Nunes Patrique, Morais Goreti Ribeiro, Palma Elisa, Silva Francisco, Oliveira Maria Cristina, Ferreira Vera F C, Mendes Filipa, Gano Lurdes, Vicente Miranda Hugo, Outeiro Tiago F, Santos Isabel, Paulo António
Centro de Ciências e Tecnologias e Nucleares, IST, Universidade de Lisboa, Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal.
Org Biomol Chem. 2015 May 14;13(18):5182-94. doi: 10.1039/c5ob00124b.
Merging classical organic anticancer drugs with metal-based compounds in one single molecule offers the possibility of exploring new approaches for cancer theranostics, i.e. the combination of diagnostic and therapeutic modalities. For this purpose, we have synthesized and biologically evaluated a series of Re(I)/(99m)Tc(I) tricarbonyl complexes (Re1–Re4 and Tc1–Tc4, respectively) stabilized by a cysteamine-based (N,S,O) chelator and containing 2-(4′-aminophenyl)benzothiazole pharmacophores. With the exception of Re1, all the Re complexes have shown a moderate cytotoxicity in MCF7 and PC3 cancer cells (IC50 values in the 15.9–32.1 μM range after 72 h of incubation). The cytotoxic activity of the Re complexes is well correlated with cellular uptake that was quantified using the isostructural (99m)Tc congeners. There is an augmented cytotoxic effect for Re3 and Re4 (versusRe1 and Re2), and the highest cellular uptake for Tc3 and Tc4, which display a long ether-containing linker to couple the pharmacophore to the (N,S,O)-chelator framework. Moreover, fluorescence microscopy clearly confirmed the cytosolic accumulation of the most cytotoxic compound (Re3). Biodistribution studies of Tc1–Tc4 in mice confirmed that these moderately lipophilic complexes (logDo/w = 1.95–2.32) have a favorable bioavailability. Tc3 and Tc4 presented a faster excretion, as they undergo metabolic transformations, in contrast to complexes Tc1 and Tc2. In summary, our results show that benzothiazole-containing Re(I)/(99m)Tc(I) tricarbonyl complexes stabilized by cysteamine-based (N,S,O)-chelators have potential to be further applied in the design of new tools for cancer theranostics.
将经典的有机抗癌药物与金属基化合物融合在一个分子中，为探索癌症诊疗新方法提供了可能，即诊断与治疗方式的结合。为此，我们合成并对一系列由基于半胱胺的（N，S，O）螯合剂稳定且含有2-（4'-氨基苯基）苯并噻唑药效基团的Re（I）/（99m）Tc（I）三羰基配合物（分别为Re1–Re4和Tc1–Tc4）进行了生物学评估。除Re1外，所有Re配合物在MCF7和PC3癌细胞中均表现出中等细胞毒性（孵育72小时后IC50值在15.9–32.1μM范围内）。Re配合物的细胞毒性活性与使用同结构的（99m）Tc类似物定量的细胞摄取密切相关。Re3和Re4具有增强的细胞毒性作用（相对于Re1和Re2），而Tc3和Tc4的细胞摄取最高，它们具有长的含醚连接子以将药效基团与（N，S，O）-螯合剂框架偶联。此外，荧光显微镜清楚地证实了细胞毒性最强的化合物（Re3）在细胞质中的积累。Tc1–Tc4在小鼠体内的生物分布研究证实，这些中等亲脂性配合物（logDo/w = 1.95–2.32）具有良好的生物利用度。与配合物Tc1和Tc2相比，Tc3和Tc4由于经历代谢转化而排泄更快。总之，我们的结果表明，由基于半胱胺的（N，S，O）-螯合剂稳定的含苯并噻唑的Re（I）/（99m）Tc（I）三羰基配合物有潜力进一步应用于新型癌症诊疗工具的设计。
