Natural Products in Drug Discovery - Drug Design and Discovery - page 105

moiety. One of the most potent is shown as compound 708 in Figure 6.14. This compound is one of
a series of cyclic acetals that showed remarkably enhanced potency as well as presenting excellent
chemical and metabolic stability.
6.6 CONCLUDINGREMARKS
One of the most exciting developments in the study of secondary metabolites, not touched on in
this chapter, is the sequencing and annotation of bacterial genomes. Genome mining has detected
a plethora of potential chemistry still to be revealed. Challenges also await as scientists endeavor
to elucidate the mechanisms that regulate the expression of these cryptic pathways. Issues of
supply of these precious materials have frequently plagued the efforts of drug discovery from
higher organisms, such as marine sponges or plants. But there is hope. Jay Keasling's work on
engineering of a high-producing terpene cyclase pathway in bacteria promises to enable large-
scale economical production of the antimalarial drug artemisinin and thereby unlock the supply
chain for these life-saving chemicals.
Natural products remain a fascinating and incredibly rich source of leads for drug discovery.
Owing to developments in chemical and biosynthetic technologies, the moment is right for the explo-
ration for new chemistry and further exploitation of known secondary metabolites. The advances
in molecular biology will enable experiments aimed at a more fundamental understanding of the
intrinsic biological roles for secondary metabolites and this knowledge can be expected to illuminate
future applications in drug research.
FURTHER READING
Chang, M. C. Y. and Keasling, J. D. (2006) Production of isoprenoid pharmaceuticals by engineered microbes.
Nature Chemical Biology , 2, 674-681.
Dewick, P. M. (2002) Medicinal Natural Products: A Biosynthetic Approach , 2nd edn., John Wiley & Sons
Ltd., West Sussex, England.
Hesse, M. (2002) Alkaloids Nature's Curse or Blessing , Wiley-VCH, Zurich.
Hopwood, D. A. (2007) Streptomyces in Nature and Medicine. The Antibiotic Makers . Oxford University Press,
New York.
Koehn, F. E. and Carter, G. T. (2005) The evolving role of natural products in drug discovery. Nature Reviews-
Drug Discovery , 4, 206-220.
Mann, J., Davidson, R. S., Hobbs, J. B., Banthorpe, D. V., and Harborne, J. B. (1994) Natural Products: Their
Chemistry and Signii cance , Longman, Essex, England.
Weissman, K. J. and Leadlay, P. F. (2005) Combinatorial biosynthesis of reduced polyketides. Nature Reviews
Microbiology , 3, 925-936.
Wender, P. A., Baryza, J. L., Hilinski, M. K., Horan, J. C., Kan, Cindy, V., and Vishal, A. (2007) Beyond natural
products: Synthetic analogues of bryostatin 1. Drug Discovery Research , 127-162.