The conventional paradigm for drug development is slow and ineffective, falling a step behind emerging global outbreaks such as the new SARS COVID-19. Repurposing existing drugs is one route to remedying this inefficiency. Herein, we report the use of commercial, low-cost aminoglycosides with specific structural frameworks as building blocks for the design and synthesis of inhibitors for heparanase (HPSE), a clinically proven cancer target. Through functional group modification, we transform the polyamine and/or polyhydroxy groups of selected aminoglycosides into N- and O-sulfation, respectively. This changes the pharmacology of the aminoglycosides from initiation of apoptosis in prokaryotes to potential cancer treatment through modulation of HPSE activity. The structure-activity relationship (SAR) studies indicated that the N-sulfated tobramycin derivatives are better inhibitors relative to the kanamycin and apramycin as well as its corresponding O-sulfated derivatives. Interestingly, the incorporation of a lipophilic scaffold onto specific regions of the designed inhibitors further enhanced the potencies. The lead compounds exhibit high inhibition (IC50 &lt; 100 nM) against heparanase and are highly selective against HPSE. Additionally, these compounds show little or no off-target effects toward platelet factor four (PF4) and antithrombin III, which are heparin-binding proteins.

Design and synthesis of aminoglycoside-based heparin sulfate mimetic as heparanase inhibitors

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