2,4-Diaryl-5H-chromeno [4,3-b]pyridines: Synthesis, Topoisomerase I and II Inhibitory Activity, and Cytotoxicity
Pritam Thapa, Eung-Seok Lee
Bulletin of the Korean Chemical Society (Print)
Topoisomerase enzyme, since its discovery, has been a promising target for the discovery of anticancer agents. 1 In our earlier study, we have designed and synthesized flexible 2,4,6-trisubstituted pyridine derivatives and studied their topoisomerase inhibitory activity and cytotoxicity against several human cancer cell lines. 2 Further optimization of the flexible 2,4,6-trisubstituted pyridine derivatives led us to synthesize various rigid analogues. 3 In continuation of the previously
... chromeno[4,3-b]pyridine derivatives, 3b herein we have prepared eleven 2,4-diaryl-5H-chromeno-[4,3-b]pyridine derivatives (Figure 1(b) ). All compounds were evaluated for their topoisomerase I and II inhibitory activity and cytotoxicity against several human cancer cell lines. Prepared compounds contain rigid chromeno [4,3b]pyridine skeleton at one side of the central pyridine. Chromeno[4,3-b]pyridine and chromene skeleton were found to have a wide range of biological activities such as estrogen receptor β-selective ligand, 4 TNF-α inhibition, 5 and anti-inflammatory activity. 6 Results and Discussion Synthetic Chemistry. At first, pyridinium iodide salts 2 (R = b-e, g) were synthesized by refluxing aryl methyl ketones 1 (R = b-e, g) with iodine and pyridine at 140 °C for 3 h in 72.5-96.2% yield. Secondly, on the basis of Claisenschmidt condensation reaction, 7 4-chromanone derivatives 5 (R 1 = a-f) were synthesized by reacting 4-chromanone (3) with various aryl aldehydes 4 (R 1 = a-f) in the presence of NaOH and ethanol at room temperature as illustrated in Scheme 1. Compounds 5 (R 1 = a-f) were obtained in 46.1-90.5% yield. Finally, on the basis of modified Kröhnke synthesis, 8 2,4-diaryl-5H-chromeno[4,3-b]pyridine derivatives 6 (R = b-e, g, R 1 = a-f) were synthesized by reacting 4-chromanone derivatives 5 (R 1 = a-f) and pyridinium iodide salts 2 (R = b-e, g) in the presence of NH 4 OAc and glacial acetic acid for 12-24 h at 100-110 °C. Eleven rigid analogues, 2,4diaryl-5H-chromeno[4,3-b]pyridine derivatives (7-17), were synthesized in 7.5-51.9% yield as shown in Figure 2 . Topo I and II Inhibitory Activity. Synthesized 2,4-diaryl-5H-chromeno[4,3-b]pyridine derivatives (7-17) were evaluated for their topo I and II inhibitory activities. The results of topo inhibitory activities of evaluated compounds are displayed in Figure 3 , and Table 1 . Camptothecin and etoposide, well known topo I and II inhibitors respectively, were used as positive controls. Compounds 7-17 were evaluated for topo I inhibitory activity both at 100 and 20 µM concentration. It is found that entire compounds showed strong topo I inhibitory activity in the range of 61.3-96.0% (as compared to 57.5% of camptothecin) at 100 µM. Compound 17 showed the most significant activity. Only compound 8 showed topo I inhibition of 17.0% (as compared to 18.4% of camptothecin) at 20 µM. The topo I inhibitory activity of evaluated compounds is summarized in Figure 3 , and Table 1. Compounds 7-17 were tested for topo II inhibition at 100 µM and only those with considerable topo II inhibitory activity at 100 µM were evaluated for 20 µM. From the Scheme 1. Synthesis of 2,4-diaryl-5H-chromeno[4,3-b]pyridine derivatives, Reagents and conditions; i) I2, pyridine, 140 °C, 3 h, 72.5-96.2%; ii) NaOH, EtOH, room temperature, 46.1-90.5% ; iii) NH4OAc, glacial AcOH, 12-24 h, 100-110 °C, 7.5-51.9%. Figure 1. Structure of (a) 2,4,6-trisubstituted pyridines, and (b) 2,4diaryl-5H-chromeno[4,3-b]pyridine.