Chemistry Department, Lomonosov Moscow State University, 1/3 Leninskie Gory, 119991 Moscow, Russia.
International Institute of Solution Chemistry of Advanced Materials and Technologies, ITMO University, 9 Lomonosov Street, 191002 Saint-Petersburg, Russia.
Int J Mol Sci. 2023 Feb 7;24(4):3340. doi: 10.3390/ijms24043340.
The search for new anticancer drugs based on biogenic metals, which have weaker side effects compared to platinum-based drugs, remains an urgent task in medicinal chemistry. Titanocene dichloride, a coordination compound of fully biocompatible titanium, has failed in pre-clinical trials but continues to attract the attention of researchers as a structural framework for the development of new cytotoxic compounds. In this study, a series of titanocene (IV) carboxylate complexes, both new and those known from the literature, was synthesized, and their structures were confirmed by a complex of physicochemical methods and X-ray diffraction analysis (including one previously unknown structure based on perfluorinated benzoic acid). The comprehensive comparison of three approaches for the synthesis of titanocene derivatives known from the literature (the nucleophilic substitution of chloride anions of titanocene dichloride with sodium and silver salts of carboxylic acids as well as the reaction of dimethyltitanocene with carboxylic acids themselves) made it possible to optimize these methods to obtain higher yields of individual target compounds, generalize the advantages and disadvantages of these techniques, and determine the substrate frames of each method. The redox potentials of all obtained titanocene derivatives were determined by cyclic voltammetry. The relationship between the structure of ligands, the reduction potentials of titanocene (IV), and their relative stability in redox processes, as obtained in this work, can be used for the design and synthesis of new effective cytotoxic titanocene complexes. The study of the stability of the carboxylate-containing derivatives of titanocene obtained in the work in aqueous media showed that they were more resistant to hydrolysis than titanocene dichloride. Preliminary tests of the cytotoxicity of the synthesised titanocene dicarboxilates on MCF7 and MCF7-10A cell lines demonstrated an IC50 ≥ 100 μM for all the obtained compounds.
基于生物源金属的新型抗癌药物的研究，由于其副作用较基于铂类药物的弱，因此仍然是药物化学领域的一项紧迫任务。二氯二茂钛，一种完全生物相容的钛的配位化合物，在临床前试验中失败，但作为开发新的细胞毒性化合物的结构框架，它继续吸引着研究人员的关注。在这项研究中，合成了一系列茂钛（IV）羧酸盐配合物，包括新的和文献中已知的配合物，并通过物理化学方法和 X 射线衍射分析（包括一个基于全氟化苯甲酸的先前未知结构）确认了它们的结构。综合比较了三种合成文献中已知的茂钛衍生物的方法（二茂钛二氯化物的氯离子与羧酸的钠和银盐的亲核取代反应，以及二甲基茂钛与羧酸本身的反应），使得可以优化这些方法以获得各个目标化合物的更高产率，概括这些技术的优缺点，并确定每种方法的底物框架。所有获得的茂钛衍生物的氧化还原电位均通过循环伏安法确定。在这项工作中获得的配体结构、茂钛（IV）的还原电位及其在氧化还原过程中的相对稳定性之间的关系可用于设计和合成新的有效细胞毒性茂钛配合物。研究了在工作中获得的含羧酸盐的茂钛衍生物在水介质中的稳定性，表明它们比二茂钛二氯化物更能抵抗水解。对 MCF7 和 MCF7-10A 细胞系进行的所合成的茂钛二羧酸盐的细胞毒性初步测试表明，所有获得的化合物的 IC50≥100μM。
