Biomedical Engineering Reference
In-Depth Information
definition, the exploration of this region has been a fruitful endeavor for the discov-
ery of biologically active and medicinally useful compounds; however, to restrict all
screening campaigns to molecules with a relatively narrow range of properties risks
the omission of many potentially biologically active molecules that reside in under-
represented and underexplored regions of chemical space [5]. Expanding the region
of chemical space explored by screening collections may help to discover small-
molecule modulators for classically undruggable targets and so serve to expand the
“druggable” genome [24]: a key challenge in chemical biology [9]. In fact, a number
of DOS campaigns have already discovered small molecules capable of modulating
nontraditional drug targets such as protein-DNA interactions [25,26] and protein-
protein interactions [27].
While both natural products and proprietary compound collections obviously have
their place in the discovery of novel biologically active compounds, the deliberate
synthesis of libraries of high-quality compounds (in terms of structural complexity
and variety) represents a third, distinct option that can prove superior for some
applications. This is where DOS comes in. As noted above, the term
diversity-
oriented synthesis
did not appear in the literature until 2000 [1,28]; however, it is fair
to say that many of the ideas behind DOS had existed for some time before then.
A review article from 1997 by Spaller et al. suggested that combinatorial libraries
may be suggested to fall into two categories:
focused libraries
, where a number of
closely related compounds based on a privileged structure are synthesized with a
known target in mind, and
prospecting libraries
, where an entirely new lead com-
pound is sought, so the objective is to screen a large number of structurally varied
compounds in the hope of finding a lead with a novel mode of action [29]. The focused
libraries can be considered to be the result of a “classical” combinatorial chemistry
approach, and further reference made here to combinatorial chemistry refers to the
synthesis of this type of library. On the other hand, it can be argued that the syntheses
of these prospecting libraries could probably be considered to be early examples
of diversity-oriented syntheses, as they were produced with aims similar to those of
contemporary DOS libraries: to achieve high levels of structural variety and bioactive
chemical space coverage. However, it was when the term
DOS
was coined in 2000
that the ideas and strategies underpinning modern diversity-driven synthesis began
to become more formalized.
1.4 COMPARING DOS, TOS, AND COMBINATORIAL CHEMISTRY:
FOCUSED LIBRARY SYNTHESIS
The aim of efficiently synthesizing large numbers of structurally diverse compounds
capable of effectively interrogating useful areas of chemical space is not easy to
realize, for a number of reasons. Principal among them is the fact that the synthetic
challenge of producing a biologically relevant DOS library has to be approached
from the direction opposite to that of more traditional chemical synthesis [1,2]. In
both TOS (of natural and unnatural products) and focused library synthesis, a target
structure (or structures) are in mind at the beginning of the synthetic campaign. These
structures are then broken down rationally into simpler starting materials and building
