de la Cueva-Alique Isabel, Muñoz-Moreno Laura, Benabdelouahab Yosra, Elie Benelita T, El Amrani Mohammed Amin, Mosquera Marta E G, Contel María, Bajo Ana M, Cuenca Tomás, Royo Eva
Departamento de Química Orgánica y Química Inorgánica, Facultad de Biología, Ciencias Ambientales y Química, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain.
Departamento de Biología de Sistemas, Facultad de Biología, Ciencias Ambientales y Química, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain.
J Inorg Biochem. 2016 Mar;156:22-34. doi: 10.1016/j.jinorgbio.2015.12.002. Epub 2015 Dec 9.
The synthesis and characterization of new enantiopure cyclopentadienyl titanium oximato compounds (S,R)-[(η(5)-C5H5)Ti{к(2)NO,(R)NH·HCl}Cl2] (R=Ph (phenyl) 1a·HCl, Bn (benzyl) 1b·HCl, 2-pic (2-picolyl) 1c·HCl), (S,R)-[(η(5)-C5H5)TiCl2{к(2)NO,(Ph)NH}] (1a) and (S,R)-[(η(5)-C5H5)2TiCl{к(2)NO,(R)NH}] (R=Ph 2a, Bn 2b, 2-pic 2c), along with studies on their behavior 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.
报道了新型对映体纯环戊二烯基钛肟酸酯化合物（S，R）-[（η⁵-C₅H₅）Ti{κ²NO，（R）NH·HCl}Cl₂]（R = Ph（苯基）1a·HCl、Bn（苄基）1b·HCl、2-pic（2-吡啶甲基）1c·HCl）、（S，R）-[（η⁵-C₅H₅）TiCl₂{κ²NO，（Ph）NH}]（1a）和（S，R）-[（η⁵-C₅H₅）₂TiCl{κ²NO，（R）NH}]（R = Ph 2a、Bn 2b、2-pic 2c）的合成与表征，以及它们在不同pD值的D₂O中的行为研究。通过单晶X射线晶体学确定了先前描述的铵肟（2S，5R）-{NOH，（Bn）NH·HCl}（b·HCl）和新型钛衍生物1a的结构。评估了这些化合物对雄激素非依赖性前列腺癌PC-3细胞的细胞毒性、细胞黏附及迁移的影响。化合物2b和2c的细胞毒性比二氯二茂钛和游离肟前体配体的加和剂量更强，探究了这些新型化合物的协同效应。进一步评估了2b和2c对人肾Caki-1、结肠DLD-1和三阴性乳腺癌MDA-MB-231癌细胞系的细胞毒性。发现2c对PC-3和Caki-1的活性高于高活性的二氯二茂钛Y（双-[(对甲氧基苄基)环戊二烯基]钛(IV)二氯化物），同时与非致瘤性人肾（HEK-293T）细胞系相比，对肾癌具有选择性。化合物2b尤其是2c在Caki-1癌细胞系中具有凋亡作用。细胞黏附及伤口愈合试验证实，衍生物1c·HCl、2b和2c影响PC-3细胞系的黏附及迁移模式。还研究了新型化合物与质粒（pBR322）DNA的相互作用，结果表明肟酸根Ti(IV)衍生物在生理pH下与DNA的相互作用较弱或无相互作用。
