Design, Synthesis, and Biological Evaluation of Novel 7H-[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazine Inhibitors as Antitumor Agents
Ismail, Muhammad I; Mohamady, Samy; Samir, Nermin; Abouzid, Khaled;
Abstract
A series of novel anticancer hydrazinotriazolothiadiazine-based derivatives were designed based on the structure-activity relationship of the previously reported anticancer triazolothiadiazines. These derivatives were synthesized and biologically screened against full NCI-60 cancer cell lines revealing compound 5l with a potential antiproliferative effect. 5l was screened over 16 kinases to study its cytotoxic mechanism which showed to inhibit glycogen synthase kinase-3 β (GSK-3β) with IC50 equal to 0.883 μM and 14-fold selectivity over CDK2. Also, 5l increased active caspase-3 levels, induced cell cycle arrest at the G2-M phase, and increased the percentage of Annexin V-fluorescein isothiocyanate-positive apoptotic cells in PC-3 prostate cancer-treated cells. Molecular docking and dynamics were performed to predict the binding mode of 5l in the GSK-3β ATP binding site. 5l can be utilized as a starting scaffold for developing potential GSK-3β inhibitors.
Other data
Title | Design, Synthesis, and Biological Evaluation of Novel 7H-[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazine Inhibitors as Antitumor Agents | Authors | Ismail, Muhammad I; Mohamady, Samy; Samir, Nermin; Abouzid, Khaled | Keywords | GLYCOGEN-SYNTHASE KINASE-3;CANCER CELLS;PROTEIN-KINASES;CELL-PROLIFERATION;TRIAZOLO-THIADIAZINES;MOLECULAR-DYNAMICS;POTENT INHIBITORS;CRYSTAL-STRUCTURE | Issue Date | 18-Aug-2020 | Publisher | AMER CHEMICAL SOC | Journal | ACS omega | ISSN | 2470-1343 | DOI | 10.1021/acsomega.0c01829 | PubMed ID | 32832771 | Scopus ID | 2-s2.0-85091021404 | Web of science ID | WOS:000563015100026 |
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