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
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A series of sulfur 1,2,4-triazine derivatives were prepared and evaluated as anticancer compounds for two human breast cancer cell lines (MCF-7, MDA-MB-231) with some of them acting as low micromolar inhibitors. Evaluation of the cytotoxicity using a 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltetrazolium bromide (MTT) assay, the inhibition of [ 3 H]thymidine incorporation into DNA, and collagen synthesis inhibition demonstrated that these products exhibit cytotoxic effects on these breast cancer cell lines in vitro. The most effective were disulfide and sulfenamide compounds with two valence sulfur atoms. A structure-activity relationship study was performed using X-ray analysis and theoretical calculations at an ab initio density functional theory (DFT) level.
A convenient, three‐step synthesis of 1:1 thiacrown ether macrocycles 5a–c containing a fused cyclopenteno[c]2,2′‐bipyridine subunit has been accomplished through first homocoupling of 1,2,4‐triazine bisulfides 3a–c tethered to poly(ethylene glycol) chains with potassium cyanide and secondDiels–Alder/retro‐Diels–Alder reaction of such obtained thiamacrocycles 4a–c with 1‐pyrrolidino‐1‐cyclopentene. Macrocycles 5a–c were oxidized to nonracemic monosulfoxides 6a–c by using Davis' oxaziridine and tested in the asymmetric addition of the diethylzinc to benzaldehyde. The crystal structure determinations of 5a–c and 6b and theoretical calculations at the DFT/B3LYP/6‐311G** level were used to establish their cis or trans conformations in the solid state and the gas phase.
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