Qin Qi-Pin, Meng Ting, Tan Ming-Xiong, Liu Yan-Cheng, Luo Xu-Jian, Zou Bi-Qun, Liang Hong
Guangxi Key Laboratory of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin, 541004, PR China.
Guangxi Key Laboratory of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin, 541004, PR China.
Eur J Med Chem. 2018 Jan 1;143:1597-1603. doi: 10.1016/j.ejmech.2017.10.058. Epub 2017 Oct 25.
A new copper(II) complex of dasatinib (DAS) was synthesized and characterized via ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction analysis, H and C NMR spectroscopy, and elemental analysis. The composition of the new complex (1) was found to be [Cu(DAS + H)(NO)(HO)]NO·(HO)·(CHOH). Through MTT assay, it was found that 1 had high cytotoxicity towards A549, HeLa, BEL-7402, Hep-G2, NCI-H460, and MGC80-3 tumor cell lines, with IC values in 4.04-13.04 μM. The Hep-G2 cells were the most sensitive to 1. It is worth noting that compared with DAS and cisplatin, 1 not only had higher in vitro anticancer activity but also exhibited greater selective toxicity towards Hep-G2 cells than for normal HL-7702 cells. Experimental results from cell apoptosis analysis, cellular uptake, TRAP-silver staining assay, RT-PCR, western blot, and transfection assays showed that 1 was most likely a telomerase inhibitor that targeted c-myc G-quadruplex DNA. The high cytotoxicity and biological behaviors of 1 could be correlated with the central copper(II) atom in the coordinated mode with DAS.
合成了一种新的达沙替尼（DAS）铜（II）配合物，并通过电喷雾电离质谱（ESI-MS）、紫外可见光谱（UV-Vis）、红外光谱（IR）、单晶X射线衍射分析、氢核磁共振（H NMR）和碳核磁共振（C NMR）光谱以及元素分析对其进行了表征。发现新配合物（1）的组成为[Cu（DAS + H）（NO）（H₂O）]NO₃·（H₂O）·（C₂H₅OH）。通过MTT法测定发现，1对A549、HeLa、BEL-7402、Hep-G2、NCI-H460和MGC80-3肿瘤细胞系具有高细胞毒性，IC₅₀值在4.04 - 13.04 μM之间。Hep-G2细胞对1最为敏感。值得注意的是，与DAS和顺铂相比，1不仅具有更高的体外抗癌活性，而且对Hep-G2细胞表现出比对正常HL-7702细胞更大的选择性毒性。细胞凋亡分析、细胞摄取、抗酒石酸酸性磷酸酶-银染色测定、逆转录聚合酶链反应（RT-PCR）、蛋白质免疫印迹法（western blot）和转染测定的实验结果表明，1很可能是一种靶向c-myc G-四链体DNA的端粒酶抑制剂。1的高细胞毒性和生物学行为可能与其与DAS配位模式中的中心铜（II）原子有关。
