Natural Products in the "Marketplace": Interfacing Synthesis and Biology

Abstract

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.

Figure 1.

Extremes of non-diverse vs. diverse leads (chemical targets) in a molecular collection sorted by chemotype.

Figure 2.

FDA-approved NP analogs.

Figure 3.

Used from Ref. 16 (Ertl, Roggo and Schuffenhauer, J. Chem. Inf. Model. 2008, 48, 68). Natural products differ from most synthetic molecules, but overlap with drugs, which have been optimized for biocompatibility. NPs are preoptimized.

Figure 4.

Structural complexity and synthetic complexity are related, but not identical.

Figure 5.

Eravacycline, an analog of tetracycline from Tetraphase.

Figure 6.

A screen of synthetic himbacine analogs enabled the discovery of Vorapaxar.

Figure 7.

Isofludelone, a fully synthetic epothilone B analog under clinical investigation.

Figure 8.

Myers’ erythromycin / solithromycin analog FSM-100573.

Figure 9.

Activity against VanA-resistant bacteria restored by Boger’s vancomycin amidine analog.

Figure 10.

A urea side-chain restores potency of vinblastine alkaloids against resistant cell lines.

Figure 11.

DZ-2384 inhibits microtubule dynamics via a novel mechanism of action.

Figure 12.

Recent total syntheses of pleuromutilin.

Figure 13.

Substitution of C6 carbon with nitrogen enables the design of a 4-step route to artemisinin chemical space.

Figure 14.

CD spiroketal redesign decreases synthetic complexity and enables the discovery of a thermodynamically more stable and equipotent analog, 36.

Figure 15.

Methyl deletion and oxygen substitution stabilize the SalA scaffold, maintain potency and selectivity, and enable a short synthesis.

Figure 16.

Dynamic retrosynthetic analysis expands the basis set of retrosynthesis to include structural perturbations.