Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

Drugs
are discovered through the biological screening of collections
of compounds, followed by optimization toward functional end points.
The properties of screening collections are often balanced between
diversity, physicochemical favorability, intrinsic complexity, and
synthetic tractability (Huggins, D. J.; et al. ACS Chem. Biol. 2011, 6, 208; DOI: 10.1021/cb100420r). Whereas natural product (NP) collections excel in the first three
attributes, NPs suffer a disadvantage on the last point. Academic
total synthesis research has worked to solve this problem by devising
syntheses of NP leads, diversifying late-stage intermediates, or derivatizing
the NP target. This work has led to the discovery of reaction mechanisms,
the invention of new methods, and the development of FDA-approved
drugs. Few drugs, however, are themselves NPs; instead, NP analogues
predominate. Here we highlight past examples of NP analogue development
and successful NP-derived drugs. More recently, chemists have explored
how NP analogues alter the retrosynthetic analysis of complex scaffolds,
merging structural design and synthetic design. This strategy maintains
the intrinsic complexity of the NP but can alter the physicochemical
properties of the scaffold, like core instability that renders the
NP a poor chemotype. Focused libraries based on these syntheses may
exclude the NP but maintain the molecular properties that distinguish
NP space from synthetic space (Stratton, C. F.; et al. Bioorg.
Med. Chem. Lett. 2015, 25,
4802; DOI: 10.1016/j.bmcl.2015.07.014), properties that have statistical
advantages in clinical progression (Luker, T.; et al. Bioorg.
Med. Chem. Lett. 2011, 21,
5673, DOI: 10.1016/j.bmcl.2011.07.074; Ritchie, T. J.; Macdonald,
S. J. F. Drug Discovery Today 2009, 14, 1011, DOI: 10.1016/j.drudis.2009.07.014). Research that expedites synthetic access to NP motifs can prevent
homogeneity of chemical matter available for lead discovery. Easily
accessed, focused libraries of NP scaffolds can fill empty but active
gaps in screening sets and expand the molecular diversity of synthetic
collections.