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双核银(I)-N-杂环卡宾(NHC)配合物对人结肠癌的靶向促凋亡、抗转移和抑制细胞生长作用。

Human colon cancer targeted pro-apoptotic, anti-metastatic and cytostatic effects of binuclear Silver(I)-N-Heterocyclic carbene (NHC) complexes.

作者信息

Asif Muhammad, Iqbal Muhammad Adnan, Hussein Mouayed A, Oon Chern Ein, Haque Rosenani A, Khadeer Ahamed Mohamed B, Abdul Majid Aman Shah, Abdul Majid Amin Malik Shah

机构信息

EMAN Testing and Research Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800-USM, Penang, Malaysia.

School of Chemical Sciences, Universiti Sains Malaysia, 11800-USM, Penang, Malaysia; Department of Chemistry, University of Agriculture, Faisalabad 38000, Pakistan; Community College, University of Agriculture, Faisalabad 38000, Pakistan.

出版信息

Eur J Med Chem. 2016 Jan 27;108:177-187. doi: 10.1016/j.ejmech.2015.11.034. Epub 2015 Nov 25.

Abstract

The current mechanistic study was conducted to explore the effects of increased lipophilicity of binuclear silver(I)-NHC complexes on cytotoxicity. Two new silver(I)-N-Heterocyclic Carbene (NHC) complexes (3 and 4), having lypophilic terminal alkyl chains (Octyl and Decyl), were derived from meta-xylyl linked bis-benzimidazolium salts (1 and 2). Each of the synthesized compounds was characterized by microanalysis and spectroscopic techniques. The complexes were tested for their cytotoxicity against a panel of human cancer c as well normal cell lines using MTT assay. Based on MTT assay results, complex 4 was found to be selectively toxic towards human colorectal carcinoma cell line (HCT 116). Complex 4 was further studied in detail to explore the mechanism of cell death and findings of the study revealed that complex 4 has promising pro-apoptotic and anti-metastatic activities against HCT 116 cells. Furthermore, it showed pronounced cytostatic effects in HCT 116 multicellular spheroid model. Hence, binuclear silver(I)-NHC complexes with longer terminal aliphatic chains have worth to be further studied against human colon cancer for the purpose of drug development.

摘要

进行当前的机理研究以探索双核银(I)-NHC配合物亲脂性增加对细胞毒性的影响。两种具有亲脂性末端烷基链(辛基和癸基)的新型银(I)-N-杂环卡宾(NHC)配合物(3和4),由间二甲苯基连接的双苯并咪唑盐(1和2)衍生而来。每种合成化合物均通过微量分析和光谱技术进行表征。使用MTT法测试了这些配合物对一组人类癌细胞以及正常细胞系的细胞毒性。根据MTT法结果,发现配合物4对人结肠癌细胞系(HCT 116)具有选择性毒性。对配合物4进行了进一步详细研究以探索细胞死亡机制,研究结果表明配合物4对HCT 116细胞具有有前景的促凋亡和抗转移活性。此外,它在HCT 116多细胞球体模型中显示出明显的细胞生长抑制作用。因此,具有较长末端脂肪链的双核银(I)-NHC配合物对于抗人结肠癌的药物开发而言值得进一步研究。

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