Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that are mutated in a variety of cancers to confer a gain-of-function activity resulting in the accumulation of an oncometabolite, D-2-hydroxyglutarate (2-HG). Accumulation of 2-HG can result in epigenetic dysregulation and a block in cellular differentiation, suggesting these mutations play a role in neoplasia. Based on its potential as a cancer target, a number of small molecule inhibitors have been developed to specifically inhibit mutant forms of IDH (mIDH1 and mIDH2). We present a comprehensive suite of in vitro preclinical drug development assays that can be used as a tool-box to identify lead compounds for mIDH drug discovery programs, as well as what we believe is the most comprehensive publically available dataset on the top mIDH inhibitors. This involved biochemical, cell-based, and tier-one ADME techniques.
Two exceedingly short synthetic routes to the key intermediate 2 for the synthesis of the pentacyclic triterpene germanicol 1 have been developed. In the first, the ( S)-epoxide of farnesyl bromide is transformed in just three steps to the tetracyclic intermediate 7, which is converted to chiral 2 by treatment with polyphosphoric acid. The second synthetic route to 2 involves the coupling of the ( S)-epoxide 8 with vinyl iodide 9 to give 10 and two-stage acid-catalyzed cyclization of 10 to form 2. During the course of this work we have also discovered a very unusual intramolecular 1,5-proton shift from a carbocation to a C-C double bond. The details of the process have been confirmed by (2)H-labeling experiments.
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.
This report describes the synthesis of a range of chiral polycyclic molecules (tricyclic to pentacyclic) from achiral polyene precursors by enantioselective proton-initiated polycyclization promoted by the 1:1 complex of o,o'-dichloro-BINOL and SbCl(5). Excellent yields (ca. 90% per ring formed) and enantioselectivety (20:1 to 50:1) were obtained. The process is practical as well as efficient, because the chiral ligand is both readily prepared from R,R- or S,S-BINOL and easily recovered from the reaction mixture by extraction.
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