Biomedical Engineering Reference
In-Depth Information
9.6 SUMMARY
The historically uneven exploration of chemical space using synthesis presents a huge
challenge to synthetic chemists: to develop synthetic approaches that allow chemical
space to be probed more systematically. This challenge has required the development
of synthetic approaches that allow molecule scaffolds to be varied combinatorially.
In this chapter we have described some of the remarkable approaches that have been
exploited in the diversity-oriented synthesis of natural product-like libraries.
Development of the branching and folding pathway strategies has enabled the syn-
thesis of libraries based on up to about 30 scaffolds. These strategies are extremely
ingenious; however, extension to many scores of alternative scaffolds is likely to be
difficult (and very unlikely to be general). How feasible will it be, then, to devise
reliable syntheses of molecules based on hundreds, or even thousands, of distinct
scaffolds? Oligomer-based approaches provide the first glimpse into how this chal-
lenge might be met. The assembly of oligomeric substrates iteratively, using reliable
reactions, may be combined with cyclization reactions of broad scope. A significant
challenge will be to identify a broader range of reactions that have the broad scope and
chemoselectivity needed to yield molecular scaffolds combinatorially. Nevertheless,
it is at least possible that oligomer-based approaches will be harnessed in the future
to yield libraries that target huge swathes of chemical space.
The success of diversity-oriented approaches to natural product-like molecules
must ultimately be assessed in terms of their impact on the discovery of novel bio-
logically active small molecules: both small-molecule tools and lead molecules for
drug discovery programs. It is not the structural similarity of small molecules to
natural products that is ultimately important—it is the discovery of small molecules
that have biological functions that are not found in known natural products. Many
diversity-oriented approaches to natural product-like molecules have yielded spe-
cific small molecules with exciting biological functions. The discovery of such
molecules bodes well for the ultimate success of the field. To maximize the impact, it
is essential that the collections of natural product-like molecules that result be made
widely available to scientists addressing the most pressing problems in both biology
and medicine.
REFERENCES
1. For reviews of the chemical genetic approach, see (a) M. Fisher, A. Nelson, in:
New Fron-
tiers in Chemical Biology
, M. E. Bunnage, Ed., Royal Society of Chemistry, Cambridge,
UK,
2011
, Chap. 1; (b) D. P. Walsh, Y. T. Chang,
Chem. Rev.
2006
,
106
, 2476-2530;
(c) S. L. Schreiber,
Nat. Chem. Biol.
2005
,
1
, 64-66.
2. S. L. Schreiber,
Proc. Natl. Acad. Sci. U.S.A.
2011
,
108
, 6699-6702.
3. (a) B. Munos,
Nature
2009
,
8
, 959-968; (b) J. Drews,
Science
2000
,
287
, 1960-1964.
4. (a) A. M. Boldi,
Curr. Opin. Chem. Biol.
2004
,
8
, 281-286; (b) K. Kumar, H. Waldmann,
Angew. Chem. Int. Ed.
2008
,
48
, 3224-3242; (c) C. Cordier, D. Morton, S. Murrison,
A. Nelson, C. O'Leary-Steele,
Nat. Prod. Rep.
2008
,
25
, 719-737.
