1006030-80-3Relevant academic research and scientific papers
GLP-1 receptor agonist compounds having stabilized regions
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Page/Page column 42, (2016/01/09)
The disclosure provides GLP-1 receptor agonist compounds having stabilized regions corresponding to alpha-helical regions of the natural peptide compounds. The disclosure also provides benzamide-containing exendin-4 analogs and alkene-constrained exendin-4 analogs, both of which have stabilized regions corresponding to alpha-helical regions of exendin-4.
Perturbation of the c-Myc-Max Protein-Protein Interaction via Synthetic α-Helix Mimetics
Jung, Kwan-Young,Wang, Huabo,Teriete, Peter,Yap, Jeremy L.,Chen, Lijia,Lanning, Maryanna E.,Hu, Angela,Lambert, Lester J.,Holien, Toril,Sundan, Anders,Cosford, Nicholas D. P.,Prochownik, Edward V.,Fletcher, Steven
, p. 3002 - 3024 (2015/04/27)
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 IC50 values as low as 5.6 μM. 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. (Chemical Equation Presented).
Conformational properties of O-alkylated benzamides
Prabhakaran, Panchami,Azzarito, Valeria,Jacobs, Tia,Hardie, Michaele J.,Kilner, Colin A.,Edwards, Thomas A.,Warriner, Stuart L.,Wilson, Andrew J.
, p. 4485 - 4491 (2012/07/27)
In this article, we report the synthesis, solid-state and solution-state conformational studies of O-alkylated aromatic benzamides based on two scaffolds. Intramolecular hydrogen bonding provides conformational pre-organization and side chains can interact with each other within a molecule. In the solid-state three-dimensional arrangement, the molecules further interact with each other through non-covalent interactions. Given, the demonstrated potential of this class of scaffolds to act as helix mimetics for the inhibition of protein-protein interactions (PPIs), these results provide key insight for future inhibitor design.
2-O-Alkylated para-benzamide α-helix mimetics: The role of scaffold curvature
Azzarito, Valeria,Prabhakaran, Panchami,Bartlett, Alice I.,Murphy, Natasha S.,Hardie, Michaele J.,Kilner, Colin A.,Edwards, Thomas A.,Warriner, Stuart L.,Wilson, Andrew J.
, p. 6469 - 6472 (2012/09/08)
The design and synthesis of a new 2-O-alklyated benzamide α-helix mimetic is described. Comparison with regioisomeric 3-O-alkylated benzamides permits a preliminary evaluation of the role that mimetic curvature has in determining molecular recognition properties.
Design, synthesis, and evaluation of an a-helix mimetic library targeting protein-protein interactions
Shaginian, Alex,Whitby, Landon R.,Hong, Sukwon,Hwang, Inkyu,Farooqi, Bilal,et al.
supporting information; experimental part, p. 5564 - 5572 (2009/09/25)
The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small-molecule library targeting protein - protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix),where the added subunits are designed to mimic all possible permutation s of the naturally occurring i, i + 4, i + 7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead α-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an α-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.
Synthesis of functionalised aromatic oligamide rods
Plante, Jeffrey,Campbell, Fred,Malkova, Barbora,Kilner, Colin,Warriner, Stuart L.,Wilson, Andrew J.
, p. 138 - 146 (2008/09/20)
A current goal in synthetic chemistry is the design and synthesis of molecules that adopt well defined conformations - so called foldamers. In this manuscript we describe a modular approach for construction of rod shaped para-oligobenzamide molecules. Our approach permits regiospecific incorporation of side chains through a phenolic ether linkage on the scaffold; a feature that partly restricts the conformation of the rod through intramolecular hydrogen-bonding. The Royal Society of Chemistry 2008.
