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October 11, 2011
VIP: Urolithin as a Converging Scaffold Linking Ellagic Acid and Coumarin Analogues: Design of Novel Potent Protein Kinase CK2 Inhibitors
Giorgio Cozza, Alessandra Gianoncelli, Paolo Bonvini, Elisa Zorzi, Riccardo Pasquale, Angelo Rosolen, Lorenzo A. Pinna, Flavio Meggio, Giuseppe Zagotto, Stefano Moro*
Protein kinase CK2 is a ubiquitous, essential, and highly pleiotropic protein kinase, the abnormally high constitutive activity of which is thought to mediate its pathogenic potential in neoplasia. CK2 has also been demonstrated to be a potential target for anti-infective drugs and in the treatment of other relevant diseases such as glomerulonephritis, a progressive inflammation implicated in chronic renal failure and immunogenic renal injury.
A collaborative research effort led by Stefano Moro and colleagues at the University of Padova (Italy) has revealed urolithins as a novel class of molecules able to efficiently inhibit CK2. Starting from the previous identification of 3,8-dibromo-7-hydroxy-4-methylchromen-2-one and ellagic acid as potent CK2 inhibitors (Ki: 20 and 60 nM, respectively), an X-ray-driven “structural merging approach” was applied to the design of a novel series of potential CK2 inhibitors. The identification of urolithin as a converging scaffold linking ellagic acid and coumarin analogues, followed by molecular optimization, led to a novel potent urolithin derivative: 4-bromo-3,8-dihydroxybenzo[c]chromen-6-one, which shows a Ki value of 7 nM. Although this cell-permeable compound does not elicit a potent cytotoxic effect, it could be promising for alternative therapeutic applications in which the cytotoxic effect is not strictly required, such as in viral infections and in other inflammatory diseases like glomerulonephritis.
Received July 11, 2011; published online October 4, 2011, DOI: 10.1002/cmdc.201100338.