Stereoelectronic effects dictate molecular conformation and biological function of heterocyclic amides

Reid, Robert C., Yau, Mei-Kwan, Singh, Ranee, Lim, Junxian and Fairlie, David P. (2014) Stereoelectronic effects dictate molecular conformation and biological function of heterocyclic amides. Journal of the American Chemical Society, 136 34: 11914-11917. doi:10.1021/ja506518t


Author Reid, Robert C.
Yau, Mei-Kwan
Singh, Ranee
Lim, Junxian
Fairlie, David P.
Title Stereoelectronic effects dictate molecular conformation and biological function of heterocyclic amides
Journal name Journal of the American Chemical Society   Check publisher's open access policy
ISSN 0002-7863
1520-5126
1943-2984
Publication date 2014-08-27
Sub-type Article (original research)
DOI 10.1021/ja506518t
Open Access Status
Volume 136
Issue 34
Start page 11914
End page 11917
Total pages 4
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2015
Language eng
Formatted abstract
Heterocycles adjacent to amides can have important influences on molecular conformation due to stereoelectronic effects exerted by the heteroatom. This was shown for imidazole- and thiazole-amides by comparing low energy conformations (ab initio MP2 and DFT calculations), charge distribution, dipole moments, and known crystal structures which support a general principle. Switching a heteroatom from nitrogen to sulfur altered the amide conformation, producing different three-dimensional electrostatic surfaces. Differences were attributed to different dipole and orbital alignments and spectacularly translated into opposing agonist vs antagonist functions in modulating a G-protein coupled receptor for inflammatory protein complement C3a on human macrophages. Influences of the heteroatom were confirmed by locking the amide conformation using fused bicyclic rings. These findings show that stereoelectronic effects of heterocycles modulate molecular conformation and can impart strikingly different biological properties.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Mon, 01 Sep 2014, 13:58:22 EST by David Fairlie on behalf of Chemistry, Department of