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, A.; Madia, V. N.; Pescatori, L.; Saccoliti, F.; Tudino, V.; De Leo, A.; Bortolami, M.; De Vita, D.; Scipione, L.; Pepi, F.; Costi, R.; Rivara, S.; Scalvini, L.; Mor, M.; Ferrara, F. F.; Pavoni, E.; Roscilli, G.; Cassinelli, G.; Milazzo, F. M.; Battistuzzi, G.; Di Santo, R.; Giannini, G.. - 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

Pescatori L.;Rivara S.;Scalvini L.;Mor M.;
2018-01-01

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.
Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity / Messore, A.; Madia, V. N.; Pescatori, L.; Saccoliti, F.; Tudino, V.; De Leo, A.; Bortolami, M.; De Vita, D.; Scipione, L.; Pepi, F.; Costi, R.; Rivara, S.; Scalvini, L.; Mor, M.; Ferrara, F. F.; Pavoni, E.; Roscilli, G.; Cassinelli, G.; Milazzo, F. M.; Battistuzzi, G.; Di Santo, R.; Giannini, G.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 61:23(2018), pp. 10834-10859. [10.1021/acs.jmedchem.8b01497]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2861603
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