Abdel-Aziz Hatem A, Eldehna Wagdy M, Keeton Adam B, Piazza Gary A, Kadi Adnan A, Attwa Mohamed W, Abdelhameed Ali S, Attia Mohamed I
Department of Applied Organic Chemistry, National Research Centre, Giza.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
Drug Des Devel Ther. 2017 Aug 9;11:2333-2346. doi: 10.2147/DDDT.S140164. eCollection 2017.
In continuation of our endeavor with respect to the development of potent and effective isatin-based anticancer agents, we adopted the molecular hybridization approach to design and synthesize four different sets of isatin-quinazoline ( and )/phthalazine ()/quinoxaline () hybrids. The antiproliferative activity of the target hybrids was assessed towards HT-29 (colon), ZR-75 (breast) and A-549 (lung) human cancer cell lines. Hybrids emerged as the most active antiproliferative congener in this study. Compound induced apoptosis via increasing caspase 3/7 activity by about 5-fold in the A-549 human cancer cell line. In addition, it exhibited an increase in the G1 phase and a decrease in the S and G2/M phases in the cell cycle effect assay. Furthermore, it displayed an inhibitory concentration 50% value of 9.5 µM against multidrug-resistant NCI-H69AR lung cancer cell line. The hybrid was also subjected to in vitro metabolic investigations through its incubation with rat liver microsomes and analysis of the resulting metabolites with the aid of liquid chromatography-mass spectrometry.
为持续推进我们在开发高效有效的基于异吲哚酮的抗癌药物方面的工作，我们采用分子杂交方法设计并合成了四组不同的异吲哚酮 - 喹唑啉（和）/酞嗪（）/喹喔啉（）杂化物。评估了目标杂化物对HT - 29（结肠）、ZR - 75（乳腺）和A - 549（肺）人癌细胞系的抗增殖活性。在本研究中，杂化物表现为最具活性的抗增殖同系物。化合物在A - 549人癌细胞系中通过使半胱天冬酶3/7活性增加约5倍诱导细胞凋亡。此外，在细胞周期效应试验中，它表现出G1期增加，S期和G2/M期减少。此外，它对多药耐药的NCI - H69AR肺癌细胞系的半数抑制浓度值为9.5 μM。还通过将杂化物与大鼠肝微粒体孵育并借助液相色谱 - 质谱分析所得代谢物，对其进行了体外代谢研究。
