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targets must also be structurally and functionally diverse.
Nature is one of the greatest sources of diverse small molecules with a broad bioactivity
profile. However, a major limitation of screening natural products is their limited availability. 5
Therefore, synthetic small molecules constitute a major portion of the modern screening palette.
Advances in the field of synthetic organic chemistry have led to development of many
methodologies for efficient assembly of small molecules. The field of combinatorial synthesis
has evolved in the past two decades as a consequence of the demand for diverse small molecules
for biomedical research. 6 The synthetic strategy that is most commonly utilized in the
combinatorial approach involves appending different building blocks around a common
structural core. This approach has been greatly facilitated by development of practical
technologies that allow the streamlined parallel synthesis of large numbers of compounds
(thousands) in a short period of time. Although this approach will undoubtedly continue to lead
to identification of additional biological agents, researchers have questioned whether the level of
structural diversity that is achieved is sufficient to complement the wide variety of modern
biomedical targets. 7 The appendage diversity that is achieved by varying substituents around a
common core is thought to limit the compounds to a narrow “chemical space”. Very often, and
particularly in the pharmaceutical company setting, the molecules accessed in this manner are
designed to fall within defined physico-chemical parameters that increase their chances of
becoming drug candidates. 8 For example, the well known Lipinski rules for drug-like molecules
consider properties aimed at increasing bio-availability (molecular weight, solubility, number of
hydrogen-bond donors and acceptors, etc). 9
The need for novel, chemically diverse small molecules has been made clear in the
National Institutes of Health (NIH) roadmap for medical research (http://nihroadmap.nih.gov/).
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