Scaffold-hopping of bioactive natural product aurones has been studied for the first time. 2-Arylideneimidazo[1,2-a]pyridinones as potential topoisomerase IIα (hTopoIIα)-targeting anticancer compounds were considered. A multifunctional activator, polyphosphoric acid, enabled to realize a cascade reaction of 2-aminopyridine with 2,3-epoxyesters toward synthesis of 2-arylideneimidazo[1,2-a]pyridinones. Most of the compounds exhibited hTopoIIα-selective poison activity with efficiency more than etoposide and DNA-binding property, while not interacting with hTopo I. The compounds showed pronounced antiproliferative activities in nanomolar range with relatively poor toxicity to normal cells, inhibition of invasiveness, and apoptotic effect. The activities for inhibition of tubulin assembly, CDK1 and pCDK1, were also observed. Interestingly, the hTopoIIα inhibitory (in vitro and ex vivo studies) and antiproliferative activities of representative potent compounds were found to be manifold higher compared to corresponding parent aurones bearing alike substitutions, indicating the importance of such scaffold-hopping strategy in medicinal chemistry research.
(Z)-2-(3,4,5-Trimethoxybenzylidene)imidazo[1,2-a]pyridin-3(2H)-one (3a): Red solid, 100 mg, 32% yield, m.p. 180-182 °C;
1H NMR (400 MHz,CDCl3): δ 7.61 (d, J = 6.9 Hz, 1H), 7.56 (s, 2H), 7.22 (s, 1H), 7.15-7.11 (m, 1H), 6.91 (d, J = 9.5 Hz, 1H), 6.23 (dd, J = 6.9 Hz, J = 6.4 Hz, 1H), 3.94 (s, 6H), 3.92 (s, 3H) ppm;
13C{1H}NMR (100 MHz, CDCl3):δ 167.4, 155.9, 153.2, 140.7, 137.7, 137.2, 130.2, 129.1, 125.9, 119.4, 110.1, 109.1, 61.0, 56.2 ppm;
IR (ATR): νmax2980, 1705, 1649, 1259, 1123 cm-1;
HRMS (ESI) m/z: calcd. for C17H16N2O4Na [M + Na]+ 335.1008, found: 335.1016 .
(Z)-2-(4-Methoxybenzylidene)benzofuran-3(2H)-one (C1): Yellow solid, 151 mg, 60% yield, m.p. 160-162 °C;
1H NMR (400 MHz,CDCl3): δ 8.23 (d, J = 7.9Hz,J = 1.4 Hz, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.69 (dd, J = 8.5Hz,J = 7.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 7.8Hz,J = 7.2 Hz, 1H), 7.03 (d, J = 8.9 Hz, 2H), 6.75 (s, 1H), 3.89 (s, 3H) ppm;
13C{1H}NMR (100 MHz, CDCl3):δ178.4, 163.4, 162.4, 156.2, 133.6, 127.9, 125.6, 125.1, 124.0, 123.9, 117.9, 114.5, 106.2, 55.5 ppm;
IR (ATR): νmax 3050, 1645, 1377, 1265, 1193 cm -1;HRMS (ESI) m/z: calcd. for C16H12O3Na[M + Na]+ 275.0684, found: 275.0689.
Scaffold-Hopping of Aurones: 2-Arylideneimidazo[1,2-a]pyridinones as Topoisomerase IIα-Inhibiting Anticancer Agents
Associate Professor, Department of Medicinal Chemistry
Areas of Interest:Anticancer drug discovery: Design and synthesis of heterocyclic compounds as human DNA topoisomerase I and II inhibitors, and their SAR studies
skguchhait@niper.ac.in
Dr. Chanakya Nath Kundu
Professor
Ph. D. Jadavpur University, 2002
M.Sc. Kalyani University, 1997
Email : cnkundu@kiitbiotech.ac.in
SARITA