Technologies
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WARF: P04455US

Neoglycorandomization and Digitoxin Analogs


INVENTORS -

Jon Thorson, Joseph Langenhan

The Wisconsin Alumni Research Foundation (WARF) is seeking commercial partners interested in developing a method of glycosylating natural compounds to create a large library of diverse compounds for high throughput screening.
OVERVIEWMany of the compounds used in drug discovery by pharmaceutical companies are glycosylated bacterial secondary metabolites. A glycosylated metabolite consists of a central core structure (aglycon) and various sugar (glycosyl) attachments.

Because the sugar moieties of many of these metabolites define their biological activities, altering the carbohydrate ligands through processes such as glycorandomization (see WARF reference number P04020US) can lead to valuable new pharmaceuticals.
THE INVENTIONUW-Madison researchers have now developed a different approach to glycosylating natural compounds to create a large library of diverse compounds for high throughput screening. This approach, neoglycorandomization, uses a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation. It is based on the chemoselective formation of glycosidic bonds between the reducing sugars and an aglycon with a secondary alkoxyamine.

To form a neoglycoside, the alkoxyamine-containing aglycon is reacted with at least one reducing sugar selected from the group consisting of L-sugars, D-sugars, amino-sugars, deoxy-sugars, dideoxy-sugars, glucose epimers, substituted sugars, uronic acids, and oligosaccharides.
APPLICATIONS
  • Synthesis of large libraries of novel compounds for drug discovery
KEY BENEFITS
  • May generate large libraries of compounds with enhanced desirable properties and diminished side effects
  • Other chemical groups can be added to further increase the diversity of such compounds
  • Compounds created using this method may be valuable in the treatment of cancer .
  • Uses unprotected and non-activated reducing sugars
  • Method is robust and has been expanded toward a vast array of scaffolds including steroids, indolocarbazoles, cochicines, anthracylines, glycopeptides and aromatic Nrf2-activators.
  • Broadly applicable to carbonyls, amines, and hydroxyls
  • Amenable to automated synthesis
  • May be used to produce oligosaccharide-substituted natural products
  • Complementary to the glycorandomization methods described in WARF reference number P04020US
STAGE OF DEVELOPMENTThis method was used to generate a library of neoglycoside digitoxin analogs that included compounds with significantly enhanced tumor-specificity and cytotoxic potency toward human cancer cells. These compounds were significantly less potent against the traditional target for digitoxin – the human Na+/K+-ATPase.
Contact Information
For current licensing status, please contact Rafael Diaz at rdiaz@warf.org or 608-960-9847.
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