Precursor Directed Biosynthesis of
Useful Pharmaceutical Intermediates
Dr Steven L Cobb
s.l.cobb@durham.ac.uk
http://www.dur.ac.uk/chemistry/cobb.group/
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Manipulating natural processes to
access complex (useful?) molecules
Dr Steven L Cobb
s.l.cobb@durham.ac.uk
http://www.dur.ac.uk/chemistry/cobb.group/
2
Overview
Part 1: Natural products: Diversity and Drug discovery
Part 2: Combining chemistry and then biology – new compound libraries
Part 3: Combining biology and then chemistry – new compound libraries
Part 4:
19F
NMR as a tool to identify new (biosynthetic) pathways and novel enzymes
Novel chemistry
Biocatalysts
Building blocks
New natural products
Novel chemistry
Biocatalysts
Compound libraries
(small molecules)
Compound libraries
(complex molecules)
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Part 1: Natural products: Diversity and Drug discovery
“Drug Discovery and Natural Products: End of an Era or an Endless Frontier?”
Vederas and Li, Science, 2009, 325, 169
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Part 1: Natural products: Diversity and Drug discovery
Ziconotide (Prialt), a peptide toxin from cone snails
approved in 2004 for treatment of chronic pain
resulting from spinal cord injury.
The cytotoxic trabectedin
(Yondelis) is approved in
Europe for the treatment of
advanced soft-tissue sarcoma
Vederas and Li, Science, 2009, 325, 169
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Part 1: Using nature to access complexity
Combinatorial biosynthesis
Analogs produced by modification of biosynthetic genes.
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Taken from Nat. Prod. Rep., 2008, 25, 25–34
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Part 2:
Combining chemistry and then biology – new compound libraries
Precursor-directed biosynthesis of fluorinated iturin A in Bacillus spp.
Stephen Moran , Dilip K. Rai , Benjamin R. Clark and Cormac D. Murphy Org. Biomol.
Chem., 2009, 7, 644-646
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Part 2:
Combining chemistry and then biology – new compound libraries
New pacidamycin antibiotics through precursor-directed biosynthesis
S. Grüschow, E. J. Rackham, B. Elkins, P. L. A. Newill, L. Hill, and R. J. M. Goss
ChemBioChem., 2009, 10, 355-360
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Part 2:
Combining chemistry and then biology – new compound libraries
Current work Joint PhD student with Comrac Murphy (UCD)
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.
Part
3:
Combining biology and then chemistry – new compound libraries
Gene expression enabling synthetic diversification of unnatural products:chemogenetic
generation pacidamycin analogs
A. Deb Roy, S. Grüschow, N. Cairns, R. J. M. Goss J. Am. Chem. Soc., 2010, 134, 1224-12245.
Needed in this area:
new/ improved reactions in aqueous chemistry
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Part 3:
Combining biology and then chemistry – new compound libraries
Current work with Comrac Murphy (UCD)
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Part 4:
19F NMR as a tool to identify new pathways and novel enzymes
Prof. David O’Hagan
S. Cobb PhD Thesis – St. Andrews University 2005
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Part 4:
19F NMR as a tool to identify new pathways and novel enzymes
Cobb, O'Hagan et al.
Chem. Commun.,
2004, 592-593
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19F
NMR as a tool to identify new pathways and novel enzymes
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Part 4:
19F NMR as a tool to identify new pathways and novel enzymes
The process ….
1. Feed fluorine containing compound into bacteria (cell free extracts)
2. Incubate
3. Run 19F NMR analysis
4. Any new 19F NMR peaks ? – if so identify and purify metabolites produced
5. Purify enzyme or enzymes responsible - new biocatalysts
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Part 4:
19F NMR as a tool to identify new pathways and novel enzymes
Leverhulme Trust (with Cormac Murphy)
Fluorinated drug metabolism
(Murphy and Sandford)
Prof. Graham Sandford, Durham University (Brock Fine Chemicals Ltd)
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Manipulating natural processes to
access complex (useful?) molecules
Dr Steven L Cobb
s.l.cobb@durham.ac.uk
http://www.dur.ac.uk/chemistry/cobb.group/
18
Part 3:
Combining biology and then chemistry – new compound libraries
Total synthesis approaches to natural product derivatives based on the combination
of chemical synthesis and metabolic engineering
Andreas Kirschning , Florian Taft and Tobias Knobloch Org. Biomol. Chem., 2007, 5, 3245-3259
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