Biomedical Engineering Reference
In-Depth Information
8.5 DIVERSITY-ORIENTED STRATEGIES BASED ON NONPEPTIDIC
NATURAL PRODUCT SCAFFOLDS
Natural products represent the largest segment of macrocyclic drugs and an important
source of new drugs [79]. Their complex architectural structures have been refined
through the process of evolution to address several selection criteria, among which:
biological activity, acceptable chemical stability and bioavailability for the intended
purpose. It should be noted that the therapeutic indication and biological target
for which they are optimized in drug discovery is often remote from their natural
purpose. Nevertheless, natural products have served as templates for the generation
of diversified libraries, essentially using two main approaches (Figure 8.7). In the
first approach, the natural product itself (
58
) is used as a precursor that is further
functionalized on areas (X and Y) available for functional group modifications to
modulate its properties (e.g.,
59
). In the second, essential elements of molecular
recognition are kept constant and diversification is effected using simpler fragments
(e.g.,
60
). Whereas the first approach lends itself to narrow structural optimization,
the second is amenable to broader chemical space coverage and is an interesting
avenue to retain the most critical features of the natural product while synthetically
simplifying it considerably with accessible building blocks. For examples of the first
approach, readers are referred to the comprehensive review by Arya and co-workers
[80]. Examples of the second approach are elaborated in more detail in the following
sections [80].
FIGURE 8.7
Natural products as templates for the generation of diversified libraries using
two principal approaches: (1) the natural product is used as a precursor for further function-
alization on areas (X and Y); and (2) essential elements of molecular recognition are kept
constant and the diversification is achieved using simpler fragments.
