RESUMO
A three-component cascade reaction for the synthesis of 1,3,4-selenadiazoles and their derivatives from arylaldehydes, hydrazine, and elemental selenium by using molecular iodine is reported. This strategy is operationally simple, well-suited to a wide range of functional groups, and provides the desired products in moderate to excellent yields. The proposed mechanism predicts that the reaction tolerated a radical process.
RESUMO
Glycogen synthase kinase-3ß (GSK3ß) controls many physiological pathways, and is implicated in many diseases including Alzheimer's and several cancers. GSK3ß-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3ß protect against Alzheimer's disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3ß with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3ß, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3ß. Our model predicts that phosphorylation of GSK3ß Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3ß to be inactive, and are consistent with biochemical evidence for the TDZD-8-interacting residues of GSK3ß. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3ß as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3ß can facilitate the identification of novel GSK3ß inhibitors of high potency and specificity.
