Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity

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

Research output: Contribution to journalArticlepeer-review


Heparanase is the sole mammalian enzyme capable of cleaving glycosaminoglycan heparan sulfate side chains of heparan sulfate proteoglycans. Its altered activity is intimately associated with tumor growth, angiogenesis, and metastasis. Thus, its implication in cancer progression makes it an attractive target in anticancer therapy. Herein, we describe the design, synthesis, and biological evaluation of new benzazoles as heparanase inhibitors. Most of the designed derivatives were active at micromolar or submicromolar concentration, and the most promising compounds are fluorinated and/or amino acids derivatives 13a, 14d, and 15 that showed IC50 0.16-0.82 μM. Molecular docking studies were performed to rationalize their interaction with the enzyme catalytic site. Importantly, invasion assay confirmed the antimetastatic potential of compounds 14d and 15. Consistently with its ability to inhibit heparanase, compound 15 proved to decrease expression of genes encoding for proangiogenic factors such as MMP-9, VEGF, and FGFs in tumor cells.

Original languageEnglish
Pages (from-to)6918-6936
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number15
Publication statusPublished - Aug 9 2018


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