Enkephalin pseudopeptides: resistance to in vitro proteolytic degradation afforded by amide bond replacements extends to remote sites

Five analogs of leucine enkephalin containing the CH2S group as an amide bond replacement were evaluated with respect to resistance toward degradation by human serum in an HPLC-based assay using both ultraviolet and electrochemical detection. Analogs with the modification at the 1-2, 2-3, 3-4, or 4-5 peptide linkages demonstrated half-lives of 118, 85, 134, and 318 min vs. 12 min for the parent peptide. A pseudopeptide analog with additional D-Ala2 protection had a half-life of greater than 1000 min, while the potent [D-Ala2]-leucine enkephalin analog showed approximately a 10-fold increase in stability. The significant increase in stability for a compound with protection only at the C-terminus suggests that serum enzymes may have greater specificity toward backbone changes than previously realized.     

Facile reduction of peptide oxime endothelin antagonist during trialkylsilane/TFA cleavage after solid-phase synthesis

Summary We describe a new solid-phase strategy for the selective reduction of the C=N bond in peptide oximes using a trialkylsilane in trifluoroacetic acid. The reduction is performed directly on the resin-bound peptide, with concomitant cleavage of the peptide from the resin and deblocking of protected side chains.     

Synthesis and activity of phosphono desmuramyldipeptide analogs

Summary Two phosphono desmuramyldipeptide analogs, 6 and 11, were synthesized and evaluated for immunomodulatory activity. Phthalimido-and adamantyl-substituted side chains as a replacement for the N-acetylmuraminic acid were coupled with appropriate dipeptides using DPPA as the coupling reagent. Introduction of a phosphonamidate moiety in compound 6 resulted in lower biological activity.     

A solid-phase synthesis of three aza-, iminoaza- and reduced aza-peptides from the same precursor

Using the Boc-strategy, a step-by-step synthesis on the PAM solid supportof three aza-, iminoaza- and reduced aza-peptide homologues is described.From the same hydrazinocarbonyl peptide-PAM precursor, the coupling ofeither a Boc-amino acid or a Boc-amino aldehyde gives rise to an aza-peptideor an iminoaza-peptide containing theC-CO-NH-N-CO-NH-C orC-CH=N-N-CO-NH-C surrogate of the peptide motif, respectively. In situreduction of the latter by NaBH₃CN leads to a reducedaza-peptide containing theC-CH₂-NH-N-CO-NH-C moiety. The key step synthesis of thehydrazinocarbonyl peptide-PAM precursor is carried out by coupling on thegrowing peptide chain the N-Boc-aza-amino acid chloride obtained by theaction of triphosgene on the corresponding N-Boc-hydrazine. Thesemodifications have been introduced in position 1-2 of the YLGYLEQLLRbenzodiazepine-like decapeptide     

Synthesis and biological evaluation of novel analogues of Gly-l-Pro-l-Glu (GPE) as neuroprotective agents

This study investigated the anti-inflammatory effects of novel pseudotripeptides (GPE 1–3) as potential candidates to counteract neuroinflammation processes in Alzheimer’s disease.GPE 1–3 pseudotripeptides are synthetic derivatives of Gly-l-Pro-l-Glu (GPE), the N-terminal tripeptide of IGF-1, obtained through the introduction of isosteres of the amidic bond (aminomethylene unit) to increase the metabolic stability of the native tripeptide. The results showed that all synthetic derivatives possessed higher half-lives (t_1/2?>?4?h) than GPE (t_1/2?=?30?min) in human plasma and had good water solubility. The biological results demonstrated that GPE 1–3 had protective properties in several experimental models of treated THP-1 cells. Notably, the novel pseudotripeptides influenced inflammatory cytokine expression (IL-1β, IL-18, and TNF-α) in Aβ_25–35-, PMA-, and LPS-treated THP-1 cells. In PMA-differentiated THP-1 macrophages, both GPE 1 and GPE 3 reduced the expression levels of all selected cyto-chemokines, even though GPE 3 showed the best neuroprotective properties.     

Synthesis,conformation and biological activity of centrally modified pseudopeptidic analogues of For-Met-Leu-Phe-OMe

Summary. For-Met-βAlaψ[CSNH]-Phe-OMe (3), For-Met-βAlaψ[CH₂NH]-Phe-OMe (5), For-Met-NH-pC₆H₄-SO₂-Phe-OMe (8a), For-Met-NH-mC₆H₄-SO₂-Phe-OMe (8b) and the corresponding N-Boc precursors (2, 4, 7a, b) have been synthesized and their activity towards human neutrophils has been evaluated in comparison with that shown by the reference tripeptide For-Met-Leu-Phe-OMe (fMLF-OMe). Chemotaxis, lysozyme release and superoxide anion production have been measured. ¹H NMR titration experiments and IR spectra have been discussed in order to ascertain the preferred solution conformation adopted by the tripeptide 3 with particular reference to the presence of a folded conformation centred at the centrally positioned thionated β-residue.     

A solid-phase synthesis of three aza-, iminoaza- and reduced aza-peptides from the same precursor

Summary Using the Boc-strategy, a step-by-step synthesis on the PAM solid support of three aza-, iminoaza- and reduced aza-peptide homologues is described. From the same hydrazinocarbonyl peptide-PAM precursor, the coupling of either a Boc-amino acid or a Boc-amino aldehyde gives rise to an aza-peptide or an iminoaza-peptide, containing the C^α-CO-NH-N^α-CO-NH-C^α or C^α-CH=N-N^α-CO-NH-C^α surrogate, of the peptide motif, respetively. In situ reduction of the latter by NaBH₃CN leads to a reduced aza-peptide containing the C^α-CH₂-NH-N^α-CO-NH-C^α moiety. The key step synthesis of the hydrazinocarbonyl peptide-PAM precursor is carried out by coupling on the growing peptide chain theN-Boc-azaamino acid chloride obtained by the action of triphosgene on the, correspondingN-Boc-hydrazine. These modifications have been introduced in position 1–2 of the YLGYLEQLLR benzodiazepine-like decapeptide.