Cabral Lília I L, Brás Elisa M, Henriques Marta S C, Marques Catia, Frija Luís M T, Barreira Luísa, Paixão José António, Fausto Rui, Cristiano Maria Lurdes S
Department of Chemistry and Pharmacy, F.C.T., University of Algarve, 8005-039, Faro, Portugal.
Center of Marine Sciences, CCMar, University of Algarve, 8005-039, Faro, Portugal.
Chemistry. 2018 Mar 2;24(13):3251-3262. doi: 10.1002/chem.201705319. Epub 2018 Feb 5.
Reports showing that the copper concentration is considerably higher in neoplasms than in normal tissues prompted the need to develop selective copper chelators. We disclosed recently that some N-linked tetrazole-saccharinates bind selectively to copper, forming complexes that are highly cytotoxic towards cancer cells. Because tetrazole-saccharinates are photolabile, due to the photoreactivity of tetrazoles, we proposed thiadiazolyl-saccharinates as an alternative. Herein we describe the synthesis, structure, and monomeric photochemistry of a sulphanyl-bridged thiadiazolyl-saccharinate, 3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulphanyl]-1,2-benzothiazole 1,1-dioxide (MTSB). The monomeric structure, charge density analysis, and characteristic infrared spectrum of MTSB were investigated theoretically, using quantum chemical calculations, and also experimentally, using matrix-isolation infrared spectroscopy. The crystal structure was investigated by combining X-ray crystallography with infrared and Raman spectroscopies. Results show that the structure of isolated MTSB is similar to that found in the crystal, with an S⋅⋅⋅N interaction clearly contributing to the structure of the molecule and of the crystal. Matrix irradiation revealed a high photostability of MTSB, compared to parent tetrazole-saccharinates and to the 5-methyl-1,3,4-thiadiazole building block, emphasizing the photostabilizing effect of the saccharyl system. Finally, in vitro toxicity assays of MTSB showed a copper concentration-dependent toxicity against cancer cells, without affecting normal cells. In particular, MTSB was most effective towards the hepatic (HepG2), neuroblastoma (SH-SY5), and lymphoma cell lines (U937). Thus, MTSB represents a promising lead for cancer chemotherapy based on chelating agents.
报告显示肿瘤组织中的铜浓度显著高于正常组织，这促使人们需要开发选择性铜螯合剂。我们最近披露，一些N-连接的四唑-糖精酸盐能选择性地与铜结合，形成对癌细胞具有高度细胞毒性的复合物。由于四唑具有光反应性，导致四唑-糖精酸盐具有光不稳定的特性，因此我们提出噻二唑基-糖精酸盐作为替代品。在此，我们描述了一种硫烷基桥连的噻二唑基-糖精酸盐3-[(5-甲基-1,3,4-噻二唑-2-基)硫烷基]-1,2-苯并噻唑1,1-二氧化物（MTSB）的合成、结构和单体光化学性质。使用量子化学计算从理论上研究了MTSB的单体结构、电荷密度分析和特征红外光谱，同时使用基质隔离红外光谱进行了实验研究。通过将X射线晶体学与红外光谱和拉曼光谱相结合来研究晶体结构。结果表明，分离出的MTSB的结构与晶体中的结构相似，其中S⋅⋅⋅N相互作用明显有助于分子和晶体的结构。基质辐照显示，与母体四唑-糖精酸盐和5-甲基-1,3,4-噻二唑结构单元相比，MTSB具有很高的光稳定性，突出了糖基体系的光稳定作用。最后，MTSB的体外毒性试验表明，其对癌细胞的毒性具有铜浓度依赖性，而不影响正常细胞。特别是，MTSB对肝癌细胞系（HepG2）、神经母细胞瘤细胞系（SH-SY5）和淋巴瘤细胞系（U937）最为有效。因此，MTSB代表了一种基于螯合剂的癌症化疗的有前景的先导化合物。
