From Functional Fatty Acids to Potent and Selective Natural-Product-Inspired Mimetics via Conformational Profiling.

Fatty acids play important signaling roles in biology, albeit typically lacking potency or selectivity, due to their substantial conformational flexibility. While being recognized as having properties of potentially great value as therapeutics, it is often the case that the functionally relevant conformation of the natural fatty acid is not known, thereby complicating efforts to develop natural-product-inspired ligands that have similar functional properties along with enhanced potency and selectivity profiles. In other words, without structural information associated with a particular functional relationship and the hopelessly unbiased conformational preferences of the endogenous ligand, one is molecularly ill-informed regarding the precise ligand-receptor interactions that play a role in driving the biological activity of interest.

General Enantioselective and Stereochemically Divergent Four-Stage Approach to Fused Tetracyclic Terpenoid Systems.

Tetracyclic terpenoid-derived natural products are a broad class of medically relevant agents that include well-known steroid hormones and related structures, as well as more synthetically challenging congeners such as limonoids, cardenolides, lanostanes, and cucurbitanes, among others. These structurally related compound classes present synthetically disparate challenges based, in part, on the position and stereochemistry of the numerous quaternary carbon centers that are common to their tetracyclic skeletons. While de novo syntheses of such targets have been a topic of great interest for over 50 years, semisynthesis is often how synthetic variants of these natural products are explored as biologically relevant materials and how such agents are further matured as therapeutics.

An Enantiodefined Conformationally Constrained Fatty Acid Mimetic and Potent Inhibitor of ToxT.

The chiral conformation that palmitoleic acid takes when it is bound to ToxT, the master regulator of virulence genes in the bacterial pathogen , was used as inspiration to design a novel class of fatty acid mimetics. The best mimetic, based on a chiral hydrindane, was found to be a potent inhibitor of this target. The synthetic chemistry that enabled these studies was based on the sequential use of a stereoselective annulative cross-coupling reaction and dissolving metal reduction to establish the C13 and C9 stereocenters, respectively.