Chemistry Reference
In-Depth Information
Like
in situ
DCC,
in situ
Click chemistry permits synthesis and screening to be combined
into a single step with the target biomolecule guiding the assembly of fragments. A key
differentiating attribute of these complementary concepts is that Click chemistry utilizes
an irreversible reaction to lock the fragments together whereas DCC utilizes a reversible
reaction to link fragments (Figure 7.3). Another important aspect of
in situ
Click chemistry
is that the reaction avoids the combination of strong nucleophilic and electrophilic func-
tional groups typical in DCC. The reactive partner fragments for Click chemistry are thus
bioorthogonal under any reaction conditions.
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24
]
The Click reaction occurs almost exclus-
ively within the target's binding site, withminimal background reaction in the bulk solution,
meaning that the formation of a triazole from Click chemistry fragments
in situ
virtually
guarantees that the resulting triazole will be a potent lead compound for drug discovery;
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24
]
the examples described later in this chapter exemplify this. A potential disadvantage of
in situ
Click chemistry for drug lead compound discovery is the possibility that effective
inhibitors are not assembled in the presence of the target and are thus 'missed opportunities'
in the screening campaign, i.e. false negatives.
high affinity ligand
with triazole linker
N
3
target
biomolecule
N
3
Click
reaction
N
3
N
3
Fragments with
complementary functional
groups (azide and alkyne) for
Click chemistry
Figure 7.3
Schematic representation of target-templated
in situ
Click chemistry.
7.6
In Situ
Medicinal Chemistry: Current State of Play
Both of the
in situ
synthesis approaches described here have had considerable success
with respect to the discovery of potent hit compounds for the target interrogated. DCC,
benefiting from about a 5 year head start on Click chemistry, has so far been more broadly
applied with respect to target diversity and number of active research groups. The entries
in Table 7.1 list the most recent published examples of
in situ
DCC (2006-mid-2007) and
in situ
Click chemistry since its inception (2002 onwards). These publications exemplify
the growing academic interest in the application of these informed chemistries for drug
discovery; however, it is not readily apparent what may be occurring in the pharmaceutical
industry, nor is it evident what progress either of these approaches has made towards
advancing compounds into the drug discovery pipeline. It is, however, arguably an area
that the pharmaceutical industry is unlikely to ignore given its tremendous potential as
outlined here.
