Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 9190401, Israel.
Sci Rep. 2018 Jun 26;8(1):9705. doi: 10.1038/s41598-018-27735-0.
Racemic and enantiomerically pure titanium(IV) complexes with ortho-brominated or para-nitrated chiral diaminobis(phenolato) ligands were prepared with NH and NMe cyclohexyldiamino bridges through ligand to metal chiral induction. The hydrolytic behavior of the complexes was evaluated, identifying the N-methylated complex as the most stable. A representative NH complex hydrolyzed to first give a dimeric structure in solution as deduced by NMR diffusion measurements, followed by formation of clusters with higher nuclearity, as was supported by X-ray characterization of a tetranuclear cluster obtained in trace amounts following 30 days in water solutions. The cytotoxicity of the enantiomerically pure and racemic complexes was measured on HT-29 human colon cancer cell line based on the MTT assay; all stereochemical configurations of the N-methylated complex were inactive, whereas for the NH complexes, the racemic mixtures were mostly inactive but the pure enantiomers exhibited similarly high cytotoxicity, supporting a polynuclear active species. Analysis of the two enantiomers of the most active brominated complex for their cytotoxicity on human ovarian A2780, cisplatin resistant A2780cp and multi-drug-resistant A2780adr cell lines as well as for their apoptosis induction on the A2780 line revealed similar reactivity, supporting a similar mechanism for the two enantiomers.
手性二氨基双（苯并二酚）配体的外消旋和对映体纯钛（IV）配合物通过配体到金属的手性诱导，用 NH 和 NMe 环己二胺桥制备。评估了配合物的水解行为，确定 N-甲基化配合物最稳定。代表性的 NH 配合物首先在溶液中水解，如 NMR 扩散测量所推断的那样，形成具有更高核数的簇，这得到了在水溶液中 30 天后以痕量获得的四核簇的 X 射线表征的支持。根据 MTT 测定，在手性纯和外消旋配合物上测量了 HT-29 人结肠癌细胞系的细胞毒性；所有 N-甲基化配合物的立体化学构型均无活性，而对于 NH 配合物，外消旋混合物大多无活性，但纯对映异构体表现出相似的高细胞毒性，支持多核活性物质。对最活性的溴化配合物的两种对映体在人卵巢 A2780、顺铂耐药 A2780cp 和多药耐药 A2780adr 细胞系上的细胞毒性以及在 A2780 系上的细胞凋亡诱导进行分析，发现反应相似，支持两种对映体的类似机制。
