The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 9190401, Israel), Fax: (+972) 2-6584282.
Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem, 9190401, Israel.
Chemistry. 2016 Jul 11;22(29):9986-95. doi: 10.1002/chem.201601389. Epub 2016 Jun 20.
Octahedral titanium(IV) complexes of phenolato hexadentate ligands were developed and showed very high stability for days in water solutions. In vitro cytotoxicity studies showed that, whereas tetrakis(phenolato) systems are generally of low activity presumably due to inaccessibility, smaller bis(phenolato)bis(alkoxo) complexes feature high anticancer activity and accessibility even without formulations, also toward a cisplatin-resistant cell line. An all-aliphatic control complex was unstable and inactive. A leading phenolato complex also revealed: 1) high durability in fully aqueous solutions; accordingly, negligible loss of activity after preincubation for three days in medium or in serum; 2) maximal cellular accumulation and induction of apoptosis following 24-48 h of administration; 3) reduced impact on noncancerous fibroblast cells; 4) in vivo efficacy toward lymphoma cells in murine model; 5) high activity in NCI-60 panel, with average GI50 of 4.6±2 μm. This newly developed family of Ti(IV) complexes is thus of great potential for anticancer therapy.
八面体钛(IV)配合物的苯酚六齿配体得到发展，并在水溶液中表现出非常高的稳定性，可稳定数天。体外细胞毒性研究表明，尽管四(苯酚)体系通常由于难以接近而活性较低，但较小的双(苯酚)双(烷氧基)配合物具有很高的抗癌活性和可及性，即使没有制剂，对顺铂耐药细胞系也是如此。全脂族对照配合物不稳定且无活性。一种主要的苯酚配合物还表现出：1）在完全水性溶液中的高耐久性；因此，在培养基或血清中预孵育三天后，活性几乎没有损失；2）给药 24-48 小时后最大程度的细胞积累和诱导细胞凋亡；3）对非癌细胞系成纤维细胞的影响较小；4）在淋巴瘤细胞的小鼠模型中的体内疗效；5）在 NCI-60 组中具有高活性，平均 GI50 为 4.6±2μm。因此，这种新开发的钛(IV)配合物家族具有很大的抗癌治疗潜力。
