Biomedical Engineering Reference
In-Depth Information
molecules generated by a given procedure are structurally similar are common
limitations of traditional combinatorial chemistry. Indeed, combinatorial protocols
are generally designed to provide focused libraries of structurally related compounds
expected to act on a known biological target and are therefore intended to alter a single
process. The idea of structural diversity combined to structural complexity was first
introduced by Schreiber and coworkers, with the solid-phase synthesis of a library
containing two millions of discrete small molecules [8,9]. The success of this method
resulted from a small number of high-yielding synthetic steps that led to
90% pure
compounds readily available for biological screens. This seminal work paved the way
to the development of a novel concept called diversity-oriented synthesis (DOS) [10].
Target-oriented synthesis is defined by the multistep preparation of a natural product.
The synthetic strategy is designed by means of retrosynthetic analysis and usually
leads to a single substrate in low quantity. In contrast, diversity-oriented synthesis is
characterized by a short sequence of three to five reliable synthetic steps. The
chemistry is developed and optimized in a way that does not necessitate intermediate
tedious purification, making possible the production of thousands of molecules.
The synthesis of libraries, often inspired by natural products or drug-like molecules,
requires the implementation of a forward synthetic planning that involves complex-
ity-generating reactions and diversity-generating processes to transform simple
substrates into more complex and structurally diverse molecules. As a result, a large
number of complex analogues can be synthesized, in a single effort, for each
molecular framework generated. The molecular structures are already known from
the forward synthetic planning and the route toward preparing a higher quantity of a
lead molecule has already been optimized. The method provides compounds readily
available for biological evaluation over a shorter period and avoids the rather
cumbersome isolation, characterization, synthesis, and adaptation for biological
screening of the thousands of natural products “yet to be discovered.” It is also
likely that compounds originating from DOS are unique molecules that have little
resemblance to those observed in Nature. These are, therefore, complementary.
This chapter will describe this emerging area, with particular emphasis on
recent examples of DOS that led to the discovery of biologically active molecules and
the elucidation of associated cellular mechanisms [11-13]. Computational methods
used to assist optimal DOS planningwill not be discussed here as articles and reviews
have covered these areas extensively [14,15]. Rather, this chapter will illustrate some
of the most powerful reactions used in the context of diversity-oriented synthesis and
discuss the need to expand our chemical repertoire to access structurally diverse and
complex small molecules that would otherwise remain inaccessible.
H
15.3. ALTERNATIVE APPROACHES TO IDENTIFYING
BIOLOGICALLY ACTIVE SMALL MOLECULES
Prior to the development of DOS, several methods have been conceived to explore
the binding landscape of interesting macromolecules (Figure 15.1). Typically,
these methods consider a known cellular target for which small molecule binders
have already been identified. The objective is to enhance the binding properties
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