Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

Abstract

Deregulation of various protein kinases is considered as one of the important factors resulting in cancer development and metastasis, thus multi-targeting the kinase family is one of the most important strategies in current cancer therapy.

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation

“…The three most potent antiproliferative derivatives in coumarin-triazole series 8 , 10 and 21 were further screened for their inhibitory activity against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases to determine the mechanism of their promising anticancer activity. Their IC 50 values were estimated in μM comparing with the references erlotinib, sorafenib and roscovitine, respectively [ 43 , 44 , 45 ], and depicted in Table 3 .…”

“…The promising kinase inhibitory results of the coumarin-triazole-glycoside targets 8 and 10 potentiate us to carry out the molecular docking to study their binding orientation within the active sites of EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases (PDB codes: 1M17, 4ASD and 3DDQ, respectively) [ 45 , 46 , 47 , 48 ]. Validation of the docking processes using MOE-Dock software (Molecular Operating Environment) version 2014.0901 [ 49 , 50 , 51 ] was done through re-docking of the original ligands erlotinib, sorafenib and roscovitine within the binding sites of EGFR, VEGFR-2 and CDK-2/cyclin A2, revealing energy scores of −11.75, −10.42 and −11.36 kcal/mol with small RMSD values of 0.74, 1.33 and 0.81 Å, respectively, between the co-crystallized ligands and their docked poses.…”

“…Validation of the docking processes using MOE-Dock software (Molecular Operating Environment) version 2014.0901 [ 49 , 50 , 51 ] was done through re-docking of the original ligands erlotinib, sorafenib and roscovitine within the binding sites of EGFR, VEGFR-2 and CDK-2/cyclin A2, revealing energy scores of −11.75, −10.42 and −11.36 kcal/mol with small RMSD values of 0.74, 1.33 and 0.81 Å, respectively, between the co-crystallized ligands and their docked poses. As reported, binding of the original ligands with the essential amino acids as Met769 though H-bonding in EGFR, Glu885, Cys919, Asp1046 and Phe1047 through H-bonding and arene–cation interactions in VEGFR-2 and Glu81, Leu83, Ile10 through H-bonding and arene–cation interactions in CDK-2, is considered as key interactions that help in obtaining the best score values [ 45 , 46 , 47 , 48 ].…”

“…The promising compounds 8 , 10 and 21 were further examined for their inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 [ 43 , 44 , 45 ].…”

“…Then, the geometry optimization and energy minimization were applied to get the Conf Search module in MOE, followed by saving of the moe file for the upcoming docking process. The co-crystallized structures of EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases with their ligands erlotinib, sorafenib and roscovitine were downloaded (PDB codes: 1M17, 4ASD and 3DDQ, respectively) [ 45 , 46 , 47 , 48 ] from the protein data bank. All minimizations were performed using MOE until an RMSD gradient of 0.05 kcal∙mol −1 Å −1 with the MMFF94x force field and the partial charges were automatically calculated.…”