Kröhnke pyridines: Rapid and facile access to Mcl-1 inhibitors

[Display omitted] The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 α-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The conden...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-06, Vol.28 (10), p.1949-1953
Main Authors: Conlon, Ivie L., Van Eker, Daniel, Abdelmalak, Sameh, Murphy, William A., Bashir, Hassan, Sun, Michael, Chauhan, Jay, Varney, Kristen M., Godoy-Ruiz, Raquel, Wilder, Paul T., Fletcher, Steven
Format: Article
Language:English
Subjects:
Apoptosis
Binding Sites
Cancer
Humans
Inhibitory Concentration 50
Kröhnke
Magnetic Resonance Spectroscopy
Mcl-1
Molecular Docking Simulation
Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors
Myeloid Cell Leukemia Sequence 1 Protein - metabolism
Protein Interaction Domains and Motifs
Protein Structure, Tertiary
Protein-protein interaction
Pyridines - chemistry
Pyridines - metabolism
Structure-Activity Relationship
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Summary:[Display omitted] The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 α-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The condensation of α-pyridinium methyl ketone salts and α,β-unsaturated carbonyl compounds in the presence of a source of ammonia, or the Kröhnke pyridine synthesis, is a simple approach to afford highly functionalized pyridines. We adapted this chemistry to rapidly generate low-micromolar inhibitors of Mcl-1 wherein the 2,4,6-substituents were predicted to mimic the i, i + 2 and i + 7 side chains of the BH3 α-helix.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.03.050