Branowska Danuta, Ławecka Justyna, Sobiczewski Mariusz, Karczmarzyk Zbigniew, Wysocki Waldemar, Wolińska Ewa, Olender Ewa, Mirosław Barbara, Perzyna Alicja, Bielawska Anna, Bielawski Krzysztof
Faculty of Science, Siedlce University, 3 Maja 54, 08-110 Siedlce, Poland.
2Department of Crystallography, Faculty of Chemistry, Maria Curie-Skłodowska University, Pl. Marii Curie-Sklodowskiej 3, 20-031 Lublin, Poland.
Monatsh Chem. 2018;149(8):1409-1420. doi: 10.1007/s00706-018-2206-y. Epub 2018 Jun 27.
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 [H]-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 (ER) as molecular target to find possible binding orientation and intermolecular interactions of investigated disulfanes within the active site of ER. 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.
制备了一系列新型的1,2,4-三嗪不对称二硫醚，并评估了它们对MCF-7人乳腺癌细胞的抗癌活性，其中一些化合物表现为低微摩尔抑制剂。通过MTT法评估细胞毒性，[H]-胸腺嘧啶掺入DNA的抑制实验表明这些产物在体外对乳腺癌细胞具有细胞毒性作用。与苯丁酸氮芥（47 μM）相比，最有效的化合物（59和60 μM）是在芳环上带有甲基和甲氧基取代基的二硫醚。此外，通过使用2,3-二氯-5,6-二氰基苯醌（DDQ），由硫醇和对称二硫醚温和高效地合成硫-硫键，以22-74%的产率获得了所有14种新化合物。通过X射线分析确定了新获得化合物的分子结构。使用密度泛函理论（DFT）水平的理论计算以及基于剑桥结构数据库（CSD）的C-S-S-C扭转角值的统计分布，对二硫键系统的构象偏好进行了表征。DFT计算和CSD搜索表明，C-S-S-C扭转角有两个优先构象，接近±90°，并且在生理条件下S-S键具有相对较大的旋转自由度。以人雌激素受体α（ER）为分子靶点进行分子对接研究，以寻找所研究的二硫醚在ER活性位点内可能的结合取向和分子间相互作用。对于大多数抗癌活性二硫醚，二硫键桥的硫原子与蛋白质残基Cys530和Ala350的S-H和C-H基团之间的S…H-S和S…H-C氢键在与雌激素受体的相互作用中起关键作用。
