Biomedical Engineering Reference
In-Depth Information
generation of diversity in macrocycles via two approaches: through the assembly
of linear precursors followed by macrocyclization mediated by one of the well-
established methods, such as RCM, click, or macrolactamization [92], or as a point
of diversification at the macrocyclization step. The latter approach represents the
basis of the diversity-oriented strategy called MiB (multicomponent macrocycliza-
tion including bifunctional building blocks, Scheme 8.16; see also the works of Yudin
and co-workers, Scheme 8.3) [93]. In this context, the Ugi four-component reaction
between a primary amine, a carboxylic acid, a carbonyl, and an isocyanide has been
used extensively [94]. The underlying principle in such an approach is to create com-
plex macrocycles from simple building blocks with maximal diversity and versatility
in terms of design. Wessjohann and co-workers have explored this avenue in several
directions, one of which is presented in Scheme 8.16. The concept relies on the
reaction between two bifunctional components
87
and
88
, reacted with additional
components C3 and C4, together containing an amine, an aldehyde, a carboxylic
acid, and an isocyanide. Two sequential Ugi four-component reactions led first to
dimerization, then to ring closure.
The success of the reaction relies on the rigidity of scaffolds A and B, which
prevent chain folding. For example, the reaction of diamine
90
with bis-isocyanide
91
gave, in the presence of acetic acid and an aldehyde, two macrocycles,
92
and
93
,
macrocyclized head to head and head to tail. The same group has reported multiple
variations around this theme, demonstrating the potential of this approach to generate
diverse libraries of macrocycles based on natural and unnatural building blocks [93b].
In summary, natural product-inspired macrocycles definitely constitute an area
worthy of further investment. They provide distinct, yet complementary coverage
of chemical space compared to other structures, and probably distinct PK-ADME
properties as well. By mimicking some of nature's secondary structures, they can
be expected to benefit indirectly from the evolutionary pressure that has conferred
natural macrocycles with their unique properties. Additionally, they will by design
be more synthetically accessible and diversifiable than natural products, hopefully
combining the best of both worlds.
8.6 CONCLUSIONS
Macrocycles represent a unique and very promising niche in the chemical space
of druggable molecules. Structurally, they have the potential to reach targets that
are very difficult to reach for traditional small molecules (high hanging fruits), as
exemplified by the bioactive macrocycles developed for the HCV NS3/4A protease,
or protein-protein interactions, such as those involved in immunomodulation or
inflammation. This is due to macrocycles' ability to display distant pharmacophores
on semirigid templates and provide large, yet conformationally defined interacting
surfaces. Macrocycles are also considered challenging to synthesize and to diversify.
More than ever, given the increasing number of targets and the limited chemical
space covered in traditional libraries, medicinal chemistry needs access to novel and
original scaffolds and chemical diversity. We believe that the multiple approaches
reported in this chapter offer new avenues for exploiting and expanding macrocycle
