3 research outputs found
Regiochemistry of the Condensation of 2‑Aroyl-cyclohexanones and 2‑Cyanoacetamide: <sup>13</sup>C‑Labeling Studies and Semiempirical MO Calculations
Hydroxy-aryl-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles
represent
interesting chemical scaffolds, but synthetic access to these compounds
is limited. The reaction of 2-aroyl-cyclohexanones with 2-cyanoacetamide
and base in ethanol has been reported to lead to the formation of
the tetrahydroisoquinoline isomer. We show that depending on the electronic
nature of the <i>para-</i>substituent on the aryl ring,
formation of the regioisomeric tetrahydroquinoline isomer can significantly
compete. The electron-donating or -withdrawing properties of the <i>para-</i>substituent of the aryl ring determines the ratio of
product isomers. A series of 2-aroyl-cyclohexanones, with <i>para</i>-substituents ranging from electron-donating to electron-withdrawing,
were reacted with [2-<sup>13</sup>C]-cyanoacetamide. The product ratio
and absolute regiochemistry were directly determined by quantitative <sup>13</sup>C, HMBC, and NOESY NMR spectroscopy on the reaction mixtures.
A clear relationship between the regioisomeric product ratio and the
Hammett sigma values of the substituents is demonstrated. This is
explained by the separate in situ yields, which reveal that the pathway
leading to the tetrahydroquinoline regioisomer is significantly more
sensitive toward the electronic nature of the <i>para</i>-substituent than the pathway leading to the tetrahydroisoquinoline.
Semiempirical AM1 molecular orbital calculations on the starting electrophile
2-aroyl-cyclohexanone support a correlation between the energy of
the LUMOs and the regioisomeric product ratio. Our results facilitate
synthetic access to a range of these interesting synthetic intermediates
Chemical Subtleties in Small-Molecule Modulation of Peptide Receptor Function: The Case of CXCR3 Biaryl-Type Ligands
The G protein-coupled chemokine receptor CXCR3 plays
a role in
numerous inflammatory events. The endogenous ligands for the chemokine
receptors are peptides, but in this study we disclose small-molecule
ligands that are able to activate CXCR3. A class of biaryl-type compounds
that is assembled by convenient synthetic routes is described as a
new class of CXCR3 agonists. Intriguingly, structure–activity
relationship and structure–function relationship studies reveal
that subtle chemical modifications on the outer aryl ring (e.g., either
the size or position of a halogen atom) result in a full spectrum
of agonist efficacies on CXCR3. Quantum mechanics calculations and
nuclear Overhauser effect spectroscopy NMR studies suggest that the
biaryl dihedral angle and the electronic nature of <i>ortho</i>-substituents play an important role in determining agonist efficacies.
Compounds <b>38</b> (VUF11222) and <b>39</b> (VUF11418)
are the first reported nonpeptidomimetic agonists on CXCR3, rendering
them highly useful chemical tools for detailed assessment of CXCR3
activation as well as for studying downstream CXCR3 signaling
A Prospective Cross-Screening Study on G-Protein-Coupled Receptors: Lessons Learned in Virtual Compound Library Design
We present the systematic prospective evaluation of a
protein-based and a ligand-based virtual screening platform against
a set of three G-protein-coupled receptors (GPCRs): the β-2
adrenoreceptor (ADRB2), the adenosine A<sub>2A</sub> receptor (AA2AR),
and the sphingosine 1-phosphate receptor (S1PR1). Novel bioactive
compounds were identified using a consensus scoring procedure combining
ligand-based (frequent substructure ranking) and structure-based (Snooker)
tools, and all 900 selected compounds were screened against all three
receptors. A striking number of ligands showed affinity/activity for
GPCRs other than the intended target, which could be partly attributed
to the fuzziness and overlap of protein-based pharmacophore models.
Surprisingly, the phosphodiesterase 5 (PDE5) inhibitor sildenafil
was found to possess submicromolar affinity for AA2AR. Overall, this
is one of the first published prospective chemogenomics studies that
demonstrate the identification of novel cross-pharmacology between
unrelated protein targets. The lessons learned from this study can
be used to guide future virtual ligand design efforts