Transcript Synthesis of natural product like scaffolds for new drug

Professor Stephen Pyne
School of Chemistry, University of Wollongong, New South Wales 2522, Australia
[email protected]
 Research within the Pyne group is concerned with a number of projects that involve the organic chemical synthesis of bioactive molecules.
This includes:
The total synthesis of bioactive azasugar alkaloids with potential applications as anti-diabetic drugs.
 The total synthesis of bioactive Stemona alkaloids with potential applications as acetylcholinesterase inhibitors (useful in Alzheimer's disease).
 The discovery of new chemical reactions to prepare novel drug-like scaffolds for new drug discovery (with Eli Lilly)
 The development of organoboron reagents in conjunction with metal-catalysed reactions to prepare bioactive heterocycles.
 The development of new antibacterials active against pathogenic bacteria and Clostridium difficile infections.
 Other projects include natural products chemistry in collaboration with scientists in Thailand and Nigeria.
Organic Chemical Synthesis Projects
Synthesis of natural product like scaffolds for new drug discovery
The total synthesis of bioactive azasugar alkaloids with
potential applications as anti-diabetic drugs
We have and are currently developing novel concise chemical synthesis methods for
preparing a number of bioactive azasugar alkaloids that have glycosidase inhibitory
activities and thus have potential to be developed as anti-diabetic drugs.
We have employed the borono-Mannich reaction to prepare many of these alkaloids
as shown below in the Scheme.
Previous work: correction of the structure of the
anti-diabetic alkaloid Uniflorine A
Biological Screening Assays (Eli Lilly Open Drug Discovery Program)
Uniflorine A was isolated in 2000 from the leaves of the tree Eugenia uniflora L. The
water-soluble extract of these leaves has been used as an antidiabetic agent in
Paraguayan traditional medicine. Our synthetic studies resulted in us correcting the
structure of uniflorine A from a suggested indolizidine to a pyrrolizidine.
Eugenia uniflora L.
(Surinam cherry)
Ritthiwigrom, Pyne, Org. Lett. 2008, 10, 2769-2771; J. Org. Chem. 2010, 75, 815-824.
Previous work: the successful synthesis of other alkaloids for
structure confirmation and biological testing as glycosidase inhibitors
Drugs to treat drug resistant bacterial and Clostridium difficile
Infections (with Paul Keller)
Earlier we discovered a novel series of active binaphthyl, dicationic peptide-based
compounds which show antibacterial activity that is generally close to, or better than,
that of vancomycin against Staphylococcus aureus and S. epidermidis and superior
against vancomycin resistant Enterococcus faecium (VRE).
From our large collection of >200 compounds, two of our peptides showed in vitro
antibacterial potency against a range of Gram-positive pathogens including strains of
S. aureus resistant to vancomycin, methicillin, and linezolid.
Current work: the synthesis, structure confirmation
and glycosidase activity of the hyacinthacine C alkaloids
Examples from our peptide class of antibiotics.
isolated
from
Other bioactive alkaloid targets for synthesis:
These studies gave rise to the commercial development of two examples by Valevia
for antimicrobial applications, which make this class of compounds an exciting
prospect for further antibacterial drug discovery.
We are now aiming to further advance our peptide antibiotics into efficacious
therapeutics to treat C. difficile infection.
Acknowledgements
This research is supported by the Australian Research Council, the
NHMRC and the University of Wollongong.