Use of 10% sulfuric acid/dioxane for removal of N-α-tertiary-butyloxycarbonyl group during solid phase peptide synthesis

The hazards and high costs associated with the use of trifluoroacetic acid (TFA) in the removal of the N-α-tertiary-butyloxycarbonyl (Boc) group during solid phase peptide synthesis prompted an examination of alternative acidolytic reagents for α-amino group deprotection. N-α-Boc-glycine and N-α-Boc-isoleucine resins as well as an N-α-Boc-peptide resin were used to test the lability to various deprotection mixtures of both the N-α-Boc resin group as well as the amino acid or peptide-O benzyl ester resin linkage. Of the combinations tried, several were found, including 10% H₂SO₄/dioxane, which gave results roughly comparable to 50% TFA/CH₂Cl₂. Several peptides, 5–10 amino acid residues in length, have been successfully synthesized using the 10% H₂SO₄/dioxane mixture and were found to be comparable in purity to the same peptides prepared using the standard TFA/CH₂Cl₂ method of N-α-Boc removal. Thus, for the peptides examined, 10% H₂SO₄dioxane was found to be an inexpensive, safe, and practical alternative reagent to the more costly and hazardous 50% TFA/CH₂Cl₂ commonly used in the deprotection step of solid phase peptide synthesis.     

Synthesis of the very acid-sensitive Fmoc-Cys(Mmt)-OH and its application in solid-phase peptide synthesis

S-4-methoxytrityl cysteine was synthesized and converted into the corresponding Fmoc-Cys(Mmt)-OH by its reaction with Fmoc-OSu. As compared to the corresponding Fmoc-Cys(Trt)-OH, the S-Mmt-function was found to be considerably more acid labile. Quantitative S-Mmt-removal occurs selectively in the presence of groups of the tert butyl type and S-Trt by treatment with 0.5–1.0% TFA. The new derivative was successfully utilized in the SPPS of Tyr¹-somatostatin on 2-chlorotrityl resin. In this synthesis groups of the Trt-type were exclusively used for amino acid side-chain protection. Quantitative cleavage from the resin and complete deprotection was performed by treatment with 3% TFA in DCM–TES (95:5) for 30 min at RT. We observed no reduction of tryptophan under these conditions. © Munksgaard 1996.     

Efficient solution-phase synthesis of multiple O-phosphoseryl-containing peptides related to casein and statherin

The multiple Ser(P)-containing peptides, H-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-NHMe-TFA, H-Asp-Ser(P)-Ser(P)-Glu-Glu-NHMe-TFA and H-Glu-Ser(P)-Ser(^P)-Glu-Glu-NHMe-TFA were prepared by the use of Boc-Ser(PO₃Ph₂)-OH in the Boc mode of solution phase peptide synthesis followed by platinum-mediated hydrogenolytic de-protection of the Ser(PO₃Ph₂)-containing peptides. The protected peptides were assembled using the mixed anhydride coupling methods with 40% TFA/CH₂C1₂ used for removal of the Boc group from intermediate Boc-protected peptides.     

Cyclic Opioid Peptide Agonists and Antagonists Obtained Via Ring‐Closing Metathesis

The opioid peptide H‐Tyr‐c[D‐Cys‐Phe‐Phe‐Cys]NH₂ cyclized via a methylene dithiother is a potent and selective μ opioid agonist (Przydial M.J. et al., J Peptide Res, 66, 2005, 255). Dicarba analogues of this peptide with Tyr, 2′,6′‐dimethyltyrosine (Dmt), 3‐[2,6‐dimethyl‐4‐hydroxyphenyl)propanoic acid (Dhp) or (2S)‐2‐methyl‐3‐(2,6‐dimethyl‐4‐hydroxyphenyl)propanoic acid [(2S)‐Mdp] in the 1‐position were prepared. The peptides were synthesized on solid‐phase by substituting d ‐allylglycine and (2S)‐2‐amino‐5‐hexenoic acid in position 2 and 5, respectively, followed by ring‐closing metathesis. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated –CH₂–CH₂– bridged peptides. All six Tyr¹‐ and Dmt¹‐dicarba analogues retained high μ and δ opioid agonist potency and showed only slight or no preference for μ over δ receptors. As expected, the six Dhp¹‐ and (2S)‐Mdp¹‐dicarba analogues turned out to be μ opioid antagonists but, surprisingly, displayed a range of different efficacies (agonism, partial agonism or antagonism) at the δ receptor. The obtained results indicate that the μ versus δ receptor selectivity and the efficacy at the δ receptor of these cyclic peptides depend on distinct conformational characteristics of the 15‐membered peptide ring structure, which may affect the spatial positioning of the exocyclic residue and of the Phe³ and Phe⁴ side chains.     

脑活素注射液中肽分析方法的研究

目的：探讨含多肽类药物的检验方法。方法：采用乙腈／水(含0.1％TFA)多肽淋洗系统分析了脑活素注射液的肽谱,进而用PICO-TAG氨基酸分析法分析了该药品水解前、后总氨基酸含量,两者的差值即为肽的含量。结果：本法结果可靠,专属性强。结论：试验结果反映了该药品的内在质量,为脑活素的全面质控提供了可靠的方法依据。     

Radiosynthesis of [18F]LBT‐999, a selective radioligand for the visualization of the dopamine transporter with PET

LBT‐999 (8‐((E)‐4‐fluoro‐but‐2‐enyl)‐3β‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2β‐carboxylic acid methyl ester) is a cocaine derivative belonging to a new generation of highly selective dopamine transporter ligands (K_D:9 nM). LBT‐999 was labelled with fluorine‐18 at its fluoromethylvinyl moiety using the following two‐step radiochemical process: (a) No‐carrier‐added nucleophilic aliphatic radiofluorination from (E)‐1, 4‐ditosyloxybut‐2‐ene and the activated K[¹⁸F]F‐Kryptofix^®222 complex in acetonitrile at 70°C for 10 min giving (E)‐1‐[¹⁸F]fluoro‐4‐tosyloxybut‐2‐ene, followed by (b) condensation of the latter with 3β‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2β‐carboxylic acid methyl ester in N,N‐dimethylformamide containing potassium iodide for 20 min at 90°C and (c) HPLC purification (SunFire? C18, eluent H₂O/CH₃CN/TFA (72:28:0.1 (v/v/v)). Radiochemically pure (> 95%) [¹⁸F]LBT‐999 (2.03–2.96 GBq, 37–111 GBq/μmol) was obtained in 95–100 min starting from a 44.4 GBq [¹⁸F]fluoride ion production batch (4.6–6.7% non‐decay‐corrected overall yield). Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of 2‐exo‐(2′‐[18F]Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane ([18F]F2PhEP), a potent epibatidine‐based radioligand for nicotinic acetylcholine receptor PET imaging

2‐exo‐(2′‐Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane (F₂PhEP), a novel, epibatidine‐based, α4β2‐selective nicotinic acetylcholine receptor antagonist of low toxicity, as well as the corresponding N‐Boc‐protected chloro‐ and bromo derivatives as precursors for labelling with fluorine‐18 were synthesized from 7‐tert‐butoxycarbonyl‐7‐azabicyclo[2.2.1]hept‐2‐ene in 13, 19 and 8% overall yield, respectively. [¹⁸F]F₂PhEP was prepared in 8–9% overall yield (non‐decay‐corrected) using 1 mg of the bromo derivative in the following two‐step radiochemical process: (1) no‐carrier‐added nucleophilic heteroaromatic ortho‐radiofluorination with the activated K[¹⁸F]F‐Kryptofix^®₂₂₂ complex in DMSO using microwave activation at 250 W for 90 s, followed by (2) quantitative TFA‐induced removal of the N‐Boc protective group. Radiochemically pure (>95%) [¹⁸F]F₂PhEP (1.48–1.66 GBq, 74–148 GBq/µmol) was obtained after semi‐preparative HPLC (Symmetry^® C18, eluent aqueous 0.05 M NaH₂PO₄ CH₃CN: 78/22 (v:v)) in 75–80 min starting from an 18.5 GBq aliquot of a cyclotron‐produced [¹⁸F]fluoride production batch. Copyright © 2006 John Wiley & Sons, Ltd.     

Oxygen-17 n.m.r. of peptides

Peptide-¹⁷O chemical shifts of linear dipeptides with and without protecting groups in H₂O, CH₃OH, CH₂Cl₂, CHCl₃, CCl₄, CH₃CN and DMSO were between 256–350 ppm downfield from external water. Increasing solvent H-bond donating ability correlated with shifts to higher field. The ¹⁷O resonance of several cyclic dipeptides appeared at higher field relative to comparable linear dipeptides (303–317 p.p.m. vs. 327–337 p.p.m.). Separate signals were simultaneously observed by ¹³C and ¹⁷O n.m.r. for cis and trans N-tert.-butyl-formamide in binary mixtures with H₂O, (CH₃)₂CO, and CCl₄. The differences in the ¹⁷O nuclear screening of the amide isomers and most probably for cis and trans peptides were independent of contributions from H-bonding at the amide or peptide linkage, apparently reflecting differences between geometric isomers in electron distribution and through space effects. Peptide-¹⁷O of Gly-Ala, Gly-Leu and Gly-Glu in aqueous solution experienced upfield shifts of 6–12 p.p.m. and 12–16 p.p.m. upon deprotonation of the C-terminal COOH and of the N-terminal NH+₃ groups respectively. These observations were rationalized in terms of the attendant changes in substituent effects, especially on the ± electron donating ability of the N atom at the peptide linkage and increased partial negative charge on the peptide oxygen. Temperature studies of peptide-¹⁷O of Gly-Ala between pH 1.5–9.0 revealed a chemical shift coefficient of 0.08 p.p.m./K and similar behavior of T₁ and T₂ relaxation times. Ea for molecular rotation was 5 kcal/mol between 301–331·K. Rotational correlation times, _c, were within the range expected from the Stokes-Einstein relation.     

11C labelling of AG957—a potential tyrphostin radiotracer for PET

Carbon‐11 labelled 4‐(N‐2,5‐dihydroxybenzyl)amino methyl benzoate (AG957), a potential radiotracer for imaging bcr–abl receptors was synthesized. [¹¹C]AG957 was prepared by labelling 4‐aminobenzoic acid using [¹¹C]CH₃I, which affords the corresponding [¹¹C] methyl ester in excellent yields. Subsequent condensation of the amino group with 2,5‐dihydroxy‐benzaldehyde formed the respective Schiff base. Reduction of this compound with NaBH₃CN gave [¹¹C]AG957 in overall decay corrected radiochemical yield of 65–75% (based on ¹¹CH₃I) with an average specific radioactivity of 40 GBq/μmol (1.1 Ci/μmol). The total synthesis time from EOB including formulation was 45 min. At physiological pH, the compound was found to be sufficiently stable for in vitro and in vivo investigations. Copyright © 2002 John Wiley & Sons, Ltd.     

Potent pseudopeptide bombesin-like agonists and antagonists

Bombesin-like pseudopeptides have been synthesized, and certain physicochemical properties and biological activities have been examined. Bombesin and the related peptide litorin were modified at positions 13–14 and 8–9, respectively, with ψ[CH₂S] and ψ[CH₂N(CH₃)]. [Phe¹³ψ[CH₂S]Leu¹⁴]bombesin and [Phe⁸ψ[CH₂S]-Leu⁹]litorin bound to the murine pancreatic bombesin gastrin releasing peptide receptor with similar dissociation constants (K_d= 3.9 and 3.4 nM. respectively). Increased potency was achieved by oxidation of the thiomethylene ether to two diastereomeric sulfoxides (isomer I, K_d= 1.6 nM and isomer II, K_d= 0.89nM. Further oxidation to the sulfone decreased potency ([Phe⁸ψ[CH₂SO₂]Leu⁹]litoin, K_d= 9.9nM). All five analogs were receptor antagonists as determined by phosphatidylinositol turnover in murine pancreas. In contrast to these peptide backbone substitutions, a ψCH₂N(CH₃)] at the 8–9 amide bond position resulted in an agonist. The analogs were compared with those of litorin (K_d= 0.1 nM) and [Leu⁹]litorin (K_d= 0.17 nM) by CD and fluorescence spectroscopy. The CD spectra demonstrated ordered conformation for all the peptides in TFE. Different conformations corresponding to agonist and antagonist peptides were suggested by CD. Based on the pH-dependence of the fluorescence spectra of the peptides in a zwitterionic detergent, two titratable groups were identified (pK_a= 6.3 and 8.5). The lower pK_a is found in the agonist analogs but not in the ψ[CH₂S]-containing antagonist.     

Use of 1,8‐bis‐(dimethylamino)‐naphthalene/H18F complex as new radiofluorinating agent

Radiopharmaceuticals containing an ¹⁸F label are of increasing interest due to their utilization in PET imaging. However, the bottleneck in these applications is the limited methods available for introduction of this radionuclide into biologically interesting molecules. In this work, we have evaluated a new radiofluorination method based on the properties of the complex between 1,8‐(dimethylamino)‐naphthalene ( PS ) and [¹⁸F]–HF. The results obtained on various model substrates suggest that, in some limited cases, this new procedure can be regarded as a possible alternative to the traditional nucleophilic route using K₂₂₂/K₂CO₃ in CH₃CN. Copyright © 2004 John Wiley & Sons, Ltd.     

A solid‐phase synthetic strategy for the preparation of peptide‐based affinity labels: synthesis of dynorphin A analogs

Abstract: Solid‐phase synthetic methodology was developed for the preparation of peptide‐based affinity labels. The initial peptides synthesized were dynorphin A (Dyn A) analogs [Phe(p‐X)⁴,d ‐Pro¹⁰]Dyn A(1–11)NH₂ containing isothiocyanate (X = –N=C=S) and bromoacetamide (X = –NHCOCH₂Br) groups. The peptides were assembled on solid supports using Fmoc‐protected amino acids, and the side chain amine to be functionalized, Phe(p‐NH₂), was protected by the Alloc (allyloxycarbonyl) group. Following removal of the Alloc group by palladium(0), the reactive isothiocyanate and bromoacetamide functionalities were successfully introduced while the peptides were still attached to the resin. Synthesis of these peptides was carried out on polystyrene (PS) and polyethylene glycol–polystyrene (PEG–PS) resins containing the PAL [peptide amide linker, 5‐(4‐Fmoc‐aminomethyl‐3,5‐dimethoxyphenoxy)valeric acid] linker. Both the rate of Alloc deprotection and the purity of the crude affinity‐labeled peptides obtained were found to be dependent on the resin used for peptide assembly.     

Sila-Pharmaka, 7 Mitt. N-Quaternäre Derivate basischer Sila-benzhydryläther

N-Quaternary Derivatives of Basic Silabenzhydryl Ethers Quaternary ammonium salts 1–10 of some biologically active silabenzhydryl ethers were synthesized for the first time by the reaction of the corresponding free bases A–E with CH₃l, CH₃ Br or CH₃Cl in CH₃CN. The structures of 1–10 were confirmed by elementary analysis and ¹ H-NMR spectroscopy. The pharmacological effects of some compounds were compared with those of the corresponding free bases and of analogous carbon compounds.     

Application of Multidimensional Screening and Analysis and Computer Simulation Software for Rapid HPLC Method Development

A comprehensive automated strategy for the development of a reversed-phase high-performance liquid chromatography-UV chromatographic method for a basic drug candidate (pKa 7.7), its impurities, and degradants was demonstrated by using multidimensional screening and analysis (MeDuSA) and Drylab^® computer optimization software. Phase 1 of the strategy employed an automated column selection system and solvent screening (MeDuSA). Samples were screened using ten columns of varying selectivity and high pH stability in combination with four mobile phases of differing pH (pH 2, 4, 7, and 10) containing acetonitrile and methanol as organic modifiers. The best chromatographic conditions (greater number of resolved impurities, tailing factor ~1.0, resolution >1.4) were obtained using the methyl hybrid organic–inorganic polymer phase Xbridge C18 and pH 7 and pH 10 ammonium acetate/methanol/acetonitrile mobile phase. Further screening in MeDuSA using mobile phases A: 0.01 M NH₄OAc in CH₃CN/water (5:95), and B: 0.01 M NH₄OAc in CH₃CN/water (95:5) at pH 7 demonstrated that CH₃CN is the more critical organic modifier for selectivity. In phase 2, DryLab^® software was used to model the effect of temperature, pH, and ionic strength of the buffer on resolution and peak shape to determine the design space of the method and establish the optimal operating conditions. In silico optimization supported by DryLab^® enabled the determination of the optimum conditions without carrying out trial-and-error simulations. Excellent agreement between Drylab^® simulation and experimental results was obtained. As a result of this strategy, a method with the highest resolution of all components, optimum tailing factor (~1.05), and decreased run time (from 35 to 14 min compared to the original method) was developed faster and with higher efficiency in comparison to the traditional method development process.     

Identification and characterization of flavonoids from semen zizyphi spinosae by high-performance liquid chromatography/linear ion trap FTICR hybrid mass spectrometry

Semen zizyphi spinosae (SZS) has been used to treat insomnia and anxiety for thousands of years. In this paper, a novel high-performance liquid chromatography coupled with the photodiode array detector/linear ion trap-MS ⁿ (HPLC-PDA/LTQ-MS ⁿ ) method was established to separate and identify flavonoids from the extract of SZS. Separation was performed on an HYPERSIL C₁₈ column by gradient elution using CH₃CN/H₂O–CH₃COOH as the mobile phase at a flow rate of 0.8 ml/min. UV spectral data, accurate molecular weights, and multi-stage MS/MS fragmentation information were obtained. Electrospray ionization/MS/MS fragmentation patterns were proposed. Nineteen flavonoid glycosides were identified or tentatively characterized based on their retention time, UV spectral data, accurate molecular weights, and mass fragmentation behavior. The method was useful for separation and identification of the flavonoid components from SZS and could be applied to other complex samples, especially for minor constituents.     

Structural effects of the selective reduction of amide carbonyl groups in motilin 1–12 as determined by nuclear magnetic resonance

Motilin is a 22-residue peptide stimulating stomach and intestinal motility. The motilin 1–12 fragment displays biological effects similar to the native peptide. Selective reduction of the amide carbonyl groups to form CH₂NH analogs leads to a significant reduction in activity for the first two N-terminal positions and to a complete loss of activity for all other positions. The structures of motilin 1–12 and ten reduced analogs were investigated using the temperature dependence of the amide NH chemical shifts. In all the analogs, the structure of the N-terminal region (residues 1–5) was different from the structure of motilin 1–12, which is characterized by hydrogen bonding between Phe¹ and Ile⁴. The structure of the C-terminal region of analogs was similar to the structure of moth 1–12 for the first two reduction positions only (1–2 and 2–3), indicating that the C-terminal portion of motilin 1–12 is more critical for biological activity. Complete structural characterizations of motilin 1–12, [CH₂NH]^1–2, and [CH₂NH]^4–5-motilin 1–12 were performed by two-dimensional NMR spectroscopy and molecular modeling. The structural features observed confirm the differences based on the temperature dependence of the amide NH chemical shifts. These results demonstrate that conservation of the amide bond rigidity is essential for the activity of non-hydrolyzable analogs. © Munksgaard 1995.     

Protective effects of Scutellaria lindbergii root extract against oxidative-induced cell and DNA damage in mouse fibroblast-like cells

Context: Scutellaria lindbergii Rech. f. (Lamiaceae) is an Iranian species of Scutellaria which has been shown to exert antimicrobial, antioxidant and cytotoxic effects. Objective: The protective properties of total methanol extract (TME) of S. lindbergii and its fractions (defatted and CH₂Cl₂) were investigated against cytotoxic and genotoxic effects of H₂O₂ in NIH 3T3 cell line as non-malignant cells. Materials and methods: The cells were incubated with different concentrations of S. lindbergii root extracts [TME (15–250?μg ml^?1), defatted fraction (15–500?μg ml^?1) and CH₂Cl₂ fraction (5–40?μg ml^?1)] and toxic concentration of H₂O₂ (200?µM) at 37?°C for 2?h concurrently and Cell viability was quantitated by MTT assay. The antigenotoxic effect of extracts was investigated using comet assay. The cells were incubated with extracts [TME (25–250?μg ml^?1), defatted fraction (25–500?μg ml^?1) and CH₂Cl₂ fraction (5–40?μg ml^?1)] and H₂O₂ (25?µM) at 4?°C for 20?min, then the comet assay was performed. DNA damage was expressed as percentage tail DNA. Results: Total methanol extract of S. lindbergii and its fractions had a significant inhibitory effect on DNA damage. The IC₅₀ values of TME, defatted fraction and CH₂Cl₂ fraction against DNA damage were determined as 48, 138 and 8?μg ml^?1, respectively. Conclusion: S. lindbergii extracts can prevent oxidative DNA damage, which is likely due to its flavonoids and phenolic compounds as antioxidant constituents.     

Synthesis and calcium channel modulation effects of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates possessing ortho‐, meta‐, and para‐CH2S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents

A group of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates ( 13–15 ) possessing ortho‐, meta‐, and para‐CH₂S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents were synthesized using a modified Hantzsch reaction. Calcium channel (CC) modulating activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) in vitro assays. This class of –CH₂S(O)nMe and –S(O)nMe (n = 0–2) compounds ( 13–15a–f ) exhibited weaker CC antagonist activity on GPILSM (IC₅₀ = > 1.1 × 10^–5 to 4.1 × 10^–6 M range) than the reference drug nifedipine (IC₅₀ = 1.4 × 10^–8 M). The oxidation state of the sulfur atom was a determinant of smooth muscle CC antagonist activity where the relative activity profile was generally thio ( 13 , ‐CH₂SMe, ‐SMe) and sulfonyl ( 15 , ‐CH₂SO₂Me, ‐SO₂Me) > sulfinyl ( 14 , ‐CH₂SOMe, ‐SOMe). The point of attachment of the phenyl substituent was a determinant of activity for the –CH₂SMe ( 13a–c ), ‐CH₂SOMe ( 14a–c ) and SOMe ( 14d–f ) isomers where the relative potency order was meta and para > ortho. Compounds in this group ( 13–15 ), unlike Bay K 8644 (EC₅₀ = 2.3 × 10^–7 M on GPILSM), did not exhibit an agonist effect on GPILSM. The meta‐CH₂SMe ( 13b ), ortho‐CH₂SMe ( 13c ), meta‐SMe ( 13e ), and ortho‐CH₂SO₂Me ( 15c ) C‐4 phenyl derivatives exhibited respectable in vitro cardiac positive inotropic activities (EC₅₀ = 1.00 × 10^–6 to 7.57 × 10^–6 M range) relative to the reference drug Bay K 8644 (EC₅₀ = 7.70 × 10^–7 M) in the GPLA assay. In contrast to Bay K 8644, which acts as an undesirable calcium channel agonist on smooth muscle (GPILSM), compounds 13b (IC₅₀ = 4.11 × 10^–6 M), 13c (IC₅₀ = 2.29 × 10^–5 M), 13e (IC₅₀ = > 1.20 × 10^–5 M) and 15c (IC₅₀ = 6.22 × 10^–6 M) exhibited a desirable simultaneous calcium channel antagonist effect on smooth muscle at a similar ( 13b , 15c ), or lower ( 13c , 13e ), concentration relative to its cardiac agonist EC₅₀ value. Model compounds such as 13b , 13c , 13e , and 15c , that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulators that offer a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:177–186, 2000. © 2001 Wiley‐Liss, Inc.     

Conformations of ψ[CH2NH] pseudopeptides

The cyclic pseudopentapeptide cyclo[Gly-Proψ[CH₂NH]Gly-D-Phe-Pro] and its TFA salt were synthesized by solution methods, and their conformations were studied by NMR spectroscopy in both DMSO-d₆ and CDC₁₃. While intramolecular hydrogen bonding is observed with some conformers, the nature of the solvent and the presence of TFA affects the relative structural rigidities of the compounds. No evidence was found for the ψ[CH₂NH] or ψ[CH₂NH⁺₂] units acting as H donors in this series.