Journal of Medicinal Chemistry p. 10834 - 10859 (2018)
Update date:2022-08-15
Topics:
Messore, Antonella
Madia, Valentina Noemi
Pescatori, Luca
Saccoliti, Francesco
Tudino, Valeria
De Leo, Alessandro
Bortolami, Martina
De Vita, Daniela
Scipione, Luigi
Pepi, Federico
Costi, Roberta
Rivara, Silvia
Scalvini, Laura
Mor, Marco
Ferrara, Fabiana Fosca
Pavoni, Emiliano
Roscilli, Giuseppe
Cassinelli, Giuliana
Milazzo, Ferdinando M.
Battistuzzi, Gianfranco
Di Santo, Roberto
Giannini, Giuseppe
Heparanase is the only mammalian endo-β-d-glucuronidase involved in a variety of major diseases. The up-regulation of heparanase expression increases tumor size, angiogenesis, and metastasis, representing a validated target in the anti-cancer field. To date, only a few small-molecule inhibitors have been described, but none have gotten through pre-clinical development. Previously, we explored 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives as anti-heparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Herein, we report an extended investigation of new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivatives, proving that symmetrical compounds are more effective than asymmetrical analogues, with the most-potent compound, 7g, being active at nanomolar concentration against heparanase. Molecular docking studies were performed on the best-acting compounds 5c and 7g to rationalize their interaction with the enzyme. Moreover, invasion assay confirmed the anti-metastatic potential of compounds 5c, 7a, and 7g, proving the inhibition of the expression of proangiogenic factors in tumor cells.
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