Synthesis of unsymmetrical disulfanes bearing 1,2,4-triazine scaffold and their in vitro screening towards anti-breast cancer activity

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 Electronic supplementary materialThe online version of this article (10.1007/s00706-018-2206-y) contains supplementary material, which is available to authorized users.

MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer

“…Recently, the novel 1,2,4-triazole derivatives have been implicated in mediating antitumor activities. These compounds have inhibitory effects on the growth of several types of cultured cancer cells, including leukemia, and breast and colorectal cancer [6][7][8].…”

An Overview of Recent Advances in the Synthesis of Organic Unsymmetrical Disulfides

“…Bielawski and coworkers have performed an oxidative cross‐coupling between disulfides and thiols for the synthesis of 1,2,4‐triazine unsymmetrical disulfide ( Scheme 32). [11] The K 2 CO 3 was initially applied as a reagent in this approach, however, the yield of unsymmetrical disulfides was not satisfying (19–43 %). Then, 2,3‐dichloro‐5,6‐dicyanobenzoquinone (DDQ) was used as a commercially available oxidant for the reaction between aryl disulfides with thiols such as aryl, alkyl, and heteroaryl thiols which furnished the corresponding unsymmetrical disulfides in moderate yields.…”

“…The formation of the S−S bond has been employed for facilitating protein refolding, the prodrug synthesis, increase the hydrophobicity or cell permeability [8–10] . The 1,2,4‐triazine unsymmetrical disulfides displayed the anticancer activity against MCF‐7 human breast cancer cells [11] . The complexes between thiols, disulfides, and trisulfides with ruthenium porphyrins have been studied as a model for Fe−S bonds in heme proteins [12] .…”

QSAR study of unsymmetrical aromatic disulfides as potent avian SARS-CoV main protease inhibitors using quantum chemical descriptors and statistical methods

“…Perusal of the literature reveals a variety of methods for synthesizing disulfides and a great number of disulfide analogues had been designed and synthesized. For example, Xu Qiu et al [ 8 ] demonstrated a novel carbonate salts catalyzed aerobic oxidative heterocoupling of thiols for the efficient synthesis of unsymmetrical disulfides; D. Branowska et al [ 9 ] had described a series of new 1,2,4-triazine unsymmetrical disulfane analogues that were prepared and evaluated as anticancer activity compounds against MCF-7 human breast cancer cells with some of them acting as low micromolar; J. K. Vandavasi et al [ 10 ] have developed an efficient ‘one pot’ method for the synthesis of unsymmetrical dithio compounds directly from corresponding thiols and thiocarboxylic acids in the presence of DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone). In addition, F. Yang et al [ 11 ] have also developed one-pot synthesis of aromatic-aromatic and aromatic-aliphatic disulfide unsymmetrical disulfide using TCCA (Trichloroisocyanuric Acid).…”

“…Disulfides exist in many synthetic and natural products and have been applied extensively in organic transformation and medicinal chemistry. As example, ajoene and dysoxysulfone are found in garlic, onions and mahogany trees and have shown promising antifungal [ [15] , [16] ], antibacterial [ 17 ], antitumor [ 9 , 18 ], antimalarial [ 19 ] and analgesic properties [ 20 ].…”