Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity

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.