Backbone-Fluorinated 1,2,3-Triazole-Containing Dipeptide Surrogates

The 1,2,3-triazole moiety can be incorporated as a peptide bond bioisostere to provide protease resistance in peptidomimetics. Herein, we report the synthesis of peptidomimetic building blocks containing backbone-fluorinated 1,4-disubstituted 1,2,3-triazole moieties. Synthetic protocols for the preparation of various Xaa-Gly dipeptide surrogates in the form of Xaa-ψ­[triazole]-F₂Gly building blocks were established, and selected examples were introduced into the endogenous peptide opioid receptor ligand Leu-enkephalin as a model compound

<i>Cis</i>–<i>Trans</i> Amide Bond Rotamers in β‑Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, the β-peptoids (N-alkyl-β-alanines), has found use in a variety of biologically active compounds but has been sparsely studied with respect to folding propensity. Thus, we here report an investigation of the effect of structural variations on the <i>cis</i>–<i>trans</i> amide bond rotamer equilibria in a selection of monomer model systems. In addition to various side chain effects, which correlated well with previous studies of α-peptoids, we present the synthesis and investigation of <i>cis</i>–<i>trans</i> isomerism in the first examples of peptoids and β-peptoids containing thioamide bonds as well as trifluoroacetylated peptoids and β-peptoids. These systems revealed an increase in the preference for <i>cis</i>-amides as compared to their parent compounds and thus provide novel strategies for affecting the folding of peptoid constructs. By using NMR spectroscopy, X-ray crystallographic analysis, and density functional theory calculations, we present evidence for the presence of thioamide–aromatic interactions through C_sp²–H···S_amide hydrogen bonding, which stabilize certain peptoid conformations

<i>Cis</i>–<i>Trans</i> Amide Bond Rotamers in β‑Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, the β-peptoids (N-alkyl-β-alanines), has found use in a variety of biologically active compounds but has been sparsely studied with respect to folding propensity. Thus, we here report an investigation of the effect of structural variations on the <i>cis</i>–<i>trans</i> amide bond rotamer equilibria in a selection of monomer model systems. In addition to various side chain effects, which correlated well with previous studies of α-peptoids, we present the synthesis and investigation of <i>cis</i>–<i>trans</i> isomerism in the first examples of peptoids and β-peptoids containing thioamide bonds as well as trifluoroacetylated peptoids and β-peptoids. These systems revealed an increase in the preference for <i>cis</i>-amides as compared to their parent compounds and thus provide novel strategies for affecting the folding of peptoid constructs. By using NMR spectroscopy, X-ray crystallographic analysis, and density functional theory calculations, we present evidence for the presence of thioamide–aromatic interactions through C_sp²–H···S_amide hydrogen bonding, which stabilize certain peptoid conformations

Modulation in Selectivity and Allosteric Properties of Small-Molecule Ligands for CC-Chemokine Receptors

Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn­(II) or Cu­(II) in complex with 2,2′-bipyridine or 1,10-phenanthroline with similar potencies (EC₅₀ from 3.9 to 172 μM). Besides being agonists, they acted as selective allosteric enhancers of CCL3. These actions were dependent on a conserved glutamic acid at TM-7 (VII:06/7.39). A screening of 20 chelator analogues in complex with Zn­(II) identified compounds with increased potencies, with <b>7</b> reaching highest potency at CCR1 (EC₅₀ of 0.85 μM), <b>20</b> at CCR8 (0.39 μM), and <b>8</b> at CCR5 (1.0 μM). Altered selectivity for CCR1 and CCR8 over CCR5 (<b>11</b>, <b>12</b>) and a receptor-dependent separation of allosteric from intrinsic properties were achieved (<b>20</b>). The pocket similarities of CCR1 and CCR8, contrary to CCR5 as proposed by the ligand screen, were elaborated by computational modeling. These studies facilitate exploration of chemokine receptors as possible targets for therapeutic intervention

Effects of Thionation and Fluorination on Cis–Trans Isomerization in Tertiary Amides: An Investigation of <i>N</i>‑Alkylglycine (Peptoid) Rotamers

Peptoids constitute a class of peptidomimetics with potential as protease resistant, biologically active ligands. To harness the full potential of such compounds, however, detailed predictive insight into their propensity to adopt well-defined secondary structures is highly desirable. In this work we present an investigation of the effects of thioamides and/or fluorides in peptoid monomer model systems using chemical synthesis, NMR spectroscopy, and X-ray crystallography. We find that the steric environment surrounding the tertiary amide bonds is the key promoter of conformational preference, and X-ray crystallographic interrogation of our model systems did not suggest the presence of stabilizing <i>n</i> → π* interactions unless the carbonyls were altered electronically by α-halogenation or thioamide formation. In addition to the function as an investigative tool, these two types of modification may thus be utilized as stabilizers of secondary structure in future oligomer designs, such as the <i>cis-</i>amide-based polypeptoid helices that resemble the polyproline type-I helix