Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt.
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
Bioorg Chem. 2019 May;86:598-608. doi: 10.1016/j.bioorg.2019.01.053. Epub 2019 Jan 31.
The designed compounds, 4a-p, were synthesized using a simple and smooth method with an asymmetric 1,3-dipolar reaction as the key step. The chemical structures for all synthesized compounds were elucidated and confirmed by spectral analysis. The molecular complexity and the absolute stereochemistry of 4b and 4e designed analogs were determined by X-ray crystallographic analysis. The anticancer activities of the synthesized compounds were tested against colon (HCT-116), prostate (PC-3), and hepatocellular (HepG-2) cancer cell lines. Molecular modeling revealed that the compound 4d binds through hydrophobic-hydrophobic interactions with the essential amino acids (LEU: 57, GLY: 58, ILE: 61, and HIS: 96) in the p53-binding cleft, as a standard p53-MDM2 inhibitor (6SJ). The mechanism underlying the anticancer activity of compound 4d was further evaluated, and the study showed that compound 4d inhibited colony formation, cell migration, arrested cancer cell growth at G2/M, and induced apoptosis through intrinsic and extrinsic pathways. Transactivation of p53 was confirmed by flow cytometry, where compound 4d increased the level of activated p53 and induced mRNA levels of cell cycle inhibitor, p21.
设计的化合物 4a-p 通过一种简单而流畅的方法合成，其中不对称 1,3-偶极反应是关键步骤。所有合成化合物的化学结构均通过光谱分析阐明和确认。通过 X 射线晶体学分析确定了化合物 4b 和 4e 设计类似物的分子复杂性和绝对立体化学。合成化合物的抗癌活性针对结肠（HCT-116）、前列腺（PC-3）和肝细胞（HepG-2）癌细胞系进行了测试。分子建模表明，化合物 4d 通过疏水-疏水相互作用与 p53 结合凹槽中的必需氨基酸（LEU：57、GLY：58、ILE：61 和 HIS：96）结合，作为标准的 p53-MDM2 抑制剂（6SJ）。进一步评估了化合物 4d 抗癌活性的机制，研究表明，化合物 4d 通过内在和外在途径抑制集落形成、细胞迁移、将癌细胞生长阻滞在 G2/M 期并诱导细胞凋亡。通过流式细胞术证实了 p53 的转导活性，其中化合物 4d 增加了激活的 p53 水平并诱导了细胞周期抑制剂 p21 的 mRNA 水平。
