Synthesis, computational study and biological evaluation of 9-acridinyl and 1-coumarinyl-1,2,3-triazole-4-yl derivatives as topoisomerase II inhibitors

Abstract

Topoisomerase (IIB) inhibitors have been involved in the therapies of tumour progression and have become a major focus for the development of anticancer agents. New three-component hybridised ligands, 1,4-disubstituted-1,2,3-triazoles ( 8 – 17 ), were synthesised via a 1,3-dipolar cycloaddition reaction of 9-azidoacridine/3-azidocoumarin with N/O-propargyl small molecules under click reaction conditions. Cancer cell growth inhibition of the synthesised triazoles was tested against human cell-lines in the NCI-60-cell-panel, and the most active compounds tested against topoisomerase (IIB)-enzymes. The acridinyl ligands ( 8 – 10 ) revealed 60–97% cell growth inhibition in six cancer cell-panels. Cell-cycle analysis of MCF7 and DU-145 cells treated with the active acridinyl ligands exhibited cell-cycle arrest at G2/M phase and proapoptotic activity. In addition, compound 8 displayed greater inhibitory activity against topoisomerase (IIB) (IC 50 0.52 µM) compared with doxorubicin (IC 50 0.83 µM). Molecular dynamics simulation studies showed the acridine–triazole–pyrimidine hybrid pharmacophore was optimal with respect to protein–ligand interaction and fit within the binding site, with optimal orientation to allow for intercalation with the DNA bases (DG13, DC14, and DT9).

Development and validation of a high-performance thin-layer chromatography densitometric method for the simultaneous determination of novel 1-acridinyl-1,2,3-triazole derivatives

“…Pure compounds 6-10 were synthesized by the general procedure as given in Scheme 1. Data of the structure homogeneity of the studied compounds 6-10 were confirmed by 1 H-and 13 C-NMR (nuclear magnetic resonance), element analysis, and mass spectrometry (MS), cited in [7] by the same author. HPTLC aluminum plates pre-coated with silica gel 60 F 254 (20 × 20 cm, 6-8 µm particle sizes, 250 µm thickness) were obtained from Merck (Darmstadt, Germany).…”

“…The compounds were all more cytotoxic in the MCF-7 cell line and in both cell lines the 6-methyuracil derivative 6 was more cytotoxic than the uracil derivative 7 with the bulk phenytoin derivative 8 the least active (Table 2). Compound 6 displayed comparable cytotoxicity (IC50 2.70 ± 0.08 mM) with the standard doxorubicin (IC50 2.06 ± 0.04 mM), an anthracycline in clinical use as a wide spectrum antitumor agent, which exerts its action by intercalation between DNA double strands and blocks the topoisomerase IIB involved in the DNA replication process [7].…”

“…The targeted 1-acridinyl-1,2,3-triazole derivatives 6-10 were synthesized via a 1,3-dipolar cycloaddition reaction of 9-azidoacridine with the propargyl small molecules (R = 1-5) under click reaction conditions [7] as indicated in Scheme 1.…”

“…Additionally, acridines are characteristically highly crystalline, stable, attractively colored, and strongly fluorescent in nature. Acridine derivatives are characterized by unique physical and chemical properties, biological activities, and industrial applications [5][6][7]. Among these are their anti-inflammatory, anticancer, antimicrobial, antitubercular, antiparasitic, antimalarial, antiviral and fungicidal activities.…”

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

“…Compounds with a chloro and methoxy substituent at different positions displayed promising activity. Abdel-Hafez and co-workers [ 41 ] designed, synthesized and hybridized acridine and coumarin derivatives, and evaluated their in vitro cancer cell growth inhibition activity. Among the evaluated compounds, 37 presented a good anticancer profile against MCF7 and DU-145 with IC 50 , values of 2.7 and 26.1 µM, respectively, comparable to doxorubicin (IC 50 values = 2.0 and 14.2 µM).…”