Guangxi Key Laboratory of Agricultural Resources, Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, China.
Guangxi Key Laboratory of Agricultural Resources, Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, China.
Eur J Med Chem. 2019 May 15;170:195-202. doi: 10.1016/j.ejmech.2019.03.014. Epub 2019 Mar 9.
Herein, we report the design and synthesis of three novel binuclear platinum(II) complexes, [Pt(tpbtpy)Cl][Pt(DMSO)Cl] (tpbtpy-Pt), [Pt(dthbtpy)Cl][Pt(DMSO)Cl]⋅CHOH (dthbtpy-Pt), and [Pt(qlbtpy)Cl][Pt(DMSO)Cl]⋅CHOH (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) complexes tpbtpy-Pt, dthbtpy-Pt, and qlbtpy-Pt were characterized by single-crystal X-ray diffraction analysis, spectroscopic analysis (ESI-MS, IR, H NMR), and elemental analysis. Additionally, the cytotoxicity of tpbtpy-Pt, dthbtpy-Pt and qlbtpy-Pt was assessed with human non-small cell lung cancer cell line (NCIH460 cells), yielding IC values in the range of 0.35-12.09 μM with tpbtpy-Pt as the most potent and qlbtpy-Pt as the least potent complexes. Mechanistic studies indicated that tpbtpy-Pt and dthbtpy-Pt induced apoptosis through mitochondrial dysfunction and telomerase inhibition. In a NCIH460 xenograft model, when administered at 10.0 mg kg every 2 days, tpbtpy-Pt was shown to significantly reduce tumor growth (tumor growth inhibition rate (IR) = 70.1%, p < 0.05). Therefore, tpbtpy-Pt is a promising Pt(II) complex for further translational studies and clinical evaluation as an antitumor agent.
本文报道了三种新型双核铂（II）配合物的设计与合成，[Pt(tpbtpy)Cl][Pt(DMSO)Cl]（tpbtpy-Pt）、[Pt(dthbtpy)Cl][Pt(DMSO)Cl]·CHOH（dthbtpy-Pt）和[Pt(qlbtpy)Cl][Pt(DMSO)Cl]·CHOH（qlbtpy-Pt），它们分别以 4'-(3-噻吩甲酰基)-2,2':6',2″-三联吡啶（tpbtpy）、4'-(3,5-二叔丁基-2-羟基苯甲酰基)-2,2':6',2″-三联吡啶（dthbtpy）和 4'-(2-喹啉甲酰基)-2,2':6',2″-三联吡啶（qlbtpy）为配体。通过单晶 X 射线衍射分析、光谱分析（ESI-MS、IR、H NMR）和元素分析对三种新型双核铂（II）配合物 tpbtpy-Pt、dthbtpy-Pt 和 qlbtpy-Pt 进行了表征。此外，通过人非小细胞肺癌细胞系（NCIH460 细胞）评估了 tpbtpy-Pt、dthbtpy-Pt 和 qlbtpy-Pt 的细胞毒性，得到了 IC 值范围为 0.35-12.09 μM 的结果，其中 tpbtpy-Pt 的活性最强，qlbtpy-Pt 的活性最弱。机制研究表明，tpbtpy-Pt 和 dthbtpy-Pt 通过线粒体功能障碍和端粒酶抑制诱导细胞凋亡。在 NCIH460 异种移植模型中，当以 10.0 mg/kg 每 2 天给药时，tpbtpy-Pt 显著抑制肿瘤生长（肿瘤生长抑制率（IR）=70.1%，p<0.05）。因此，tpbtpy-Pt 是一种很有前途的铂（II）配合物，可进一步作为抗肿瘤药物进行转化研究和临床评估。
