Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran.
Roberval Laboratory, Université de Technologie de Compiègne, Alliance Sorbonne Université, Compiègne, France.
Biometals. 2022 Jun;35(3):549-572. doi: 10.1007/s10534-022-00387-4. Epub 2022 Apr 2.
A cadmium(II) complex containing dppt ligand with the formula [CdCl(dppt)], where dppt is 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine was synthesized, elucidated and submitted to in vitro cytotoxicity studies against human breast (MCF-7), glioblastoma (U-87), and lung (A549) cancer cell lines as well as mouse embryo normal cell line (NIH/3T3), in comparison with cisplatin employing MTT assay over 24 and 48 h. The complex exhibited the highest cytotoxic effect against MCF-7 cells among the other three cell lines with IC values of 8.7 ± 0.5 (24 h) and 1.2 ± 0.7 µM (48 h). Significantly, flow cytometric assessment of the complex-treated MCF-7 and U-87 cells demonstrated a dose-dependent induced apoptotic cell death. The cellular morphological changes were in concord with cytotoxicity and flow cytometric results. The results of comet assay showed that the complex is able to induce DNA damage in MCF-7 cells. These observations are of importance, as sustained damage to cellular DNA could lead to apoptotic cell death. The results of DNA-binding studies indicated that the complex fits into the DNA minor groove and interacts with DNA via a partial intercalation. Moreover, the complex was able to efficiently cleave pUC19 DNA through a hydrolytic mechanism. The binding affinity between the complex and apoptosis-relevant protein targets including APAF1, Bax, Bcl-2, Cas3, Cas7, and Cas9 was evaluated through molecular docking studies. In silico virtual studies revealed the complex's strong affinity towards apoptosis-related proteins; therefore the complex can act as a potential apoptosis inducer. Physicochemical, pharmacokinetics, lipophilicity, drug-likeness, and medicinal chemistry properties of the complex were also predicted through in silico absorption, distribution, metabolism and excretion studies.
合成并阐明了一种含有 dppt 配体的镉（II）配合物，其化学式为[CdCl(dppt)]，其中 dppt 是 5,6-二苯基-3-(2-吡啶基)-1,2,4-三嗪。将其与顺铂进行比较，采用 MTT 法在 24 和 48 h 时对人乳腺癌（MCF-7）、神经胶质瘤（U-87）和肺癌（A549）癌细胞系以及小鼠胚胎正常细胞系（NIH/3T3）进行了体外细胞毒性研究。该配合物对 MCF-7 细胞的细胞毒性作用最高，IC 值分别为 8.7±0.5（24 h）和 1.2±0.7 µM（48 h）。值得注意的是，用该配合物处理 MCF-7 和 U-87 细胞的流式细胞术评估表明，细胞凋亡诱导与剂量呈依赖性。细胞形态变化与细胞毒性和流式细胞术结果一致。彗星试验结果表明，该配合物能够诱导 MCF-7 细胞的 DNA 损伤。这些观察结果很重要，因为持续的细胞 DNA 损伤可能导致细胞凋亡。DNA 结合研究的结果表明，该配合物适合于 DNA 小沟，并通过部分嵌入与 DNA 相互作用。此外，该配合物能够通过水解机制有效地切割 pUC19 DNA。通过分子对接研究评估了该配合物与凋亡相关蛋白靶点（包括 APAF1、Bax、Bcl-2、Cas3、Cas7 和 Cas9）的结合亲和力。通过计算机虚拟研究发现，该配合物与凋亡相关蛋白具有很强的亲和力；因此，该配合物可以作为一种潜在的凋亡诱导剂。通过计算机吸收、分布、代谢和排泄研究还预测了该配合物的物理化学、药代动力学、亲脂性、类药性和药物化学性质。
