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.

Novel symmetrical benzazolyl derivatives endowed with potent anti-heparanase activity / 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. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 61:23(2018), pp. 10834-10859. [10.1021/acs.jmedchem.8b01497]

Novel symmetrical benzazolyl derivatives endowed with potent anti-heparanase activity

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;MOR, MARCO;FERRARA, Fabiana Fosca;Roscilli, Giuseppe;BATTISTUZZI, Gianfranco;Di Santo, Roberto
;
2018

Abstract

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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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/1221546
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