Maji Moumita, Acharya Sourav, Maji Saptarshi, Purkait Kallol, Gupta Arnab, Mukherjee Arindam
Department of Chemical Sciences and Centre for Advanced Functional materials, Indian Institute of Science Education and Research Kolkata, Mohanpur-741246, West Bengal, India.
Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur-741246, West Bengal, India.
Inorg Chem. 2020 Jul 20;59(14):10262-10274. doi: 10.1021/acs.inorgchem.0c01433. Epub 2020 Jun 25.
We report [Ru(L)(η--cym)Cl] ( and ) and [Pt(L)(DMSO)Cl] ( and ) complexes, where L is a chelate imine ligand derived from chloroethylamine and salicylaldehyde () or o-vanillin (). The complexes were characterized by single-crystal X-ray diffraction and other analytical techniques. The H nuclear magnetic resonance data show that both the Ru(II) and Pt(II) complexes start forming the aquated complex within an hour. The aquated complexes are stable at least up to 24 h. The complexes bind to the N of the model nucleobase 9-ethylguanine (9-EtG). Interaction with calf thymus (CT) DNA shows moderate binding interactions with binding constants, (3.7 ± 1.2) × 10 M and (4.3 ± 1.9) × 10 M for and , respectively. The complexes exhibit significant antiproliferative activity against human pancreas ductal adenocarcinoma (Mia PaCa-2), triple negative metastatic breast adenocarcinoma (MDA-MB-231), hepatocellular carcinoma (Hep G2), and colorectal adenocarcinoma (HT-29) cell lines. The studies show that with the same ligand the Pt(II) complexes are more potent than the Ru(II) complexes. The potencies of all the complexes toward pancreatic cancer cell line MIA PaCa-2 are more than cisplatin (CDDP). The Pt(II) and Ru(II) complexes show similar binding constants with CT-DNA, but the reactivity of the Pt(II) complex with 9-EtG is faster and their overall cell killing pathways are different. This is evident from the arrest of the cell cycle by the Ru(II) complex in the G2/M phase in contrast to the SubG1 phase arrest by the Pt(II) complex . The immunoblot study shows that increases cyclin D and Bcl-2 expression in MDA-MB-231 due to the SubG1 phase arrest where these proteins express in greater quantities. However, both and kill in the apoptotic pathway via dose-dependent activation of caspase 3. Complex depolarizes the mitochondria more efficiently than , suggesting its higher preference for the intrinsic pathway of apoptosis. Our work reveals that the same bidentate ligand with a change of the metal center, , Pt(II) or Ru(II), imparts significant variation in cytotoxic dosage and pathway of action due to specific intrinsic properties of a metal center (, coordination geometry, solution stability) manifested in a complex.
我们报道了[Ru(L)(η⁶ - cym)Cl]（ 和 ）以及[Pt(L)(DMSO)Cl]（ 和 ）配合物，其中L是一种由氯乙胺和水杨醛（ ）或邻香草醛衍生而来的螯合亚胺配体。通过单晶X射线衍射和其他分析技术对这些配合物进行了表征。¹H核磁共振数据表明，Ru(II)和Pt(II)配合物在一小时内均开始形成水合配合物。水合配合物至少在24小时内是稳定的。这些配合物与模型核碱基9 - 乙基鸟嘌呤（9 - EtG）的N原子结合。与小牛胸腺（CT）DNA的相互作用显示出适度的结合相互作用， 和 的结合常数分别为(3.7 ± 1.2) × 10⁵ M和(4.3 ± 1.9) × 10⁵ M。这些配合物对人胰腺导管腺癌（Mia PaCa - 2）、三阴性转移性乳腺腺癌（MDA - MB - 231）、肝细胞癌（Hep G2）和结肠腺癌（HT - 29）细胞系表现出显著的抗增殖活性。研究表明，对于相同的配体，Pt(II)配合物比Ru(II)配合物更有效。所有配合物对胰腺癌细胞系MIA PaCa - 2的效力均高于顺铂（CDDP）。Pt(II)和Ru(II)配合物与CT - DNA的结合常数相似，但Pt(II)配合物 与9 - EtG的反应更快，且它们的整体细胞杀伤途径不同。这从Ru(II)配合物 在G2/M期使细胞周期停滞，而Pt(II)配合物 在SubG1期使细胞周期停滞可以明显看出。免疫印迹研究表明，由于在SubG1期停滞， 使MDA - MB - 231中的细胞周期蛋白D和Bcl - 2表达增加，而这些蛋白在该时期表达量更高。然而， 和 均通过半胱天冬酶3的剂量依赖性激活在凋亡途径中发挥作用。配合物 比 更有效地使线粒体去极化，表明其对凋亡的内在途径有更高的偏好。我们的工作表明，具有相同双齿配体但金属中心不同（ 、Pt(II)或Ru(II)），由于配合物中金属中心的特定内在性质（ 、配位几何结构、溶液稳定性），在细胞毒性剂量和作用途径上会产生显著差异。
