Novel enantiopure cyclopentadienyl Ti(IV) oximato compounds as potential anticancer agents.
Novel enantiopure cyclopentadienyl Ti(IV) oximato compounds as potential anticancer agents.
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DOI：
10.1016/j.jinorgbio.2015.12.002
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发表时间：
2016-03
影响因子：
3.9
通讯作者：
Royo E
中科院分区：
文献类型：
--
作者：
de la Cueva-Alique I;Muñoz-Moreno L;Benabdelouahab Y;Elie BT;El Amrani MA;Mosquera ME;Contel M;Bajo AM;Cuenca T;Royo E
新的对映体纯钛肟酸配合物（S，R）-[（η5-C5 H5）Ti{κ2NO，（R）NH·HCl} Cl 2]的合成与表征（R = Ph（苯基）1a·HCl，Bn（苄基）1b·HCl，2-pic（2-吡啶甲基）1c·HCl）、（S，R）-[（η5-C5 H5）TiCl 2 {κ2NO，（Ph）NH}]（1a）和（S，R）-[（η5-C5 H5）2 TiCl {κ2NO，（R）NH}]（R = Ph 2a，Bn 2b，2-pic 2c），沿着研究了它们在不同pD值下在D2 O中的行为。用单晶X射线衍射法测定了（2S，5 R）-{NOH，（Bn）NH·HCl}（B·HCl）和新钛衍生物1a的结构。已经评估了化合物对雄激素非依赖性前列腺癌PC-3细胞的细胞毒性、细胞粘附和迁移的作用。化合物2b和2c比二氯二茂钛和游离肟前配体的添加剂量更具细胞毒性，从而探测这些新化合物的协同效应。已经针对人肾Caki-1、结肠DLD-1和三阴性乳腺MDA-MB-231癌细胞系进一步评价了2b和2c的细胞毒性。发现2c对PC-3和Caki-1的活性高于高活性二茂钛Y（双-[（对甲氧基苄基）双]二氯化钛（IV））的活性，同时当与非致瘤性人肾（HEK-293 T）细胞系相比时显示出对肾癌的选择性。化合物2b，尤其是2c在Caki-1癌细胞系中引起细胞凋亡。细胞粘附和伤口愈合实验证实，衍生物1c·HCl，2b和2c影响PC-3细胞系的粘附和迁移模式。新的化合物与质粒（pBR 322）DNA的相互作用也进行了研究，表明oximato钛（IV）衍生物有一个弱的或没有与DNA在生理pH值的相互作用。新的容易获得的对映体纯钛oximato化合物的报告。其中两种对PC-3和Caki-1癌细胞有很强的细胞毒性，同时诱导细胞凋亡，并与非致瘤性肾细胞系相比显示出选择性。它们还影响人前列腺癌细胞的粘附和迁移能力。
The synthesis and characterization of new enantiopure cyclopentadienyl titanium oximato compounds (S,R)-[(η5-C5H5)Ti{κ2NO,(R)NH·HCl}Cl2] (R = Ph (phenyl) 1a·HCl, Bn (benzyl) 1b·HCl, 2-pic (2-picolyl) 1c·HCl), (S,R)-[(η5-C5H5)TiCl2{κ2NO,(Ph)NH}] (1a) and (S,R)-[(η5-C5H5)2TiCl{κ2NO,(R)NH}] (R = Ph 2a, Bn 2b, 2-pic 2c), along with studies on their behaviour in D2O at different pD values are reported. The structure of previously described ammonium-oxime (2S,5R)-{NOH,(Bn)NH·HCl} (b·HCl) and novel titanium derivative 1a have been determined by single crystal X-ray crystallography. The effect of the compounds on cytotoxicity, cell adhesion and migration of the androgen-independent prostate cancer PC-3 cells has been assessed. Compounds 2b and 2c are more cytotoxic than additive doses of titanocene dichloride and free oxime proligand, probing the synergistic effect of these novel compounds. The cytotoxicity of 2b and 2c has been further evaluated against human renal Caki-1, colon DLD-1 and triple negative breast MDA-MB-231 cancer cell lines. The activity found for 2c on PC-3 and Caki-1 is higher than that of highly active Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride), while showing selectivity against renal cancer when compared to a non-tumorigenic human renal (HEK-293T) cell line. Compounds 2b and especially 2c are apoptotic in Caki-1 cancer cell lines. Cell adhesion and wound-healing assays confirmed that derivatives 1c·HCl, 2b and 2c affect the adhesion and migration patterns of the PC-3 cell line. Interactions of the novel compounds with plasmid (pBR322) DNA have also been studied, showing that the oximato Ti(IV) derivatives have a weak or no interaction with DNA at physiological pH. Novel easily accessible enantiopure cyclopentadienyl titanium oximato compounds are reported. Two of them are strongly cytotoxic against PC-3 and Caki-1 cancer cells while inducing apoptosis and showing selectivity when compared to a non-tumorigenic renal cell line. They also affect the adhesion and migration ability of human prostate cancer cells.