Split-and-pool synthesis of a 10,000-membered library of molecules resembling the natural product carpanone has been achieved. The synthesis features development of solid-phase multicomponent reactions between nitrogen nucleophiles, enones, and hydroxylamines, and a solid-phase application of the Huisgen cycloaddition affording substituted triazoles. The synthesis was performed in highcapacity (500 μm) polystyrene beads using a one bead-one stock solution strategy that enabled phenotypic screens of the resulting library. Using whole-cell fluorescence imaging, we discovered a series of molecules from the carpanone-based library that inhibit exocytosis from the Golgi apparatus. The most potent member of this series has an IC 50 of 14 μM. We also report structureactivity relationships for the molecules exhibiting this interesting phenotype. These inhibitors of exocytosis may be useful reagents for the study of vesicular traffic.
Natural
products and their derivatives continue to be wellsprings
of nascent therapeutic potential. However, many laboratories have
limited resources for biological evaluation, leaving their previously
isolated or synthesized compounds largely or completely untested.
To address this issue, the Canvass library of natural products was
assembled, in collaboration with academic and industry researchers,
for quantitative high-throughput screening (qHTS) across a diverse
set of cell-based and biochemical assays. Characterization of the
library in terms of physicochemical properties, structural diversity,
and similarity to compounds in publicly available libraries indicates
that the Canvass library contains many structural elements in common
with approved drugs. The assay data generated were analyzed using
a variety of quality control metrics, and the resultant assay profiles
were explored using statistical methods, such as clustering and compound
promiscuity analyses. Individual compounds were then sorted by structural
class and activity profiles. Differential behavior based on these
classifications, as well as noteworthy activities, are outlined herein.
One such highlight is the activity of (−)-2(S)-cathafoline, which was found to stabilize calcium levels in the
endoplasmic reticulum. The workflow described here illustrates a pilot
effort to broadly survey the biological potential of natural products
by utilizing the power of automation and high-throughput screening.
The NHC-catalyzed transformation of unsaturated aldehydes into saturated esters through an organocatalytic homoenolate process has been thoroughly studied. Leveraging a unique "Umpolung"-mediated β-protonation, this process has evolved from a test bed for homoenolate reactivity to a broader platform for asymmetric catalysis. Inspired by our success in using the β-protonation process to generate enals from ynals with good E/Z selectivity, our early studies found that an asymmetric variation of this reaction was not only feasible, but also adaptable to a kinetic resolution of secondary alcohols through NHC-catalyzed acylation. In-depth analysis of this process determined that careful catalyst and solvent pairing is critical for optimal yield and selectivity; proper choice of nonpolar solvent provided improved yield through suppression of an oxidative side reaction, while employment of a cooperative catalytic approach through inclusion of a hydrogen bond donor cocatalyst significantly improved enantioselectivity.
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