Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic; Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
Institute of Chemistry and Technology of Macromolecular Materials, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic.
J Inorg Biochem. 2019 Jun;195:182-193. doi: 10.1016/j.jinorgbio.2019.03.015. Epub 2019 Mar 22.
Ten new vanadocene complexes bearing N,N'-chelating ligands were prepared, characterized, and their cytotoxicity toward a panel of cancer cells was measured. Structures of four vanadocene compounds were determined by single crystal X-ray diffraction analysis. Complexes containing 1,2-bis(phenylimino)acenaphthene (bian) and 1,2-bis(4-methoxyphenylimino)acenaphthene (4-MeO-bian) exhibit higher cytotoxicity than those with dipyrido[3,2-a:2',3'-c]phenazine (dppz) and (E)-N-((pyridin-2-yl)methylene)benzenamine (pyma). In light of the finding, cytotoxic mechanisms of two highly effective complexes [(η-CHMe)V(bian)][OTf] (3b) and [(η-CHMe)V(4-MeO-bian)][OTf] (4b) against human A549 lung adenocarcinoma cells were investigated by following membrane leakage of intracellular lactate dehydrogenase, Trypan Blue staining and activation of tumor protein p53 (p53). Evaluated complexes have a potent dose-dependent antiproliferative activity, causing cell cycle redistribution by the increased accumulation of cells in the G2 and S phase. In accord with the observed cell cycle deceleration, cyclin-dependent kinase inhibitor-interacting protein 1 (p21), extracellular signal-regulated kinases 1 and 2 (ERK1/2), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2) and their phosphorylated forms Chk1 at serine 345 and Chk2 at threonine 68 increased. In the cells exposed to complexes, dose- and time-dependent apoptotic process is initiated by the activation of the initiator caspase 8, followed by activation of effector caspase 3/7 and phosphatidylserine externalization. Moreover, because of treatment, A549 cells activate prosurvival mitogen-activated protein kinases (MAPK) signaling and up-regulate antiapoptotic protein B-cell lymphoma (Bcl-2), thereby promoting evasion of cell death. Both complexes exhibited considerably higher cytotoxic effect than the reference anticancer drug cis-platin and the cytotoxicity was more pronounced at higher treatment time.
制备了十种新型含 N，N'螯合配体的二茂钒配合物，对其结构进行了表征，并测试了它们对一系列癌细胞的细胞毒性。通过单晶 X 射线衍射分析确定了四种二茂钒化合物的结构。含 1,2-双（苯基亚氨基）吖啶（bian）和 1,2-双（4-甲氧基苯基亚氨基）吖啶（4-MeO-bian）的配合物比含二吡啶并[3,2-a：2'，3'-c]吩嗪（dppz）和（E）-N-（（吡啶-2-基）亚甲基）苯甲胺（pyma）的配合物具有更高的细胞毒性。鉴于这一发现，通过测定细胞内乳酸脱氢酶的膜渗漏、台盼蓝染色和肿瘤蛋白 p53（p53）的激活，研究了两种高效配合物[（η-CHMe）V（bian）][OTf]（3b）和[（η-CHMe）V（4-MeO-bian）][OTf]（4b）对人 A549 肺腺癌细胞的细胞毒性机制。评估的配合物具有很强的剂量依赖性抗增殖活性，通过增加细胞在 G2 和 S 期的积累导致细胞周期重新分布。与观察到的细胞周期减速一致，细胞周期依赖性激酶抑制剂相互作用蛋白 1（p21）、细胞外信号调节激酶 1 和 2（ERK1/2）、检查点激酶 1（Chk1）、检查点激酶 2（Chk2）及其磷酸化形式 Chk1 在丝氨酸 345 和 Chk2 在苏氨酸 68 处增加。在暴露于配合物的细胞中，通过起始半胱天冬酶 8 的激活，随后激活效应半胱天冬酶 3/7 和磷脂酰丝氨酸外化，启动剂量和时间依赖性凋亡过程。此外，由于治疗，A549 细胞激活了促生存丝裂原激活蛋白激酶（MAPK）信号通路，并上调了抗凋亡蛋白 B 细胞淋巴瘤（Bcl-2），从而促进了细胞死亡的逃避。与参考抗癌药物顺铂相比，两种配合物都表现出更高的细胞毒性，并且在更高的治疗时间时毒性更为明显。
