Alesawy Mohamed S, Al-Karmalawy Ahmed A, Elkaeed Eslam B, Alswah Mohamed, Belal Ahmed, Taghour Mohammed S, Eissa Ibrahim H
Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt.
Arch Pharm (Weinheim). 2021 Mar;354(3):e2000237. doi: 10.1002/ardp.202000237. Epub 2020 Nov 23.
A new series of 1,2,4-triazolo[4,3-c]quinazoline derivatives was designed and synthesized as Topo II inhibitors and DNA intercalators. The cytotoxic effect of the new members was evaluated in vitro against a group of cancer cell lines including HCT-116, HepG-2, and MCF-7. Compounds 14 , 14 , 14 , 14 , 15 , 18 , 18 , and 19 exhibited the highest activities with IC values ranging from 5.22 to 24.24 µM. Furthermore, Topo II inhibitory activities and DNA intercalating affinities of the most promising candidates were evaluated as a possible mechanism for the antiproliferative effect. The results of the Topo II inhibition and DNA binding tests were coherent with that of in vitro cytotoxicity. Additionally, the most promising compound 18 was analyzed in HepG-2 cells for its apoptotic effect and cell cycle arrest. It was found that 18 can induce apoptosis and arrest the cell cycle at the G2-M phase. Finally, molecular docking studies were carried out for the designed compounds against the crystal structure of the DNA-Topo II complex as a potential target to explore their binding modes. On the basis of these studies, it was hypothesized that the DNA binding and/or Topo II inhibition would participate in the noted cytotoxicity of the synthesized compounds.
设计并合成了一系列新型的1,2,4-三唑并[4,3-c]喹唑啉衍生物，作为拓扑异构酶II抑制剂和DNA嵌入剂。在体外评估了这些新化合物对包括HCT-116、HepG-2和MCF-7在内的一组癌细胞系的细胞毒性作用。化合物14、14、14、14、15、18、18和19表现出最高活性，IC值范围为5.22至24.24 μM。此外，评估了最有前景的候选化合物的拓扑异构酶II抑制活性和DNA嵌入亲和力，作为其抗增殖作用的可能机制。拓扑异构酶II抑制和DNA结合试验的结果与体外细胞毒性结果一致。此外，对最有前景的化合物18在HepG-2细胞中分析了其凋亡作用和细胞周期阻滞情况。发现18可诱导凋亡并使细胞周期阻滞在G2-M期。最后，针对设计的化合物对DNA-拓扑异构酶II复合物的晶体结构进行了分子对接研究，作为潜在靶点以探索它们的结合模式。基于这些研究，推测DNA结合和/或拓扑异构酶II抑制作用参与了合成化合物所观察到的细胞毒性。
