Novel Benzazole Derivatives Endowed with Potent Antiheparanase 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 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.