Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “dipeptides”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,009 records · Page 56Linked to original sources
PubMed2004

AT2-selective angiotensin II analogues containing tyrosine-functionalized 5,5-bicyclic thiazabicycloalkane dipeptide mimetics.

This paper reports the synthesis of two angiotensin II analogues with tyrosine-functionalized 5,5-bicyclic thiazabicycloalkane dipeptide mimetics replacing the Tyr(4)-Ile(5) residues. The preparation of these analogues relies on the synthesis and incorporation of an alpha,alpha-disubstituted chimeric amino acid derivative and on-resin bicyclization to a cysteine residue. The synthesized analogues both displayed high angiotensin AT(2)/AT(1) receptor binding preferences and had AT(2) receptor affinities in the same low nanomolar range as angiotensin II itself. Conformational analysis, using experimental constraints derived from NMR studies, indicated that the Tyr(4) and His(6) residues in one of the angiotensin II analogues were in close proximity to each other.

Angiotensin II↗
PubMed2005

Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist.

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

Administration, Oral↗
PubMed2005

Interaction of papain-like cysteine proteases with dipeptide-derived nitriles.

A series of 44 dipeptide nitriles with various amino acids at the P2 position and glycine nitrile at position P1 were prepared and evaluated as inhibitors of cysteine proteinases. With respect to the important contribution of the P2-S2 interaction to the formation of enzyme-inhibitor complexes, it was focused to introduce structural diversity into the P2 side chain. Nonproteinogenic amino acids were introduced, and systematic fluorine, bromine, and phenyl scans for phenylalanine in the P2 position were performed. Moreover, the N-terminal protection was varied. Kinetic investigations were carried out with cathepsin L, S, and K as well as papain. Changes in the backbone structure of the parent N-(tert-butoxycarbonyl)-phenylalanyl-glycine-nitrile (16), such as the introduction of an R-configured amino acid or an azaamino acid into P2 as well as methylation of the P1 nitrogen, resulted in a drastic loss of affinity. Exemplarily, the cyano group of 16 was replaced by an aldehyde or methyl ketone function. Structure-activity relationships were discussed with respect to the substrate specificity of the target enzymes.

Cathepsin K↗
PubMed2006

Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach.

The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-Nal dipeptide analogue strategy, we first synthesized and evaluated a test set of cis-(2R,4R)-proline analogues (21a-g). All of these compounds showed significant binding and agonist potency at the hMC1R, hMC3R, and hMC4R. Potent cis-(2S,4R)-pyrrolidine based MCR agonists (35a-g) were subsequently developed by means of this design approach. A SAR study directed toward probing the effect of the two chiral centers in the pyrrolidine ring on biological activity revealed the importance of the (S) absolute configuration at the 2-position for binding affinity, agonist potency, and receptor selectivity. Among the four sets of the pyrrolidine diastereomers investigated, analogues with the (2S,4R) configuration were the most potent agonists across the three receptors, followed by those possessing the (2S,4S) configuration.

Binding, Competitive↗
PubMed1997

Design and synthesis of novel imidazole-substituted dipeptide amides as potent and selective inhibitors of Candida albicans myristoylCoA:protein N-myristoyltransferase and identification of related tripeptide inhibitors with mechanism-based antifungal activity.

A new class of antifungal agents has been discovered which exert their activity by blockade of myristoylCoA: protein N-myristoyltransferase (NMT; EC 2.1.3.97). Genetic experiments have established that NMT is needed to maintain the viability of Candida albicans and Cryptococcus neoformans,the two principal causes of systemic fungal infections in immunocompromised humans. Beginning with a weak octapeptide inhibitor ALYASKLS-NH2 (2, Ki = 15.3 +/- 6.4 microM), a series of imidazole-substituted Ser-Lys dipeptide amides have been designed and synthesized as potent and selective inhibitors of Candida albicans NMT. The strategy that led to these inhibitors evolved from the identification of those functional groups in the high-affinity octapeptide substrate GLYASKLS-NH2 1a necessary for tight binding, truncation of the C-terminus, replacement of the four amino acids at the N-terminus by a spacer group, and substitution of the glycine amino group with an N-linked 2-methylimidazole moiety. Initial structure-activity studies led to the identification of 31 as a potent and selective peptidomimetic inhibitor with an IC50 of 56 nM and 250-fold selectivity versus human NMT. 2-Methylimidazole as the N-terminal amine replacement in combination with a 4-substituted phenacetyl moiety imparts remarkable potency and selectivity to this novel class of inhibitors. The (S,S) stereochemistry of serine and lysine residues is critical for the inhibitory activity, since the (R,R) enantiomer 40 is 10(3)-fold less active than the (S,S) isomer 31. The inhibitory profile exhibited by this new class of NMT ligands is a function of the pKa of the imidazole substituent as illustrated by the benzimidazole analog 35 which is about 10-fold less potent than 31. The measured pKa (7.1 +/- 0.5) of 2-methylimidazole in 31 is comparable with the estimated pKa (approximately 8.0) of the glycyl residue in the high-affinity substrate 1a. Groups bulkier than methyl, such as ethyl, isopropyl, or iodo, at the imidazole 2-position have a detrimental effect on potency. Further refinement of 31 by grafting an alpha-methyl group at the benzylic position adjacent to the serine residue led to 61 with an IC50 of 40 nM. Subsequent chiral chromatography of 61 culminated in the discovery of the most potent Candida NMT inhibitor 61a reported to date with an IC50 of 20 nM and 400-fold selectivity versus the human enzyme. Both 31 and 61a are competitive inhibitors of Candida NMT with respect to the octapeptide substrate GNAASARR-NH2 with Ki(app) = 30 and 27 nM, respectively. The potency and selectivity displayed by these inhibitors are dependent upon the size and orientation of the alpha-substituent. An alpha-methyl group with the R configuration corresponding to the (S)-methyl-4-alanine in 2 confers maximum potency and selectivity. Structural modification of 31 and 61 by appending an (S)-carboxyl group beta to the cyclohexyl moiety provided the less potent tripeptide inhibitors 73a and 73b with an IC50 of 1.45 +/- 0.08 and 0.38 +/- 0.03 microM, respectively. However, these tripeptides (73a and 73b) exhibited a pronounced selectivity of 560- and 2200-fold versus the human NMT. More importantly 73a displayed fungistatic activity against C albicans with an EC50 of 51 +/- 17 microM in cell culture. Compound 73b also exhibited a similar antifungal activity. An Arf protein gel mobility shift assay for monitoring intracellular myristoylation revealed that a single dose of 200 microM of 73a or 73b produced < 50% reduction in Arf N-myristoylation, after 24 and 48 h, consistent with their fungistatic rather than fungicidal activity. In contrast, the enantiomer 73d which had an IC50 > 1000 microM against C. albicans NMT did not exhibit antifungal activity and produced no detectable reduction in Arf N-myristoylation in cultures of C. albicans. These studies confirm that the observed antifungal activity of 73a and 73b is due to the attenuation of NMT activity and that NMT represents an attractive tar

Acyltransferases↗
PubMed1998

Synthesis and activity of dipeptides, linked to targeting ligands, as specific NK cell enhancers.

Water soluble analogues of the lipophilic immunostimulant, octadecyl D-alanyl-L-glutamine, BCH-527, were synthesized and evaluated for the ability to stimulate natural killer (NK) cells. One of these compounds in which the octadecyl chain of BCH-527 was replaced with a shorter chain alcohol, 6-(D-alanyl-L-glutaminylamino)hexan-1-ol, 9, displayed an in vitro stimulation of NK cells comparable to that of interleukin 2 (IL 2). However, when the hydroxyl of 9 was linked to L-fucose to yield 1-beta-[6-(D-alanyl-L-glutaminylamino)hex-1-yl]-L- fucopyranose (BCH-2537, 1), the observed stimulation of NK cells was greater than that observed with IL 2. Further evaluation of these compounds revealed that the improved in vitro activity of BCH-2537 was more pronounced in vivo. That is, while both compounds significantly increased splenic NK cells, only BCH-2537 significantly increased the activity of these cells in vivo. In terms of a structure-activity relationship, NK cell activity was sensitive to minor structural modifications. It was influenced by conservative substitutions within the dipeptide, the length of the hydrocarbon chain, and the functionality at the end of the chain. No other compound enhanced NK cell activity to the extent exhibited by BCH-2537, although a few were equipotent to 9.

Adjuvants, Immunologic↗
PubMed1998

Studies on selectin blockers. 7. Structure-activity relationships of sialyl Lewis X mimetics based on modified Ser-Glu dipeptides.

We have previously found that heterochiral fucodipeptides, L-Ser-D-Glu (3a) and D-Ser-L-Glu (3b), exhibited up to 20-100 times more potency than a sialyl Lewis X (sLeX, 1) and a 3'-sulfated Lewis X analogue (2) toward E-selectin binding and have also proposed, from molecular dynamics calculation, that their strong activities would depend on a possible formation of the type II and/or type II' beta-turn of compounds 3a,b (Tsukida, T.; Hiramatsu, Y.; Tsujishita, H.; Kiyoi, T.; Yoshida, M.; Kurokawa, K.; Moriyama, H.; Ohmoto, H.; Wada, Y.; Saito, T.; Kondo, H. J. Med. Chem. 1997, 40, 3534-3541). To clarify our hypothesis, we synthesized several analogues of compounds 3a,b and investigated their structure-activity relationships. As a result, it was indicated that the type II and/or type II' beta-turn conformation would be a comparatively tight form and would play important roles in favorable binding to E-selectin. These findings indicate that sLeX mimetics with type II and type II' beta-turn dipeptides could be a useful methodology for the design of an active selectin blocker.

Dipeptides↗
PubMed2002

Synthesis of an optically active, bicyclic 2-pyridone dipeptide mimetic.

The eleven-step preparation of the bicyclic 2-pyridone dipeptide mimetic 1 [(3S)-6-(benzyloxycarbonylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid] in optically active form (60% ee) is described. Key steps in the synthesis of 1 include the osmium-catalyzed asymmetric dihydroxylation of olefin 13 [(6-but-3-enyl-2-methoxypyridin-3-yl)carbamic acid benzyl ester] and the intramolecular cyclization of protected diol 19 [(3'R)-[6-[4'-(tert-butyldimethylsilanyloxy)-3'-hydroxybutyl]-2-methoxypyridin-3-yl]carbamic acid benzyl ester] to afford the pyridinium salt 20 [(3S)-[3-(tert-butyldimethylsilanyloxymethyl)-5-methoxy-2,3-dihydro-1H-indolizin-6-yl]carbamic acid benzyl ester trifuoromethanesulfonic acid salt]. Several alternate methods to prepare olefin 13 are also discussed.

Dipeptides↗
PubMed2002

Incorporation of Ahc into model dipeptides as an inducer of a beta-turn with a distorted amide bond. Conformational analysis.

The proline residue of dipeptides Ser-Pro and Pro-Ser has been replaced by 7-azabicyclo[2.2.1]heptane-1-carboxylic acid (Ahc), a conformationally restricted analogue of proline that is capable of mimicking distorted amides. The conformational analysis of the new peptides in the solid state revealed that the Ahc-Ser sequence displays a type I beta-turn, which includes a distorted amide bond. In contrast, the Ser-Ahc sequence exists in a nonfolded structure.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2002

Sheet structure of an L,D-dipeptide aggregate: inclusion compounds of (S)-phenylglycyl-(R)-phenylglycine with amides.

A simple dipeptide, (S)-phenylglycyl-(R)-phenylglycine (S,R-1), formed inclusion compounds with a small amide such as formamide, acetamide, N,N-dimethylformamide (DMF), or N,N-dimethylacetamide. By single-crystal X-ray analysis, the inclusion compounds were shown to have a wavy layer structure. The molecules of S,R-1 are arranged in parallel via ionic pairing of the carboxyl and amino groups to construct the wavy layers. The guest molecules were accommodated in a channel cavity between the layers by means of hydrogen bonding with (+)NH(3) of S,R-1. The cavity is surrounded by the phenyl groups of S,R-1 that conformationally rotate so as to make the cavity size fit the guest amide.

Amides↗
PubMed2002

Synthesis of the pro-gly dipeptide alkene isostere using olefin cross-metathesis.

An approach to the synthesis of dipeptide olefin isosteres using intermolecular olefin cross-metathesis is presented. In particular, a synthesis of the Pro-Gly isostere (1) is reported. Conversion of N-BOC-proline into the corresponding vinyl-substituted carbamate provides the N-terminal cross-metathesis partner (2). Methyl 3-butenoate (3) is employed as the C-terminal component. Treatment of the two partners in an optimized molar ratio affords the cross product 1 (83% yield). Three other examples are demonstrated to evaluate the potential of the approach.

Alkenes↗
PubMed2003

"One-pot" methylation of N-Nosyl-alpha-amino acid methyl esters with diazomethane and their coupling to prepare N-methyl dipeptides.

N-Nosyl-alpha-amino acid methyl esters are methylated quantitatively with diazomethane. After proper deprotection of the amino function by treatment with the reagent system mercaptoacetic acid/sodium methoxide, the obtained N-methyl amino acid methyl esters are coupled with N-Fmoc amino acid chlorides to afford the corresponding dipeptides. The obtained products do not show any detectable extent of racemization by (1)H NMR and HPLC.

Amino Acids↗
PubMed2004

Conformationally constrained dipeptide surrogates with aromatic side-chains: synthesis of 4-aryl indolizidin-9-one amino acids by conjugate addition to a common alpha,omega-diaminoazelate enone intermediate.

Four methyl 9-oxo-8-(N-(Boc)-amino)-4-phenyl-1-azabicyclo[4.3.0]nonane carboxylates (11, 4-Ph-I(9)aa-OMe) were synthesized from (2S,8S,5E)-di-tert-butyl-4-oxo-5-ene-2,8-bis[N-(PhF)amino]azelate [(5E)-7, PhF = 9-(9-phenylfluorenyl)] via a seven-step process featuring a conjugate addition/reductive amination/lactam cyclization sequence. Various nucleophiles were used in the conjugate addition reactions on enone (5E)-7 as a general route for making alpha,omega-diaminoazelates possessing different substituents in good yield albeit low diastereoselectivity except in the case of aryl Grignard reagents (9/1 to 15/1 drs). 6-Phenylazelates (6S)-8d and (6R)-8d were separated by chromatography and diastereoselective precipitation and independently transformed into 4-Ph-I(9)aa-OMe. From (6S)-8d, (2S,4R,6R,8S)-4-Ph-I(9)aa-OMe 11 was prepared selectively in 51% yield. Reductive amination of (6R)-8d provided the desired pipecolates 9 along with desamino compound 10, which was minimized by performing the hydrogenation in the presence of ammonium acetate. Subsequent ester exchange, lactam cyclization, and amine protection provided three products (2R,4S,6S,8R)-, (2R,4S,6S,8S)-, and (2S,4S,6R,8S)-4-Ph-I(9)aa-OMe 11 in 10, 6, and 6% yields, respectively, from (6R)-8d. Ester hydrolysis of (2S,4R,6R,8S)-11 furnished 4-phenyl indolizidin-9-one N-(Boc)amino acid 3 as a novel constrained Ala-Phe dipeptide surrogate for studying conformation-activity relationships of biologically active peptides.

Amination↗
PubMed2004

Synthesis and conformational studies of dipeptides constrained by disubstituted 3-(aminoethoxy)propionic acid linkers.

A series of cyclic compounds with dimethyl-substituted 3-(aminoethoxy)propionic acid linkers have been prepared as potential beta-turn mimics. The desired linkers were prepared from disubstituted pyrones, which were coupled with dipeptides and then subjected to macrocyclization using diethylcyanophosphonate to furnish cyclic compounds 1-5. Conformational analysis was carried out using NMR and X-ray crystallography. All of the five cyclic compounds were found to exist in type I or type II beta-turn conformations.

Cross-Linking Reagents↗
PubMed2005

Silanediol inhibitors of angiotensin-converting enzyme. Synthesis and evaluation of four diastereomers of Phe[Si]Ala dipeptide analogues.

Four stereoisomers of a Phe-Ala silanediol dipeptide mimic have been evaluated as inhibitors of angiotensin-converting enzyme (ACE) and compared to ketone-based inhibitors reported by Almquist et al. One stereogenic center of the isomers was derived from the individual enantiomers of methyl 3-hydroxy-2-methylpropionate, with separation of diastereomers after introduction of the second stereogenic center. The diastereomeric identities were established by X-ray crystallography of an intermediate. Inhibition of ACE by three of the silanediol diastereomers (IC(50) = 3.8-207 nM) closely paralleled that of the corresponding diastereomeric ketones (IC(50) = 1.0-46 nM). The fourth diastereomer, corresponding to the least inhibitory ketone (IC(50) = 3200 nM), exhibited an unexpected level of inhibition in the silanediol (IC(50) = 72 nM), suggesting an alternative mode of binding to the enzyme.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

A positional scanning approach to the discovery of dipeptide-based catalysts for the enantioselective addition of vinylzinc reagents to aldehydes.

[reaction: see text] A combinatorial library of dipeptide N-acylethylenediamine-based ligands was synthesized by parallel solid-phase methods. These ligands were screened in crude form as catalysts for the asymmetric addition of vinylzinc reagents to aldehydes to give chiral allylic alcohols. Three sites of diversity on the ligands were optimized using a positional scanning approach. The optimized structure from the library, ligand 54, was found to catalyze the formation of 10 different (E)-allylic alcohols with enantioselectivities ranging from 90% to 95% ee. This ligand was effective for both aromatic and alpha-branched aldehydes, and vinylzinc reagents derived from both bulky and straight chain terminal alkynes.

Aldehydes↗