Heparanase is recognized as a master regulator of the aggressive phenotype of cancer,
an important contributor to the poor outcome of cancer patients and a prime target for therapy.
Although carbohydrate-based heparanase have been developed, but none were translated into
use in the clinic. Due to its being a desirable and druggable target for anti-cancer therapy, many
molecules have been developed, but only four carbohydrates have advanced to clinical trials.
Owing to their heparin-based nature, these molecules are heterogeneous in size and sulfation
pattern leading to nonspecific binding and unforeseen adverse effects, therefore halting their
translation into clinical use. Our goal in this grant is to develop cost-effective strategies, aided by
computational technique, for rapidly generating glycopolymers and oligosacharides with well-
defined sulfation pattern and at the same time via a synthetic route that is capable of supporting
subsequent scale up. Aminoglycosides are attractive in this light as they are commercially
available and inexpensive. Aminoglycosides target 16S bacterial ribosomal RNA and inhibit
protein synthesis. They are poly-cationic pseudo-oligosaccharides at physiological pH. Our
approach is to transform positively charged aminoglycosides into a novel class of negatively
charged aminoglycans, which no longer bind to rRNA, but can interact with heparanase. In Aim
1, we propose strategies for expedited and scalable synthesis of sulfated glycopolymers, derived
from paromomycin and neomycin, which possess similar structures and multivalent properties
found in the naturally existing HS polysaccharides. In Aim 2, we have identified commercially
available and low-cost apramycin as an ideal candidate for modification to produce the sulfated
pseudo-oligosaccharides as potential heparanase inhibitors. In Aim 3, we propose strategies for
expedited synthesis of sulfated pseudo-oligosaccharides by recombining 3-aminosugar unit of
kanamycin with its corresponding pseudo-disaccharide unit. These pseudo- oligosaccharides
possess similar structure and properties of the naturally existiing HS oligosaccharides.