Novel Benzazole Derivatives Endowed with Potent anti-Heparanase Activity

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 part of 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 anti-metastatic potential of compounds 14d and 15. Consistent with its ability to inhibit heparanase, compound 15 proved to decrease expression of genes encoding for proangiogenic factors such as MMP-9, VEGF and...