共查询到20条相似文献,搜索用时 15 毫秒
1.
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. 相似文献
2.
KLEOMENIS BARLOS DIMITRIOS GATOS OLGA HATZI NICOLE KOCH SOFIA KOUTSOGIANNI 《Chemical biology & drug design》1996,47(3):148-153
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. 相似文献
3.
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. 相似文献
4.
Irena Berezowska Carole Lemieux Nga N. Chung Brian C. Wilkes Peter W. Schiller 《Chemical biology & drug design》2009,74(4):329-334
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. 相似文献
5.
6.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(8):687-698
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 (KD: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. 相似文献
7.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(6):489-504
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. 相似文献
8.
B. VALENTINE A. STEINSCHNEIDER D. DHAWAN M.I. BURGAR T. ST. AMOUR D. FIAT 《Chemical biology & drug design》1985,25(1):56-68
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. 相似文献
9.
《Journal of labelled compounds & radiopharmaceuticals》2002,45(2):157-165
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. 相似文献
10.
J. VINCENT EDWARDS LARRY R. MCLEAN ARLENE C. WADE SCOTT R. EATON ELIZABETH A. CASHMAN KAREN A. HAGAMAN BRADFORD O. FANGER 《Chemical biology & drug design》1994,43(4):374-383
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 (Kd= 3.9 and 3.4 nM. respectively). Increased potency was achieved by oxidation of the thiomethylene ether to two diastereomeric sulfoxides (isomer I, Kd= 1.6 nM and isomer II, Kd= 0.89nM. Further oxidation to the sulfone decreased potency ([Phe8ψ[CH2SO2]Leu9]litoin, Kd= 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 (Kd= 0.1 nM) and [Leu9]litorin (Kd= 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 (pKa= 6.3 and 8.5). The lower pKa is found in the agonist analogs but not in the ψ[CH2S]-containing antagonist. 相似文献
11.
《Journal of labelled compounds & radiopharmaceuticals》2004,47(6):373-383
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. 相似文献
12.
13.
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. 相似文献
14.
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. 相似文献
15.
Claudia C. Corredor John A. Castoro Joel Young 《Journal of pharmaceutical innovation》2009,4(3):121-132
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. 相似文献
16.
Chun-Yan Niu Cai-Sheng Wu Yu-Xin Sheng 《Journal of Asian natural products research》2013,15(4):300-312
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. 相似文献
17.
YVAN BOULANGER ABDESSLEM KHIAT YANMIN CHEN DIANE GAGNON PIERRE POITRAS SERGE ST-PIERRE 《Chemical biology & drug design》1995,46(6):527-534
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. 相似文献
18.
Melika Ehtesham-Gharaee Ameneh Eshaghi Susan Shojaee Javad Asili Seyed Ahmad Emami Javad Behravan 《Drug and chemical toxicology》2015,38(3):293-299
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. 相似文献
19.
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. 相似文献
20.
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. 相似文献