Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity

Antonella Messore, Valentina Noemi Madia, Luca Pescatori, Francesco Saccoliti, Valeria Tudino, Alessandro De Leo, Martina Bortolami, Daniela De Vita, Luigi Scipione, Federico Pepi, Roberta Costi, Silvia Rivara, Laura Scalvini, Marco Mor, Fabiana Fosca Ferrara, Emiliano Pavoni, Giuseppe Roscilli, Giuliana Cassinelli, Ferdinando M Milazzo, Gianfranco Battistuzzi & 2 others Roberto Di Santo, Giuseppe Giannini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)10834-10859
Number of pages26
JournalJournal of Medicinal Chemistry
Volume61
Issue number23
DOIs
Publication statusPublished - Dec 13 2018

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Neoplasms
Glucuronidase
Acetates
Up-Regulation
heparanase
Neoplasm Metastasis
Enzymes

Cite this

Messore, A., Madia, V. N., Pescatori, L., Saccoliti, F., Tudino, V., De Leo, A., ... Giannini, G. (2018). Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity. Journal of Medicinal Chemistry, 61(23), 10834-10859. https://doi.org/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; 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, Vol. 61, No. 23, 13.12.2018, p. 10834-10859.

Research output: Contribution to journalArticle

Messore, A, Madia, VN, 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, FF, Pavoni, E, Roscilli, G, Cassinelli, G, Milazzo, FM, Battistuzzi, G, Di Santo, R & Giannini, G 2018, 'Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity', Journal of Medicinal Chemistry, vol. 61, no. 23, pp. 10834-10859. https://doi.org/10.1021/acs.jmedchem.8b01497
Messore A, Madia VN, Pescatori L, Saccoliti F, Tudino V, De Leo A et al. Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity. Journal of Medicinal Chemistry. 2018 Dec 13;61(23):10834-10859. https://doi.org/10.1021/acs.jmedchem.8b01497
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. / Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 23. pp. 10834-10859.
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