Disruption of the Microtubule Network and Inhibition of VEGFR2 Phosphorylation by Cytotoxic N,O-Coordinated Pt(II) and Ru(II) Complexes of Trimethoxy Aniline-Based Schiff Bases
Disruption of the Microtubule Network and Inhibition of VEGFR2 Phosphorylation by Cytotoxic N,O-Coordinated Pt(II) and Ru(II) Complexes of Trimethoxy Aniline-Based Schiff Bases
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DOI：
10.1021/acs.inorgchem.0c03820
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发表时间：
2021-02-08
影响因子：
4.6
通讯作者：
Mukherjee, Arindam
中科院分区：
文献类型：
--
作者：
Acharya, Sourav;Maji, Moumita;Mukherjee, Arindam
铂基配合物是最成功的化疗药物之一，尽管它们有副作用，但在癌症化疗中具有显著的基础。在过去的几十年中，钌（II）配合物已成为有效的替代品，由于其有前途的活动对铂耐药的癌症。Pt或Ru络合物的作用途径、亲脂性和细胞毒性可以通过改变连接的配体、配位模式和离去基团来调节。本文报道了一系列含N，O和N，N三种给体的三甲氧基苯胺类席夫碱的Pt（II）和Ru（II）配合物（1-5），通式为[Pt-II（L）（DMSO）Cl]，[Ru-II（L）（p-cymene）Cl]，[Ru-II（L）（p-cymene）Cl]（+）和[Pt-II（L）Cl-2]。所有的配合物的特征在于不同的分析技术。1 H NMR和电喷雾质谱（ESI-MS）数据表明，与Ru（II）类似物相比，N，O-配位的Pt（II）配合物经历较慢的水合作用。配位方式的改变使Ru配合物对水合反应更加惰性。N，O-配位络合物通过显示针对不同侵袭性癌细胞的优异的体外抗增殖活性而显示出优于N，N-配位络合物的优越性，三阴性人转移性乳腺癌MDA-MB-231、人胰腺癌MIA PaCa-2和肝细胞癌Hep G2。体外细胞毒性研究表明，Pt（II）配合物比其相应的Ru（II）类似物更有效，并且最具细胞毒性的配合物3对MDA-MB-231细胞的毒性是临床药物顺铂和奥沙利铂的10-15倍。细胞研究表明，所有的N，O-配位复合物（1-3）在孵育6小时内以剂量依赖性方式启动MDA-MB-231细胞中微管网络的破坏，并最终导致细胞周期停滞在G2/M期，并导致凋亡性细胞死亡。微管网络的破坏影响细胞骨架的灵活性，从而抑制血管内皮生长因子受体2（VEGFR 2）的酪氨酸磷酸化，这是血管生成的关键步骤。复合物1和2以剂量依赖性方式抑制VEGFR 2磷酸化。在Pt（II）和Ru（II）配合物中，前者显示出更高的细胞毒性，对细胞骨架的更强作用，更好的VEGFR 2抑制，以及与模型核碱基9-乙基鸟嘌呤（9-EtG）的强相互作用。
Platinum-based complexes are one of the most successful chemotherapeutic agents having a significant ground in cancer chemotherapy despite their side effects. During the past few decades, Ru(II) complexes have been emerging as efficient alternatives owing to their promising activities against platinum-resistant cancer. The pathway of action, lipophilicity, and cytotoxicity of a Pt or Ru complex may be tuned by varying the attached ligands, the coordination mode, and the leaving group. In this work, we report a family of Pt(II) and Ru(II) complexes (1-5) of three N,O and N,N donor-based trimethoxyanilines containing Schiff bases with the general formula [Pt-II(L)(DMSO)Cl], [Ru-II(L)(p-cymene)Cl], [Ru-II(L)(p-cymene)Cl](+), and [Pt-II(L)Cl-2]. All of the complexes are characterized by different analytical techniques. 1 H NMR and electrospray ionization mass spectrometry (ESI-MS) data suggest that the N,O-coordinated Pt(II) complexes undergo slower aquation compared to the Ru(II) analogues. The change of the coordination mode to N,N causes the Ru complexes to be more inert to aquation. The N,O-coordinating complexes show superiority over N,N-coordinating complexes by displaying excellent in vitro antiproliferative activity against different aggressive cancer cells, viz., triplenegative human metastatic breast adenocarcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. In vitro cytotoxicity studies suggest that Pt(II) complexes are more effective than their corresponding Ru(II) analogues, and the most cytotoxic complex 3 is 10-15 times more toxic than the clinical drugs cisplatin and oxaliplatin against MDA-MB-231 cells. Cellular studies show that all of the N,O-coordinated complexes (1-3) initiate disruption of the microtubule network in MDA-MB-231 cells in a dose-dependent manner within 6 h of incubation and finally lead to the arrest of the cell cycle in the G2/M phase and render apoptotic cell death. The disruption of the microtubule network affects the agility of the cytoskeleton rendering inhibition of tyrosine phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a key step in angiogenesis. Complexes 1 and 2 inhibit VEGFR2 phosphorylation in a dose-dependent fashion. Among the Pt(II) and Ru(II) complexes, the former displays higher cytotoxicity, a stronger effect on the cytoskeleton, better VEGFR2 inhibition, and strong interaction with the model nucleobase 9-ethylguanine (9-EtG).