In vitro and in vivo antitumor activities of three novel binuclear platinum(II) complexes with 4 '-substituted-2,2 ':6 ',2 ''-terpyridine ligands
In vitro and in vivo antitumor activities of three novel binuclear platinum(II) complexes with 4 '-substituted-2,2 ':6 ',2 ''-terpyridine ligands
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三种新型双核铂(II)配合物与4'-取代-2,2':6',2''-三联吡啶配体的体外和体内抗肿瘤活性
DOI：
10.1016/j.ejmech.2019.03.014
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发表时间：
2019
影响因子：
6.7
通讯作者：
Liang Hong
中科院分区：
文献类型：
--
作者：
Qin Qi-Pin;Wang Zhen-Feng;Wang Shu-Long;Luo Dong-Mei;Zou Bi-Qun;Yao Peng-Fei;Tan Ming-Xiong;Liang Hong
本文报道了三种新型双核铂(II)配合物的设计和合成，它们是：[Pt(Tpbtpy)Cl][Pt(Dmso)Cl3](tpbtpy-Pt)，[Pt(Dthbtpy)Cl][Pt(Dmso)Cl3]⋅CH3OH(dthbtpy-Pt)，[Pt(Qlbtpy)Cl][Pt(Dmso)Cl3]⋅CH3OH(qlbtpy-pt)，4‘-(3，5-二(1，1-dimethylethyl)-2-hydroxy-benzaldehyde)-2，2′：6′，2″-terpyridine(Dthbtpy)和4′-(2-quinolinecarboxaldehyde)-2，2′：6′，2″-terpyridine(Qlbtpy)分别作为配体。三种新型双核铂(II)配合物pbtpy-Pt、dthbtpy-pt和qlbtpy-Pt均经单晶X射线衍射分析、光谱分析(ESI-MS、IR、1H核磁共振)和元素分析进行了表征。此外，用人非小细胞肺癌细胞系(NCIsingle BondH460 细胞)测定了tpbtpy-PT、dthbtpy-Pt和qlbtpy-Pt的细胞毒性，IC50值为0.35-12.09μM，其中tpbtpy-Ptas最强，qlbtpy-Ptas最弱。机制研究表明，Atpbtpy-Pt和dthbtpy-Ptt通过线粒体功能障碍和端粒酶抑制诱导细胞凋亡。在NCIsingle BondH460移植瘤模型中，每隔2天以10.0 mg kg−1次给药，可显著抑制肿瘤生长(肿瘤生长抑制率(IR) = 70.1%，p<； 0.05)。因此，tpbtpy-Ptt是一种很有前途的铂(II)配合物，可作为抗肿瘤药物进行进一步的翻译研究和临床评价。
Herein, we report the design and synthesis of three novel binuclear platinum(II) complexes, [Pt(tpbtpy)Cl][Pt(DMSO)Cl3] (tpbtpy-Pt), [Pt(dthbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (dthbtpy-Pt), and [Pt(qlbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (qlbtpy-Pt) with 4′-(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine (tpbtpy), 4′-(3,5-bis (1,1-dimethylethyl)-2-hydroxy-benzaldehyde)-2,2′:6′,2″-terpyridine (dthbtpy) and 4′-(2-quinolinecarboxaldehyde)-2,2′:6′,2″-terpyridine (qlbtpy) as ligands, respectively. All three novel binuclear platinum(II) complexestpbtpy-Pt,dthbtpy-Pt, andqlbtpy-Ptwere characterized by single-crystal X-ray diffraction analysis, spectroscopic analysis (ESI-MS, IR,1H NMR), and elemental analysis. Additionally, the cytotoxicity oftpbtpy-Pt,dthbtpy-Ptandqlbtpy-Ptwas assessed with human non-small cell lung cancer cell line (NCIsingle bondH460 cells), yielding IC50values in the range of 0.35–12.09μM withtpbtpy-Ptas the most potent andqlbtpy-Ptas the least potent complexes. Mechanistic studies indicated thattpbtpy-Ptanddthbtpy-Ptinduced apoptosis through mitochondrial dysfunction and telomerase inhibition. In a NCIsingle bondH460 xenograft model, when administered at 10.0 mg kg−1every 2 days,tpbtpy-Ptwas shown to significantly reduce tumor growth (tumor growth inhibition rate (IR) = 70.1%,p< 0.05). Therefore,tpbtpy-Ptis a promising Pt(II) complex for further translational studies and clinical evaluation as an antitumor agent.