADMET 和类药性特性。通过 MTT 测定法检测细胞毒性活性。通过 ELISA 测定法评估 DNA 片段化。通过流式细胞术研究细胞周期分布。通过 qRT-PCR 和 Western blot 分析测量 Bcl-2、Bax、p21 和 Cyclin D1 的表达水平。使用 Autodock/vina 软件进行分子对接。使用 ADMETlab 2.0 工具计算 ADMET 分析。SPE1、22 和 28 对所有 BCa 细胞均表现出选择性细胞毒性活性，SI 值>2。SPE 诱导细胞凋亡并导致 Bcl-2 和 Bax 水平发生显著变化。细胞周期在 S 期被阻断，所有 BCa 细胞中的 p21 和 Cyclin D1 水平被诱导。分子对接分析表明，SPE1、SPE22 和 SPE28 与 ERα、PR、EGFR 和 Her2 具有高结合亲和力。ADMET 分析表明，SPE 是类药性化合物，因为它们符合 Lipinski 的五条规则，且没有毒性。因此，这些潜在的抗癌化合物应通过体内研究进一步验证，以评估其在人类健康中的适当功能和安全性概况，并应进行全面的药物相互作用研究。
