TARGET-ORIENTED AND DIVERSITY-ORIENTED ORGANIC SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 512

the use of previously known small molecule binders, and thus themethod is inherently
limited to the discovery of ligands interacting with an already established biological
target. Nevertheless, there is no doubt that such an approach has been successful in the
process of industrial drug development, and has provided insightful structural
information and a general understanding of molecular recognition processes involved
between synthetic small molecules and biomolecules.
15.3.2. Dynamic Combinatorial Chemistry
In 1997, Huc and Lehn introduced an approach conceptually similar to fragment-
based drug discovery called “dynamic combinatorial chemistry” [18,19]. The authors
have shown that the addition of carbonic anhydrase (CA) to a library of imines in
dynamic equilibrium drove the chemical composition of the mixture toward the
formation of a compound structurally related to a known inhibitor of CA. The
selection of leads was accompanied by the disappearance of low-affinity adducts
thermodynamically stable in the absence of enzyme (Scheme 15.1, Eq. 15.2).
Dynamic combinatorial chemistry offers the advantage of combining synthesis,
screening, and amplification of small molecule binders in a single process. The
method is restricted, however, to the use of reversible covalent and supramolecular
interactions compatible with physiological conditions to accommodate the presence
of a biological template. Furthermore, the use of fragment-containing small libraries
is hampered by the necessity to analyze the composition of the complex mixture to
detect amplified lead compounds. Moreover, the method is designed to identify
small molecule binders of already known biological targets limiting the scope of
the approach.
15.3.3. In Situ Click Chemistry
Sharpless and coworkers laid down the foundation of a new concept known as “click
chemistry.” It is defined by the use of high-yielding chemoselective reactions to
assemble building blocks in a modular and efficient manner [20]. In situ click
chemistry, a process similar to fragment-based drug discovery, also resembles
dynamic combinatorial chemistry in that a biological target can serve as the reaction
vessel to template the selective assembly of two scaffolds in a kinetically controlled
fashion [21]. In pioneering work, Sharpless and coworkers have demonstrated the
power of such a method by using acetylcholine esterase (AChE) to template the 1,3-
dipolar cycloaddition of terminal alkynes and azides that led to a potent AChE binding
small molecule (Scheme 15.1, Eq. 15.3). Copper- and ruthenium-catalyzed versions
of the Huisgen cycloaddition have been further developed to control the 1,4- versus
1,5- regioselectivity of the process, respectively [22-24]. The copper-catalyzed
version is water compatible and lowers the energy barrier of the reaction, allowing
it to be carried out at room temperature and therefore in the presence of a biological
template. This method combines the advantages of both fragment-based drug
discovery and dynamic combinatorial chemistry, but shares common limitations.
Similar to dynamic combinatorial chemistry, click chemistry has been found to have
widespread applications in other chemical sciences.