3 research outputs found
Chromatography-Free Entry to Substituted Salicylonitriles: Mitsunobu-Triggered Domino Reactions of Salicylaldoximes
A mild and efficient one-pot procedure
is described to transform
salicylaldoximes into salicylonitriles using Mitsunobu chemistry.
The reactions proceed through the corresponding 1,2-benzisoxazoles
that undergo the Kemp elimination in situ to generate the target salicylonitriles
in excellent yields. The chemistry exhibits a broad scope, and the
salicylonitriles can be readily isolated by a simple acid–base
workup. In addition to functioning as useful synthetic precursors,
salicylonitriles may serve as more cell penetrable bioisosteres of
carboxylic acids
Amphipathic α‑Helix Mimetics Based on a 1,2-Diphenylacetylene Scaffold
In order to mimic amphipathic α-helices, a novel scaffold based on a 1,2-diphenylacetylene was designed. NMR and computational modeling confirmed that an intramolecular hydrogen bond favors conformations of the 1,2-diphenylacetylene that allow for accurate mimicry of the <i>i</i>, <i>i</i> + 7 and <i>i</i> + 2, <i>i</i> + 5 side chains found on opposing faces of an α-helix
Perturbation of the c‑Myc–Max Protein–Protein Interaction via Synthetic α‑Helix Mimetics
The
rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc
is hampered by a lack of structure in its monomeric state. We describe
herein the design of novel, low-molecular-weight, synthetic α-helix
mimetics that recognize helical c-Myc in its transcriptionally active
coiled-coil structure in association with its obligate bHLH-ZIP partner
Max. These compounds perturb the heterodimer’s binding to its
canonical E-box DNA sequence without causing protein–protein
dissociation, heralding a new mechanistic class of “direct”
c-Myc inhibitors. In addition to electrophoretic mobility shift assays,
this model was corroborated by further biophysical methods, including
NMR spectroscopy and surface plasmon resonance. Several compounds
demonstrated a 2-fold or greater selectivity for c-Myc–Max
heterodimers over Max–Max homodimers with IC<sub>50</sub> values
as low as 5.6 ÎĽM. Finally, these compounds inhibited the proliferation
of c-Myc-expressing cell lines in a concentration-dependent manner
that correlated with the loss of expression of a c-Myc-dependent reporter
plasmid despite the fact that c-Myc–Max heterodimers remained
intact