Abstract

A new series of 1,2,4-triazine unsymmetrical disulfanes were prepared and evaluated as anticancer activity compounds against MCF-7 human breast cancer cells with some of them acting as low micromolar inhibitors. Evaluation of the cytotoxicity using an MTT assay, the inhibition of [³H]-thymidine incorporation into DNA demonstrated that these products exhibit cytotoxic effects on breast cancer cells in vitro. The most effective compounds with 59 and 60 µM compared to chlorambucil with 47 µM were disulfanes bearing methyl and methoxy substituent in an aromatic ring. Furthermore, all new 14 compounds were obtained with 22–74% yield via mild and efficient synthesis of the sulfur–sulfur bond formation from thiols and symmetrical disulfanes using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). The molecular structure of the newly obtained compounds was confirmed by X-ray analysis. The conformational preferences of disulfide system were characterized using theoretical calculations at DFT level and statistical distributions of C–S–S–C torsion angle values based on the Cambridge Structural Database (CSD). The DFT calculations and CSD searching show two preferential conformations for C–S–S–C torsion angle close to ± 90° and relatively large freedom of rotation on S–S bond in physiological conditions. The molecular docking studies were performed using the human estrogen receptor alpha (ERα) as molecular target to find possible binding orientation and intermolecular interactions of investigated disulfanes within the active site of ERα. The S…H–S and S…H–C hydrogen bonds between sulfur atoms of bisulfide bridge and S–H and C–H groups of Cys530 and Ala350 as protein residues play crucial role in interaction with estrogen receptor for the most anticancer active disulfane.

Graphical abstract

中文翻译：

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带有1,2,4-三嗪支架的不对称二硫烷的合成及其抗乳腺癌活性的体外筛选。

 抽象的

制备了一系列新的 1,2,4-三嗪不对称二硫烷，并评估了其对 MCF-7 人乳腺癌细胞的抗癌活性化合物，其中一些作为低微摩尔抑制剂。使用MTT测定评估细胞毒性，抑制[ ³ H]-胸苷掺入DNA表明这些产品在体外对乳腺癌细胞表现出细胞毒性作用。与 47 µM 苯丁酸氮芥相比，59 和 60 µM 的最有效化合物是在芳环中带有甲基和甲氧基取代基的二硫烷。此外，通过使用 2,3-二氯-5,6-二氰基苯醌 (DDQ) 从硫醇和对称二硫烷温和高效地合成硫-硫键，以 22-74% 的产率获得了所有新的 14 种化合物。通过X射线分析证实了新获得的化合物的分子结构。使用DFT水平的理论计算和基于剑桥结构数据库（CSD）的C-S-S-C扭转角值的统计分布来表征二硫键系统的构象偏好。 DFT计算和CSD搜索显示了生理条件下C-S-S-C扭转角接近±90°的两种优先构象以及S-S键相对较大的旋转自由度。使用人雌激素受体α（ ERα ）作为分子靶标进行分子对接研究，以找到所研究的二硫烷在ERα活性位点内可能的结合方向和分子间相互作用。 双硫桥的硫原子与作为蛋白质残基的Cys530和Ala350的S-H和C-H基团之间的S…H-S和S…H-C氢键在最具抗癌活性的二硫烷与雌激素受体的相互作用中起着至关重要的作用。

 图形概要