Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066, Bobadela LRS, Portugal.
Centro Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal.
J Biol Inorg Chem. 2019 Feb;24(1):71-89. doi: 10.1007/s00775-018-1629-6. Epub 2018 Nov 24.
The development of pharmacologically active compounds based on bis(thiosemicarbazones) (BTSC) and on their coordination to metal centers constitutes a promising field of research. We have recently explored this class of ligands and their Cu(II) complexes for the design of cancer theranostics agents with enhanced uptake by tumoral cells. In the present work, we expand our focus to aliphatic and aromatic BTSC Zn(II) complexes bearing piperidine/morpholine pendant arms. The new complexes ZnL-ZnL were characterized by a variety of analytical techniques, which included single-crystal X-ray crystallography for ZnL and ZnL. Taking advantage of the fluorescent properties of the aromatic complexes, we investigated their cellular uptake kinetics and subcellular localization. Furthermore, we tried to elucidate the mechanism of action of the cytotoxic effect observed in human cancer cell line models. The results show that the aliphatic complexes (ZnL and ZnL) have a symmetrical structure, while the aromatic counterparts (ZnL and ZnL) have an asymmetrical nature. The cytotoxic activity was higher for the aromatic BTSC complexes, as well as the cellular uptake, evaluated by measurement of intracellular Zn accumulation. Among the most active complexes, ZnL presented the fastest uptake kinetics and lysosomal localization assessed by live-cell microscopy. Detailed studies of its impact on cellular production of reactive oxygen species and impairment of lysosomal membrane integrity reinforced the influence of the pendant piperidine in the biological performance of aromatic BTSC Zn(II) complexes.
基于双（硫代缩氨基甲肟）（BTSC）并将其配位到金属中心的药理活性化合物的开发是一个很有前途的研究领域。我们最近研究了这类配体及其 Cu(II)配合物，以设计具有增强肿瘤细胞摄取能力的癌症治疗药物。在本工作中，我们将研究重点扩展到带有哌啶/吗啉侧臂的脂肪族和芳香族 BTSC Zn(II)配合物。新的配合物 ZnL-ZnL 通过各种分析技术进行了表征，其中包括 ZnL 和 ZnL 的单晶 X 射线晶体学。利用芳香族配合物的荧光性质，我们研究了它们的细胞摄取动力学和亚细胞定位。此外，我们试图阐明在人癌细胞模型中观察到的细胞毒性作用的作用机制。结果表明，脂肪族配合物（ZnL 和 ZnL）具有对称结构，而芳香族配合物（ZnL 和 ZnL）具有不对称性质。芳香族 BTSC 配合物的细胞毒性活性更高，以及通过测量细胞内 Zn 积累来评估的细胞摄取。在最活跃的配合物中，ZnL 表现出最快的摄取动力学和溶酶体定位，通过活细胞显微镜评估。对其对细胞内活性氧产生的影响及其对溶酶体膜完整性的损害的详细研究，增强了哌啶侧链在芳香族 BTSC Zn(II)配合物的生物学性能中的影响。
