Biomedical Engineering Reference
In-Depth Information
SCHEME 17.8
Synthesis of bridged bicyclic and tricyclic scaffolds and corresponding
library synthesis, resulting in about 15,000 cytisine-inspired compounds.
The DOS library was screened against BCL-2 in a traditional competition binding
assay against the BH3 peptide in the presence of an inhibitor. From the HTS, three
different hit clusters emerged showing micromolar inhibition against BCL-2 (Fig-
ure 17.15). In all cases, structurally related analogs showed similar activity, giving
further validation of the hits due to tractable SAR. Interestingly, the bridged-bicyclic
pyridone hits had similar potency for both enantiomers, lending to a hypothesis of
possible nonspecific binding. For both hit clusters from the tricyclic pyridone, stereo-
chemistry was critical for activity, as only one enantiomer shows any activity against
