A convenient one-pot system has been
developed, allowing the synthesis
of highly substituted dihydropyridines via a C–H activation/6π-electrocyclization
pathway. The reaction proceeds with high regioselectivity, and we
disclose the first example of isolated dihydropyridines lacking substitution
in the 2 position. Moreover, the use of a simple well-defined low-valent
cobalt complex without the need for reducing agents or additives in
combination with computational studies provides a clearer insight
into the C–H activation pathway than was previously reported.
On the basis of the knowledge that the proline-rich hot spot PPPRPP region of P( 151)PSNPPPRPP( 160), an oligopeptide derived from the cytosolic portion of p22 phox (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47 phox (p47), we designed a mimetic of the tripeptide PPP based on NMR and X-ray crystallographic data for the p22(151−161) peptide PPSNPPPRPPA with a peptide construct. Incorporation of the synthetic pseudo-triproline mimetic Pro-Pro-Cyp in a molecule derived from molecular modeling studies led to only a 7-fold diminution in activity in a surface plasmon resonance assay relative to the same molecule containing the natural Pro-Pro-Pro tripeptide. The alternative sequence corresponding to a Pro-Cyp-Pro insertion was inactive. This is a first example of the use of a triproline mimetic to interfere with the formation of the p47−p22 complex, which is critical for the activation of NOX, leading to the production of reactive oxygen species as superoxide anions.
Stereocontrolled methods are described for the synthesis of hitherto unreported pseudodiproline dimers in which a cyclopentane carboxylic acid is linked to a pyrrolidine residue by a stereochemically defined hydroxymethylene tether. These prolinecyclopentane (Pro-Cyp) dimers have interesting structural characteristics as seen in their X-ray crystal structures as well as their nuclear magnetic resonance (NMR) spectra in CDCl 3 . They can be considered to be novel Pro-Pro mimetics, which can be used to replace natural diproline sequences with potential applications in medicinal chemistry. They also represent a new concept in the peptidomimetic design of chimeric proline-based amino acids as carbocyclic hydroxyethylene isosteres of inhibitor molecules, in which the stereodefined bridging hydroxyl group can simulate a tetrahedral intermediate in an enzyme complex.
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