Synthesis, in vitro antitumor evaluation and structure activity relationship of heptacoordinated amino-bis(Phenolato) Ti(IV) complexes stabilized by 2,6-dipicolinic acid

IF 2.7 3区化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

JBIC Journal of Biological Inorganic Chemistry Pub Date : 2024-05-09 DOI:10.1007/s00775-024-02059-9

Shanjia Li, Xupeng Zhang, Tiankun Zhao, Nan Liu, Yong Zhang, Peng Wang, Zhongduo Yang, Thomas Huhn

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Abstract

Eighteen novel Ti(IV) complexes stabilized by different chelating amino-bis(phenolato) (ONNO, ONON, ONOO) ligands and 2,6-dipicolinic acid as a second chelator were synthesized with isolated yields ranging from 79 to 93%. Complexes were characterized by ¹H and ¹³C-NMR spectroscopy, as well as by HRMS and X-Ray diffraction analysis. The good to excellent aqueous stability of these Ti(IV) complexes can be modulated by the substitutions on the 2-position of the phenolato ligands. Most of the synthesized Ti(IV) complexes demonstrated potent inhibitory activity against Hela S3 and Hep G2 tumor cells. Among them, the naphthalenyl based Salan type 2j, 2-picolylamine based [ONON] type 2n and N-(2-hydroxyethyl) based [ONOO] type 2p demonstrated up to 40 folds enhanced cytotoxicity compared to cisplatin together with a significantly reduced activity against healthy AML12 cells. The three Ti(IV) complexes exhibited fast cellular uptake by Hela S3 cells and induced almost exclusively apoptosis. 2j could trigger higher level of ROS generation than 2p and 2n.

Graphical abstract

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由 2,6-二二氯酚酸稳定的七配位氨基双（苯酚）钛（IV）配合物的合成、体外抗肿瘤评价和结构活性关系。

研究人员合成了 18 种新型钛（IV）配合物，这些配合物由不同的螯合氨基-双（苯酚）（ONNO、ONON、ONOO）配体和作为第二螯合剂的 2,6 二甲基二羧酸稳定，分离产率在 79% 到 93% 之间。络合物通过 1H 和 13C-NMR 光谱以及 HRMS 和 X 射线衍射分析进行了表征。这些钛（IV）配合物具有良好到卓越的水稳定性，这可以通过苯酚配体 2 位上的取代来调节。合成的大多数钛（IV）配合物对 Hela S3 和 Hep G2 肿瘤细胞具有很强的抑制活性。其中，基于萘基的 Salan 2j 型、基于 2-吡啶基胺的 [ONON] 2n 型和基于 N-（2-羟乙基）的 [ONOO] 2p 型的细胞毒性比顺铂增强了 40 倍，而对健康 AML12 细胞的活性则明显降低。三种钛（IV）复合物都能被 Hela S3 细胞快速吸收，并几乎完全诱导细胞凋亡。与 2p 和 2n 相比，2j 能引发更高水平的 ROS 生成。

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来源期刊

JBIC Journal of Biological Inorganic Chemistry 化学-生化与分子生物学

CiteScore

5.90

自引率

3.30%

发文量

审稿时长

3 months

期刊介绍： Biological inorganic chemistry is a growing field of science that embraces the principles of biology and inorganic chemistry and impacts other fields ranging from medicine to the environment. JBIC (Journal of Biological Inorganic Chemistry) seeks to promote this field internationally. The Journal is primarily concerned with advances in understanding the role of metal ions within a biological matrix—be it a protein, DNA/RNA, or a cell, as well as appropriate model studies. Manuscripts describing high-quality original research on the above topics in English are invited for submission to this Journal. The Journal publishes original articles, minireviews, and commentaries on debated issues.