Ismail Muhammad I, Mohamady Samy, Samir Nermin, Abouzid Khaled A M
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, 11837 Cairo, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.
ACS Omega. 2020 Aug 6;5(32):20170-20186. doi: 10.1021/acsomega.0c01829. eCollection 2020 Aug 18.
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 with a potential antiproliferative effect. was screened over 16 kinases to study its cytotoxic mechanism which showed to inhibit glycogen synthase kinase-3 β (GSK-3β) with IC equal to 0.883 μM and 14-fold selectivity over CDK2. Also, 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 in the GSK-3β ATP binding site. can be utilized as a starting scaffold for developing potential GSK-3β inhibitors.
基于先前报道的抗癌三唑并噻二嗪的构效关系，设计了一系列新型的基于肼基三唑并噻二嗪的抗癌衍生物。合成了这些衍生物，并针对完整的NCI - 60癌细胞系进行了生物学筛选，发现化合物具有潜在的抗增殖作用。对该化合物进行了16种激酶的筛选，以研究其细胞毒性机制，结果表明它能抑制糖原合酶激酶 - 3β（GSK - 3β），IC50等于0.883 μM，对CDK2的选择性为14倍。此外，该化合物还提高了活性半胱天冬酶 - 3的水平，诱导细胞周期在G2 - M期停滞，并增加了在PC - 3前列腺癌处理细胞中膜联蛋白V - 异硫氰酸荧光素阳性凋亡细胞的百分比。进行了分子对接和动力学研究，以预测该化合物在GSK - 3β ATP结合位点的结合模式。该化合物可作为开发潜在GSK - 3β抑制剂的起始骨架。
