960117-63-9Relevant academic research and scientific papers
Stereoelectronic effects dictate molecular conformation and biological function of heterocyclic amides
Reid, Robert C.,Yau, Mei-Kwan,Singh, Ranee,Lim, Junxian,Fairlie, David P.
, p. 11914 - 11917 (2014/10/16)
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.
Potent heterocyclic ligands for human complement C3a receptor
Reid, Robert C.,Yau, Mei-Kwan,Singh, Ranee,Hamidon, Johan K.,Lim, Junxian,Stoermer, Martin J.,Fairlie, David P.
, p. 8459 - 8470 (2014/12/11)
The G-protein coupled receptor (C3aR) for human inflammatory protein complement C3a is an important component of immune, inflammatory, and metabolic diseases. A flexible compound (N2-[(2,2-diphenylethoxy)acetyl]-l-arginine, 4), known as a weak C3aR antagonist (IC50 μM), was transformed here into potent agonists (EC50 nM) of human macrophages (Ca2+ release in HMDM) by incorporating aromatic heterocycles. Antagonists were also identified. A linear correlation between binding affinity for C3aR and calculated hydrogen-bond interaction energy of the heteroatom indicated that its hydrogen-bonding capacity influenced ligand affinity and function mediated by C3aR. Hydrogen-bond accepting heterocycles (e.g., imidazole) conferred the highest affinity and agonist potency (e.g., 21, EC50 24 nM, Ca2+, HMDM) with comparable efficacy and immunostimulatory activity as that of C3a in activating human macrophages (Ca2+, IL1β, TNFα, CCL3). These potent and selective modulators of C3aR, inactivated by a C3aR antagonist, are stable C3a surrogates for interrogating roles for C3aR in physiology and disease.
Sequential copper-catalyzed vinylation/ cyclization: An efficient synthesis of functionalized oxazoles
Martin, Ruben,Cuenca, Ana,Buchwald, Stephen L.
, p. 5521 - 5524 (2008/09/17)
A modular and practical synthesis of highly substituted oxazoles has been developed. The transformation consists of a sequential copper-catalyzed amidation of vinyl halides followed by cyclization promoted by iodine. A wide variety of functionalized oxazo
