共查询到20条相似文献,搜索用时 49 毫秒
1.
EDWARD M. DEVINE ALEXANDER M. BUKO STEVEN P. CEPA STEVEN K. DAVIDSEN WILLIAM H. HOLLEMAN CAROL A. MARSELLE TERRY J. OPGENORTH TODD W. ROCKWAY THOMAS W. VON GELDERN 《Chemical biology & drug design》1992,40(6):532-537
The degradation of a prototypical small analogue of atrial natriuretic peptide (ANP) has been studied using HPLC and mass spectrometric techniques. These studies revealed that removal of the N-terminal amino acid as the primary catabolic event in vitro. Based on this information the N-terminus was remanufactured to provide a family of more stable analogues. Additional stabilization was provided through modification of the C-terminal tripeptide. Though dramatically more stable in vitro, these new analogues do not appear to have longer in vivo half-lives. 相似文献
2.
SEVERO SALVADORI MAURO MARASTONI GIANFRANCO BALBONI PIERANDREA BOREA ROBERTO TOMATIS 《Chemical biology & drug design》1989,33(2):94-102
C-Terminal amino acid residues of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) were replaced by Nα-methyl- or D-amino acids in order to examine the effect on opioid activity. In binding studies based on displacement of μ, Δ, and κ opioid receptor selective radiolabels from guinea pig brain membranes, the 13 new analogues showed, like dermorphin, a negligible affinity for the κ binding site. The introduction of Nα-methyl- or D-amino acid residues at position 5, 6, or 7 of dermorphin, when matched with C-terminal amide function modifications, generally produced analogues with reversed μ/δ specificity. 相似文献
3.
ELIZABETH E. SUGG MARIANGELA SERRA JENNIFER E. SHOOK HENRY I. YAMAMURA THOMAS F. BURKS MURRAY KORC VICTOR J. HRUBY 《Chemical biology & drug design》1988,31(6):514-519
Three new analogues of Nα-hydroxysulfonyl-[Nle28,31]CCK26-33 are reported in which the C-terminal l -Phe33 residue has been replaced by l -Leu, d -Phe or N-methyl-l -Phe. Biological evaluation in a series of binding and bioassays demonstrates that both l -stereochemistry and an aromatic side chain at position-33 are essential for full agonist activity. While the l -Leu33 and d -Phe33 analogues had reduced potencies in stimulating contraction of the guinea pig ileum or gall bladder, the d -Phe33 analogue was fourfold selective for the ileum. This latter analogue also exhibited apparent partial agonism in the rat pancreatic amylase release assay. The N-methyl-l -Phe33 analogue was almost equipotent to the parent analogue in all bioassays, suggesting that this modification might be useful for introducing enzymatic stability in CCK analogues. 相似文献
4.
Ines Torrini Gaia Mastropietro Giampiero Pagani Zecchini Mario Paglialunga Paradisi Gino Lucente Susanna Spisani 《Archiv der Pharmazie》1998,331(5):170-176
In the context of a research program aimed at elucidating the HCO-Met-Leu-Phe-OMe (fMLF-OMe) structural features which control interactions with the receptor in correspondence with the C-terminal residue, four different analogues of the native ligand have been synthesized and evaluated. Compounds 1-3 possess the general formula HCO-Met-Leu-Xaa-OMe with Xaa = N-benzylglycine, N-benzylphenylalanine, and α,α-dibenzylglycine, respectively. In the analogue 4 the constraint at the C-terminus has been obtained by incorporating a 2-oxopiperazine ring, made up of two phenylalanine residues, to replace the native C-terminal Phe residue. The consequences of the chemical modifications on the activity of the new analogues are discussed. 相似文献
5.
GEORGE STAVROPOULOS KOSTAS KARAGIANNIS STAVROS ANAGNOSTIDES ITZHAK MINISTROUSKI ZVI SELINGER MICHAEL CHOREV 《Chemical biology & drug design》1995,45(6):508-513
The analogues [Glp6,Glu(OBzl)11]SP(6-11) and [Glp5,Glu(OBzl)11]SP(5-11)) of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the N-terminal glutamine has been replaced by pyroglutamic acid, while the COOCH2C6H5 ester group has replaced the SCH3 group of the Met11 side chain. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD) and rat portal vein (RPV). The results showed that both analogues are highly potent and selective agonists on GPI through the NK-1 receptor. They are more potent than SP itself, with 1.54 and 1.25 respective values of relative potency on GPI. Their selectivity has been studied by utilizing atropine-treated guinea pig ileum (GPI + At). The analogues showed low activity on RVD and RPV tissues, which represent NK-2 and NK-3 monoreceptor assay, respectively. © Munksgaard 1995. 相似文献
6.
Synthesis,Antifolate and Anticancer Activities of N5‐Substituted 8,10‐Dideazatetrahydrofolate Analogues
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Chao Tian Zhili Zhang Shouxin Zhou Mengmeng Yuan Xiaowei Wang Junyi Liu 《Chemical biology & drug design》2016,87(3):444-454
Based on our previous work, seven N5‐substituted 8,10‐dideazatetrahydrofolate analogues and one 8‐deazatetrahydrofolate analogue were designed and synthesized as human dihydrofolate reductase (hDHFR) inhibitors. All compounds were assayed versus DHFR and five different cancer cell lines. The biological assay indicated that replacing N10 with carbon would significantly increase inhibitory activities against DHFR and cytotoxicities against cancer cell lines. Compound 19a with 4‐amino and N5‐formyl showed great antitumour activities against HL‐60, Bel‐7402 and BGC823 which were much better than MTX. 相似文献
7.
Marie-Therese Plancot Andre Delacourte Kia-Ki Han Michel Dautrevaux Gerard Biserte 《Chemical biology & drug design》1977,10(2):113-119
Highly purified human alpha-1-antitrypsin (phenotype MM) was obtained by an original method of preparative electrophoresis. The criteria of homogeneity were assured by one arc in crossed immunoelectrophoresis and one band on polyacrylamide gel. A unique N-terminal amino acid (pyroglutamic acid) and a unique C-terminal residue (lysine) were identified. Determined by gel electrophoresis, its molecular weight was 47,000 daltons. 相似文献
8.
MAURO MARASTONI SEVERO SALVADORI GIANFRANCO BALBONI SUSANNA SPISANI RICCARDO GAVIOLI SERENA TRANIELLO ROBERTO TOMATIS 《Chemical biology & drug design》1990,35(2):81-88
Acquired immunodeficiency syndrome (AIDS) is initiated by the attachment of the human immunodeficiency virus (HIV) to a surface glycoprotein CD4 present on T4 helper/inducer lymphocytes, monocytes/macrophages and other cells. A simple octapeptide (H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH, peptide T) seems to inhibit HIV infectivity and to activate human monocyte chemotaxis. In order to study in vitro metabolic stability and structure-activity relationships, peptide T and a number of analogues were prepared and tested on human monocytes by chemotactic assay. Peptide T and the shorter fragments T(3-8)-OH and T(4–8)-OH displayed potent bioactivity (maximal chemotactic activity in the range 10-11-10-10M). The C-terminal heptapeptide showed a reduction of potency, while further truncations at N-terminus of T(4–8)-OH abolished the biological action. In the octapeptide series, whereas the α-amino butyric acid (Abu) substitution for Thr4 was well tolerated, the same “slight” structural change at Thr5 or Thr8 was very detrimental. Finally, [d -Asn6]T(1-8)-OH analogue has low chemotactic activity. All these results indicate that i) the C-terminal pentapeptide is the minimum sequence required for bioactivity, ii) residues 5 to 8 appear to play a crucial biological role, iii) peptide T chemotaxis is mediated, at least in part, through the polar properties of Thr side chains at the critical positions 5 and 8, while the Thr4 does not interfere with biological characteristics of peptides. With regard to the enzymic degradation, the in vitro experiments showed the susceptibility of peptide T to rapid metabolism by human or rat plasma (T1/2 = 5.2 min), rat brain (T1/2 = 2.1 min) and kidney (T1/2 = 0.4 min) enzymes. The main metabolic product appears to be the C-terminal heptapeptide, which retains, in turn, a low enzymatic stability. 相似文献
9.
Roland Bindewald Arnulf Hubbuch Waleed Danho Erika E. Büllesbach Josef Fhles Helmut Zahn 《Chemical biology & drug design》1984,23(4):368-375
The preparation of the 4-sulfobenzyl esters of 18 amino acid derivatives is described. This carboxyl protecting group was introduced according to Hubbuch et al. (1980). The caesium or dicyclohexylammonium salts of N-terminal protected amino acids were reacted with 4-(bromomethyl)benzenesulfonate (1). After N-terminal deblocking, the amino acid-4-sulfobenzyl esters were isolated as zwitterions. The protecting group was removable by catalytic hydrogenation and by saponification. The 4-sulfobenzyl esters could be easily converted to amides and hydrazides. They were stable to 2 M hydrogen bromide in acetic acid as well as to a 10-fold excess of trifluoromethane sulfonic acid in trifluoro-acetic acid. The behaviours of +H2-Gly-Phe-Leu-OBzl-SO-3 and the corresponding methyl, benzyl and 4-nitrobenzyl esters were compared under various conditions. 相似文献
10.
11.
CLAUDINE AMAR ERNA VLKAS STEPHANE LAURENT BRUNO GAUTRAY HENRI SCHMITT 《Chemical biology & drug design》1983,22(4):434-436
A new analogue of the leucine-enkephalin in which the N -terminal tyrosine has been replaced by trans -4-hydroxycinnamic acid, has been synthetized by liquid-phase coupling methods. The central cardiovascular effects of this analogue were investigated and the results discussed. 相似文献
12.
MOHAMED EL HAJJI SYLVIE REBUFFAT DIDIER LECOMMANDEUR BERNARD BODO 《Chemical biology & drug design》1987,29(2):207-215
Trichorzianines A, membrane active peptides of the peptaibol class, were isolated from cultures of the mould Trichoderma harzianum. Trichorzianines A were separated into pure components by HPLC on octadecyl bonded and SiO2 phases successively. Nine trichorzianines A (IIa, IIIa, IIIb, IIIc, IVb, Vb, VIa, VIb and VII) were isolated from the complex microheterogeneous mixture. Their N-terminal amino acid is acetylated, the C-terminal amino alcohol is either tryptophanol or phenylalaninol, 7 to 8 of the 19 residues are α-aminoisobutyric acid. Gas chromatography on a chiral phase showed isovaline to have the d -configuration and all the other optically active amino acids and amino alcohols to have the l -configuration. The amino acid sequences were determined from their positive ion FAB mass spectra which exhibited the preferential cleavage of the Aib 12-Pro 13 amide bond as a main fragmentation. The resulting fragments subsequently underwent amide bond ruptures that generated two series of abundant acylium ions which enabled direct determination of the 1–19 sequence. The relative position of the isomeric amino acids in the sequence of trichorzianine AVII was assigned from analysis of the N- and C-terminal oligopeptides yielded by its selective acidic hydrolysis. The microheterogeneity of trichorzianines A results mainly from single or multiple substitution of amino acids at the specific positions 5, 14, 16 and 19. 相似文献
13.
The acid-base chemistry of six angiotensin II analogues (A 11) was analyzed by determining two types of terms. Macroconstants were used to characterize the molecular proton-binding and dissociating ability of the octapeptides, and group constants to quantitate the submolecular basicity of each individual protona-tion site of the derivatives. The group constant values indicated that some sites (Arg-guanidino, Tyrphenolate, C-terminal carboxylate) were of similar basicity in the different analogues, while others (Hisimidazole, N-terminal amino) were significantly different. The group constant values are interpreted by taking into consideration the intramolecular effects of the adjoining moieties and are used for microspeciation. 相似文献
14.
S. LAVIELLE G. CHASSAING J.C. BEAUJOUAN Y. TORRENS A. MARQUET 《Chemical biology & drug design》1984,24(5):480-487
The synthesis of four biotinylated analogues of Substance P is described. The affinities of these analogues and of their complexes with avidin for the 125I-Bolton Hunter Substance P binding sites on rat brain synaptosomes were determined. While these biotinylated peptides complexed to avidin retain a good biological activity on the guinea-pig ileum bioassay, we observe a net decrease in their binding affinities in the central nervous system. The present study confirms that in the central nervous system the higher affinity is related to the N-terminal tetrapeptide and establishes that the free amino group (N-α-Arg and N-α-Lys) are not essential in the binding. 相似文献
15.
The N-terminal peptide of salmon proopiocortin has been isolated and the primary structure including two disulfide bonds elucidated. The peptide consisted of 76 amino acid residues, which is 27 residues shorter than the bovine and human peptides. The N-terminal 44 residues of the teleost peptide exhibited significant sequence homology to those of the mammalian peptides. The salmon peptide, however, is lacking in the counterpart of gamma-MSH which is located between residues 51 and 64 in the mammalian peptides. 相似文献
16.
NANCY KNEIB-CORDONIER FERNANDO ALBERICIO GEORGE BARANY 《Chemical biology & drug design》1990,35(6):527-538
An approach to the solid-phase segment condensation synthesis of the 17-peptide amide human gastrin-I has been developed. Nα-amino and side-chain protection were provided by 9-fluorenylmethyloxycarbonyl (Fmoc) and tert.-butyl groups, and a series of anchors cleavable under mild conditions were used. The N-terminal pentapeptide pGlu-Gly-Pro-Trp-Leu-OH was prepared using a p-alkoxybenzyl ester linkage made by a preformed handle strategy. Cleavage, in 65% yield, was with the new Reagent M: CF3 COOH—CH2 Cl2—β-mercaptoethanol-anisole (70:30:2:1), which was optimized to preserve the labile tryptophan residue. A new preformed handle procedure expedited solid-phase synthesis of the protected “middle” hexapeptide, Fmoc-(Glu(OtBu))5-Ala-OH, anchored as an o-nitrobenzyl ester. Chains were not lost during this assembly, and final photolytic cleavage (350nm) in toluene—CF3 CH2 OH (4:1) occurred in 59% yield. Both protected intermediates were purified by simple gel filtration, whereupon they were shown to be pure by analytical HPLC, and gave satisfactory NMR and FABMS spectra. Last, the C-terminal hexapeptide, Tyr(tBu)-Gly-Trp-Met-Asp(OtBu)-Phe, was assembled on a tris(alkoxy)benzylamide “PAL” support. For the polymer-supported segment condensation, the middle and N-terminal pieces were added respectively in > 98% and 89% yields (judged by amino acid analysis and solid-phase sequencing), by overnight couplings in N,N-dimethylformamide (DMF) mediated by benzotriazolyl N-oxytrisdimethylaminophosphonium hexafluorophosphate (BOP) in the presence of 1-hydroxybenzotriazole (HOBt) and N-methylmorpholine (NMM). Racemization was 4% and 11% respectively at Ala and Leu. Cleavage with Reagent M followed by reversed-phase chromatography gave pure gastrin-I in an overall 30% isolated yield. These results compare favorably with those from a stepwise assembly. 相似文献
17.
SESHA NATARAJAN DOUGLAS RIEXINGER MARIANNE PELUSO STEVEN M. SEILER 《Chemical biology & drug design》1995,45(2):145-151
Proteolytic action of α-thrombin on human thrombin receptor results in cleavage of a portion of the N-terminus, thereby generating a‘tethered ligand’at the newly exposed N-terminus, which then activates the receptor in an intramolecular fashion. Agonist peptides incorporating the amino acid sequence of the newly exposed N-terminal portion of the cleaved receptor cause receptor activation without requiring prior cleavage of the receptor by thrombin. The pentapeptide amide Ser-Phe-Leu-Leu-Arg-NH2, which retains the N-terminal sequence of the‘tethered ligand’of the receptor, has been shown to be the minimum sequence to cause receptor activation. To understand the importance of the side chains of various residues within the pentapeptide amide, we carried out an extensive structure-activity study of the ability of peptides to stimulate gel-filtered platelet aggregation. In this study 106 pentapeptide amides were synthesized, utilizing naturally occurring l -amino acids, unnatural amino acids, D-amino acids and N-methyl amino acids for replacements. At position-1, charged residues (acidic or basic) were not tolerated, and the size and shape of the residue were important. Position-2 tolerated only aromatic residues. Position-3 accommodated various residues. A significant finding of this study was that two very different residues, [3-(2-naphthyl)]-l -alanine and l -arginine, when substituted for leucine residue at position-3, resulted in more active agonists. At position-4 aromatic and aliphatic residues were well tolerated, whereas basic and acidic residues were less tolerated. Position-5 mimicked position-3 in its ability to tolerate a wide range of residues. In general, an acidic residue was not preferred in any position. In all positions a -Phe-residue was tolerated. Positions 1 and 3 tolerated -Pro-residue, whereas positions 2, 4 and 5 did not. d -Amino acid substitution was not tolerated in any position. While N-methylation of residues at positions-3 and -4 led to poor agonists, at position-2 it resulted in an inactive analog. These studies define the side chain requirements for the‘tethered ligand’derived pentapeptide agonists of thrombin receptor for human platelet activation. Selected peptides were tested for ability to stimulate platelet membrane GTPase. A good correlation was observed between peptides that stimulate GTPase and those that stimulate platelet aggregation, with the general finding that 3-10-fold higher concentrations were required to half maximally activate GTPase when compared with the concentrations needed for activation of platelet aggregation. © Munksgaard 1995. 相似文献
18.
LSZL
NDASDI DONALD YAMASHIRO CHOH HAO LI JAN IZDEBSKI 《Chemical biology & drug design》1983,21(4):364-368
Five analogs of equine β-melanotropin have been synthesized by the solid phase method. The NH2-terminal aspartic acid was substituted with amino acids (Gly, Trp, Ile, Lys and Nα-acetyl-Asp) differing widely in physicochemical properties. On the basis of their lipolytic potencies it was concluded that this position plays a negligible role in this activity. 相似文献
19.
MARC RODRIGUEZ MARC ROLLAND MARIE-FRANCOISE LIGNON MARIE-CHRISTINE GALAS JEANINE LAUR ANDRE AUMELAS JEAN MARTINEZ 《Chemical biology & drug design》1989,34(5):394-404
Syntheses of analogues of the C-terminal heptapeptide of cholecystokinin are described. These analogues were obtained by replacing glycine 29 by a β-alanine. The C-terminal phenylalanine amide was in some cases substituted by 2-phenylethyl alcohol and/or residues of the C-terminal tetrapeptide by their d -enantiomers. These compounds were tested for their action on stimulation of amylase release from rat pancreatic acini and for their ability to inhibit binding of labeled CCK to rat pancreatic acini and guinea pig brain membranes. Some of these derivatives behaved as CCK receptor antagonists. 相似文献
20.
JANICE R. BAILIE BRIAN WALKER JOHN NELSON RICHARD F. MURPHY 《Chemical biology & drug design》1994,43(3):225-229
We report the synthesis of a cyclic analogue of epidermal growth factor sequence 33–42 with substitution of 1-aminocyclopropane-1-carboxylic acid for glycine at position 39 (N-acetyl-Cys-Val-Ile-Gly-Tyr-Ser-ACPCA-Asp-Arg-Cys-NH2). The analogue was synthesised by solid-phase methods, using t-Boc chemistry and acid-labile side-chain protecting groups. The use of the 4-methoxybenzyl protecting group for C- and N-terminal cysteine residues resulted in the spontaneous formation of the desired intramolecular disulfide bond after HF deprotection. 相似文献