Transcript Steve Cobb
Precursor Directed Biosynthesis of Useful Pharmaceutical Intermediates Dr Steven L Cobb [email protected] http://www.dur.ac.uk/chemistry/cobb.group/ 1 Manipulating natural processes to access complex (useful?) molecules Dr Steven L Cobb [email protected] 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) 3 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 4 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 5 Part 1: Using nature to access complexity Combinatorial biosynthesis Analogs produced by modification of biosynthetic genes. 6 Taken from Nat. Prod. Rep., 2008, 25, 25–34 7 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 8 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 9 Part 2: Combining chemistry and then biology – new compound libraries Current work Joint PhD student with Comrac Murphy (UCD) 10 . 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 11 Part 3: Combining biology and then chemistry – new compound libraries Current work with Comrac Murphy (UCD) 12 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 13 Part 4: 19F NMR as a tool to identify new pathways and novel enzymes Cobb, O'Hagan et al. Chem. Commun., 2004, 592-593 14 19F NMR as a tool to identify new pathways and novel enzymes 15 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 16 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) 17 Manipulating natural processes to access complex (useful?) molecules Dr Steven L Cobb [email protected] 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 19