Synthesis of unsymmetrical disulfanes bearing 1,2,4-triazine scaffold and their in vitro screening towards anti-breast cancer activity
| Autor: | Ewa Wolińska, Anna Bielawska, Krzysztof Bielawski, Mariusz Sobiczewski, Danuta Branowska, Alicja Perzyna, Zbigniew Karczmarzyk, Barbara Miroslaw, Waldemar Wysocki, Ewa Olender, Justyna Ławecka |
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| Rok vydání: | 2018 |
| Předmět: |
Disulfanes
Original Paper biology 010405 organic chemistry Stereochemistry Hydrogen bond Substituent Active site General Chemistry Dihedral angle 010402 general chemistry 01 natural sciences X-ray structure determination Anticancer activity 0104 chemical sciences chemistry.chemical_compound Conformational analysis chemistry Molecular docking biology.protein Molecule MTT assay Estrogen receptor alpha Triazine |
| Zdroj: | Monatshefte Fur Chemie |
| ISSN: | 0026-9247 |
| Popis: | 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 Electronic supplementary material The online version of this article (10.1007/s00706-018-2206-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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