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Design, Synthesis, and Biological Evaluation of Novel 7H-[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazine Inhibitors as Antitumor Agents.

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 ? (GSK-3?) with IC50 equal to 0.883 ?M 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-3? ATP binding site. 5l can be utilized as a starting scaffold for developing potential GSK-3? inhibitors.

SUBMITTER: Ismail MI 

PROVIDER: S-EPMC7439371 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Biological Evaluation of Novel 7<i>H</i>-[1,2,4]Triazolo[3,4-<i>b</i>][1,3,4]thiadiazine Inhibitors as Antitumor Agents.

Ismail Muhammad I MI   Mohamady Samy S   Samir Nermin N   Abouzid Khaled A M KAM  

ACS omega 20200806 32

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 <b>5l</b> with a potential antiproliferative effect. <b>5l</b> was screened over 16 kinases to study its cytotoxic mechanism which showed to inhibit glycogen synthase kinase-3 β (GSK-3β)  ...[more]

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