Discovery of novel triazolophthalazine derivatives as DNA intercalators and topoisomerase II inhibitors
- 8 February 2021
- journal article
- research article
- Published by Wiley in Archiv der Pharmazie
- Vol. 354 (6), e2000456
- https://doi.org/10.1002/ardp.202000456
Abstract
A new series of triazolophthalazine derivatives was designed and synthesized as topoisomerase II (Topo II) inhibitors and DNA intercalators. The synthesized derivatives were evaluated in vitro for their cytotoxic activities against three human cancer cell lines: HepG2, MCF‐7, and HCT‐116 cells. Compound IXb was the most potent counterpart with IC50 values of 5.39 ± 0.4, 3.81 ± 0.2, and 4.38 ± 0.3 µM, as it was about 1.47, 1.77, and 1.19 times more active than doxorubicin (IC50 = 7.94 ± 0.6, 6.75 ± 0.4, and 5.23 ± 0.3 µM) against HepG2, MCF‐7, and HCT‐116 cells, respectively. Additionally, the binding affinity of the synthesized compounds toward the DNA molecule was assessed using the DNA/methyl green assay. Compound IXb showed an excellent DNA binding affinity with an IC50 value of 27.16 ± 1.2 µM, which was better than that of the reference drug doxorubicin (IC50 = 31.02 ± 1.80 µM). Moreover, compound IXb was the most potent member among the tested compounds when investigated for their Topo II inhibitory activity. Furthermore, compound IXb induced apoptosis in HepG2 cells and arrested the cell cycle at the G2/M phase. Additionally, compound IXb showed Topo II poisoning effects at 2.5 μM and Topo II catalytic inhibitory effects at 5 and 10 μM. Finally, molecular docking studies were carried out against the DNA–Topo II complex and DNA, to investigate the binding patterns of the designed compounds.Keywords
This publication has 42 references indexed in Scilit:
- Synthesis and Biological Evaluation of Some [1,2,4]Triazolo[4,3-a]quinoxaline Derivatives as Novel Anticonvulsant AgentsISRN Organic Chemistry, 2013
- Discovery of small molecule cancer drugs: Successes, challenges and opportunitiesMolecular Oncology, 2012
- DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial DrugsCell Chemical Biology, 2010
- Targeting DNA topoisomerase II in cancer chemotherapyNature Reviews Cancer, 2009
- Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl–thiourea–Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cellsJournal of Inorganic Biochemistry, 2008
- Discovery of Functionally Selective 7,8,9,10-Tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABAAReceptor Agonists at the α3SubunitJournal of Medicinal Chemistry, 2005
- DNA Topoisomerases: Structure, Function, and MechanismAnnual Review of Biochemistry, 2001
- Structure-based design of non-peptide, carbohydrazide-based cathepsin K inhibitorsBioorganic & Medicinal Chemistry, 1999
- Substitution and ring closure reactions of phthalazine derivativesJournal of Heterocyclic Chemistry, 1984
- Arrest of segregation leads to accumulation of highly intertwined catenated dimers: Dissection of the final stages of SV40 DNA replicationCell, 1981