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At least 919 records · Page 51Linked to original sources
PubMed2004

Water-soluble prodrugs of dipeptide HIV protease inhibitors based on O-->N intramolecular acyl migration: Design, synthesis and kinetic study.

To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-727, a potent small-sized dipeptide-type HIV-1 protease inhibitor consisting of an Apns-Dmt core (Apns; allophenylnorstatine, Dmt; (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid) as inhibitory machinery. These prodrugs contained an O-acyl peptidomimetic structure with an ionized amino group leading to an increase in water-solubility, and were designed to regenerate the corresponding parent drugs based on the O-->N intramolecular acyl migration reaction via a five-membered ring intermediate at the alpha-hydroxy-beta-amino acid residue, that is Apns. The synthetic prodrug 3a improved the water-solubility (13 mg/mL) more than 8000-fold in comparison with the parent compound, which is the practically acceptable value as water-soluble drug. Furthermore, to understand the structural effects of the O-acyl moiety on the migration rate, we evaluated several phenylacetyl-type and benzoyl-type prodrugs. These prodrugs were stable as an HCl salt and in a strongly acidic solution corresponding to gastric juice (pH 2.0), and could be converted to the parent compounds promptly under aqueous conditions from slightly acidic to basic pH at 37 degrees C.

Acylation↗
PubMed2004

L-Homoserylaminoethanol, a novel dipeptide alcohol inhibitor of eukaryotic DNA polymerase from a plant cultured cells, Nicotina tabacum L.

We found a novel inhibitor specific to eukaryotic DNA polymerase epsilon(pol epsilon) from plant cultured cells, Nicotina tabacum L. The compound (compound 1) was a dipeptide alcohol, L-homoserylaminoethanol. The 50% inhibition of pol epsilon activity by the compound was 43.6 microg/mL, and it had almost no effect on the activities of the other eukaryotic DNA polymerases such as alpha, beta, gamma and delta, prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human telomerase, human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase, human DNA topoisomerase I and II, T4 polynucleotide kinase and bovine deoxyribonuclease I. Kinetic studies showed that inhibition of pol epsilon by the compound was non-competitive with respect to both template-primer DNA and nucleotide substrate. We succeeded in chemically synthesizing the stereoisomers, L-homoserylaminoethanol and D-homoserylaminoethanol, and found both were effective to the same extent. The IC(50) values of L- and D-homoserylaminoethanols for pol epsilon were 42.0 and 41.5 microg/mL, respectively. This represents the second discovery of a pol epsilon-specific inhibitor, and the first report on a water-soluble peptide-like compound as the inhibitor, which is required in biochemical studies of pol epsilon.

Cells, Cultured↗
PubMed2004

Stochastic-based descriptors studying peptides biological properties: modeling the bitter tasting threshold of dipeptides.

MARCH-INSIDE methodology was applied to the prediction of the bitter tasting threshold of 48 dipeptides by means of pattern recognition techniques, in this case linear discriminant analysis (LDA), and regression methods. The LDA models yielded a percentage of good classification higher than 80% with the two main families of descriptor generated by this methodology (95.8% for self return probability and 83.3% using electronic delocalization entropy). The regression models can explain more than 80% of the experimental variance of the independent variable. Two regression models were obtained with R(2) values of 0.82 and 0.88 for the whole data and the data without two outliers, respectively; having a standard deviation of 0.27 and 0.23. The predictive power of the obtained equations was assessed by the Leave-One-Out cross validation procedures, giving the same percentages of good classification as in the training set, in the LDA models, and yielding values of q(2) of 0.78 and 0.86 in the regression model, respectively. The validation of this methodology was also carried out by comparison with previous reports modeling this data with other well-known methodologies, even 3-D molecular descriptors.

Dipeptides↗
PubMed2005

The study on the interaction between seryl-histidine dipeptide and proteins by circular dichroism and molecular modeling.

The selective cleavage of proteins is very important in key biological processes. Chemical (nonenzymatic) reagents such as cyanogen bromide and transition metal complexes are used extensively with great defects. In this paper, the binding of seryl-histidine dipeptide (abbreviated as SH) with bovine serum albumin (BSA) and lysozyme were investigated by the circular dichroism spectroscopy (CD) at 298K, molecular docking studies and quantum chemical calculations based on the previous results of polyacrylamide gel electrophoresis (PAGE). From the studies of CD, it showed that SH interacted strongly with BSA and lysozyme. The change percentages of the secondary structures of BSA and lysozyme were calculated. The contents of the beta-sheets decreased remarkably. It indicated that the interactions between SH and proteins could break the hydrogen bonds of beta-sheets selectively. The docking studies between SH and BSA showed that the position of the oxygen atom of the hydroxyl group of SH (O(12)) was in favor of a nucleophilic attack on carbon atom of the amide bond of a beta-sheet (C(34)) because the distance between O(12) and C(34) was 3.37A. Natural charges, natural atomic hybrid percentages and square sums of HOMO coefficients calculated by the NBO and population analysis at HF/6-31G* supported the suggested mechanism. And so SH may be an interesting agent for the therapeutic use.

Animals↗
PubMed2005

Structure activity studies of the serine-AIB dipeptide domain in 2,3-dihydroisothiazole based growth hormone secretagogues.

A series of growth hormone secretagogues (GHSs) based on 2,3-dihydroisothiazole has been synthesized in the search for a potential treatment of growth hormone deficiency or frailty in the elderly. This paper describes the evaluation of the SAR of the benzyl-D-Ser-aminoisobutyric acid dipeptide fragment. Introduction of substituents in the peptide backbone and in the phenyl ring has been investigated, as well as replacements for the benzyl group and for the AIB residue. A number of modifications resulted in enhanced potency over the parent benzyl-D-Ser-AIB derivative.

Aminobutyrates↗
PubMed2005

Dipeptide-based highly potent doxorubicin antibody conjugates.

Highly potent and novel derivatives of doxorubicin were linked to monoclonal antibodies (mAbs) for site-specific drug delivery. Drug linker 5 consisted of a dipeptide linker attached directly to the daunosamine nitrogen of the n-butyldiacetate doxorubicin derivative 2a. Upon hydrolysis of the peptide linker and acetate groups, the free daunosamine nitrogen is able to form the highly potent 2-pyrrolinodoxorubicin (3a). The second approach involved the use of an oxazolidine carbamate (13) to mask an activating aldehyde group until proteolytic hydrolysis releases 3a. Both drug linkers were shown to be substrates for the lysosomal enzyme cathepsin B. Each molecule was conjugated to the mAbs c1F6 (anti-CD70) and cAC10 (anti-CD30) to give potent drug conjugates against renal cell carcinoma and anaplastic large cell lymphoma cell lines, respectively. The activities were immunologically selective, since antigen negative cell lines were much less sensitive to treatment with the drug conjugates. The approaches described here for attaching highly potent doxorubicin derivatives to mAbs are novel and allow for control of drug stability while covalently bound to the delivery agent.

Antigens, Neoplasm↗
PubMed2006

Dipeptide vinyl sultams: synthesis via the Wittig-Horner reaction and activity against papain, falcipain-2 and Plasmodium falciparum.

The synthesis of phosphonate derivatives of N-phenyl- and N-benzyl-gamma- and delta-sultams, and their application in the Wittig-Horner reaction with N-Boc-L-phenylalanine aldehyde to afford E- and Z-isomers, are described. These compounds were further processed to provide five dipeptide vinyl sultams, which were found to be inactive against papain at concentrations up to 50 microM. In contrast, vinyl sultams demonstrated weak activity against recombinant falcipain-2 and Plasmodium falciparum W2.

Animals↗
PubMed2004

The non-polar solvent potential of mean force for the dimerization of alanine dipeptide: the role of solute-solvent van der Waals interactions.

The non-polar component of the potential of mean force of dimerization of alanine dipeptide has been calculated in explicit solvent by free energy perturbation. We observe that the calculated PMF is inconsistent with a non-polar hydration free energy model based solely on the solute surface area. The non-linear behavior of the solute-solvent van der Waals energy is primarily responsible for the non-linear dependence of the potential of mean force with respect to the surface area. The calculated potential of mean force is reproduced by an implicit solvent model based on a solvent continuum model for the solute-solvent van der Waals interaction energy and the surface area for the work of forming the solute cavity.

Algorithms↗
PubMed2005

Cutaneous metabolism of a dipeptide influences the iontophoretic flux of a concomitant uncharged permeant.

Passive and iontophoretic transport of the model dipeptide tyrosine-phenylalanine (TyrPhe) that is subject to cutaneous metabolism and the uncharged glucose derivative benzyl-2-acetamido-2-deoxy-alpha-d-glucopyranoside (BAd-alpha-Glc) used as electroosmosis marker through heat-separated human epidermis was investigated in vitro. TyrPhe and BAd-alpha-Glc were used separately and in combination in order to determine their interaction in terms of permeability and the influence of skin metabolism of TyrPhe on permeation rate and tissue retention of itself and of BAd-alpha-Glc. TyrPhe was chemically and electrochemically stable but underwent considerable degradation in the epidermis under reflection boundary conditions with generation of degradation products tyrosine (Tyr) and phenylalanine (Phe) confirming cutaneous metabolism of TyrPhe in heat-separated human epidermis, which was more pronounced at pH 4.5 than at pH 3.0. As a result, no reproducible epidermis permeation of TyrPhe at pH 3 and no permeation at all at pH 4.5 was measured regardless of the presence of BAd-alpha-Glc, accompanied by increased levels of Tyr and Phe compared to blank runs. Low temperature (4 degrees C) at both pH values and addition of o-phenanthroline at pH 3 but not at pH 4.5 yielded reproducible TyrPhe permeation and blank, i.e., endogenous levels of Tyr and Phe evidencing inhibition of degradation. Constant voltage anodal iontophoresis marginally reduced BAd-alpha-Glc flux at pH 3 and 4.5 compared to the passive flux. In combination with TyrPhe, iontophoretic flux of BAd-alpha-Glc was increased markedly compared to the passive one when TyrPhe was metabolized in the tissue, while no such increase was observed when TyrPhe metabolism was inhibited. The increase of BAd-alpha-Glc iontophoretic flux was accompanied by a considerable decrease of the BAd-alpha-Glc amount retained in the epidermis. The presence of the generated Tyr and Phe, therefore, appears to be related to a decrease of the BAd-alpha-Glc amount retained in the epidermis upon application of an electrical voltage and an enhancement of its iontophoretic flux. Thus, an interaction between the concurrent permeants at the level of tissue retention induced by metabolism can influence the apparent iontophoretic permeation.

Dipeptides↗
PubMed2005

Spontaneous resolution of binary copper(II) complexes with racemic dipeptides: crystal structures of glycyl-L-alpha-amino-n-butyrato copper(II) monohydrate, glycyl-D-valinato copper(II) hemihydrate, and glycyl-L-valinato copper(II) hemihydrate.

Copper(II) complexes with glycyl-DL-alpha-amino-n-butyric acid (H2gly-DL-but), glycyl-DL-valine (H2gly-DL-val), glycyl-DL-norleucine (H2gly-DL-norleu), glycyl-DL-threonine (H2gly-DL-thr), glycyl-DL-serine (H2gly-DL-ser), glycyl-DL-phenylalanine (H2gly-DL-phe), and glycyl-L-valine (H2gly-L-val), have been prepared and characterized by IR, powder diffuse reflection, CD and ORD spectra, and magnetic susceptibility measurements, and by single-crystal X-ray diffraction. The crystal structures of the copper complex with H2gly-DL-but, the copper complex with H2gly-DL-val, and [Cu(gly-L-val)]n.0.5nH2O have been determined by a single-crystal X-ray diffraction method. As for the structure of the copper complex with H2gly-DL-but, the configuration around the asymmetric carbon atom is similar to that of [Cu(gly-L-val)]n.0.5nH2O. Therefore it is concluded that the copper complex with H2gly-DL-but is [Cu(gly-L-but)]n.nH2O. On the contrary, as for the structure of the copper complex with H2gly-DL-val, the configuration around the asymmetric carbon atom is different from that of [Cu(gly-L-val)]n.0.5nH2O. Therefore it is concluded that the copper complex with H2gly-dl-val is [Cu(gly-D-val)]n.0.5nH2O. So during the crystallization of the copper(II) complexes with H2gly-DL-but and H2gly-DL-val, spontaneous resolution has been observed; the four complexes have separated as [Cu(gly-D-but)]n.nH2O, [Cu(gly-L-but)]n.nH2O, [Cu(gly-D-val)]n.0.5nH2O, and [Cu(gly-L-val)]n.0.5nH2O, respectively. [Cu(gly-L-but)]n.nH2O is orthorhombic with the space group P2(1)2(1)2(1). [Cu(gly-D-val)]n.0.5nH2O and [Cu(gly-L-val)]n.0.5nH2O are monoclinic with the space group C2. In these complexes, the copper atom is in a square-pyramidal geometry, ligated by a peptide nitrogen atom, an amino nitrogen atom, a carboxyl oxygen atom, and a carboxyl oxygen atom and a peptide oxygen atom from neighboring molecules. So these complexes consist of a two-dimensional polymer chain bridged by a carboxyl oxygen atom and a peptide oxygen atom from neighboring molecules. The axial oxygen atom is located above the basal plane and the side chain of an amino acid is located below it. These polymer chains consist of only one or the other type of optical isomers; no racemic dipeptides are found. Therefore, spontaneous resolution has been observed in the crystallization of copper(II) complexes with H2gly-DL-but and H2gly-DL-val. The crystal structure of [Cu(gly-D-val)]n.0.5nH2O agrees almost completely with that of [Cu(gly-L-val)]n.0.5nH2O, except for the configuration around the asymmetric carbon atom.

Circular Dichroism↗
PubMed2005

New triorganotin (IV) derivatives of dipeptides as models for metal-protein interactions: synthesis, structural characterization and biological studies.

New non-electrolytic triorganotin(IV) derivatives of dipeptides with general formulae R3Sn(HL), where R = Ph and HL = monoanion of glycylisoleucine (H2L-1), valylvaline (H2L-2), alanylvaline (H2L-3), leucylalanine (H2L-4), leucylleucine (H2L-5); R = n-Bu and HL = monoanion of glycylisoleucine (H2L-1) and leucylalanine (H2L-4); and R = Me and HL = monoanion of leucylalanine (H2L-4) have been synthesized and characterized on the basis of infrared, multinuclear 1H, 13C and 119Sn NMR and 119Sn Mössbauer spectroscopic studies. These investigations suggest that all the ligands in R3Sn(HL) act as monoanionic bidentates coordinating through the COO- and NH2 groups. The 119Sn Mössbauer studies, together with the NMR data, indicate that, for these polymeric derivatives, the polyhedron around tin in R3Sn(HL) is a trigonal-bipyramid with the three organic groups in the equatorial positions, while the axial positions are occupied by a carboxylic oxygen and the amino nitrogen atom from the adjacent molecule. The anti-inflammatory and cardiovascular activities and toxicity of all these compounds have been determined. Four of the complexes have also been screened against some of the chosen bacterial and fungal strains. The Ph3Sn(IV) compounds exhibit better anti-inflammatory and cardiovascular activities in comparison to the Me3Sn(IV) and n-Bu3Sn(IV) analogues. n-Bu3Sn(Gly-Ile) and Ph3Sn(Ala-Val) exhibit good antibacterial activity against all the chosen strains.

Animals↗
PubMed2006

IR-LD spectroscopic characterization of L-Tryptophan containing dipeptides.

IR-spectroscopic and stereo-structural analysis of aromatic l-Tryptophan containing dipeptides l-Tryptophan-l-Tryptophan (Trp-Trp), l-Tyrosine-l-Tryptophan (Tyr-Trp) and cyclo(Trp-Trp) have been carried out by means of solid-state linear-dichroic infrared (IR-LD) spectroscopy of oriented as suspension in nematic liquid crystal solids. The experimental data have been compared with analogous ones of the simple amino acids l-Tyrosnine (l-Tyr) and l-Tryptophan (l-Trp). In cyclo(Trp-Trp), the IR-spectral changes towards the IR-ones of acyclic Trp-Trp have been determined. A theoretical analysis of Tyr-Trp at Hartree-Fock level of theory and 6-31G** basis set is also applied.

Amino Acids↗
PubMed2002

A new dipeptide, O-phosphoserylethanolamine isolated from Agkistroden blomhoffi (mamushi).

A new dipeptide was isolated from several tissues of Agkistroden blomhoffi (mamushi: a venomous snake in Japan), using ion-exchange resins and thin-layer chromatography. It was identified as O-phosphoserylethanolamine by mass spectrometry and comparison with synthetic compounds using several methods. This compound was contained in several mamushi tissues including the liver, heart, brain, bile, and muscle. The concentrations of O-phosphoserylethanolamine in the liver, brain, muscle, skin, heart, and bile were 7.17+/-3.11,16.98+/-4.25,37.37+/-7.88,37.56+/-8.97,23.93+/-6.11, and 22.21+/-5.76 micromol/g, respectively.

Agkistrodon↗
PubMed1996

The human intestinal H+/oligopeptide cotransporter hPEPT1 transports differently-charged dipeptides with identical electrogenic properties.

The human intestinal H+/oligopeptide cotransporter hPEPT1, expressed in Xenopus oocytes, transported neutral, anionic and cationic dipeptides with identical electrogenic properties and maximal evoked currents. Currents were activated by 1 H+ regardless of the net charge on the driven substrate, and were independent of Na+o, K+i and Clo-, calling into question the familiar concept of the origin of the transporter-mediated current.

Animals↗
PubMed1997

Interaction of oligonucleotide-conjugates with the dipeptide transporter system in Caco-2 cells.

Oligonucleotide-based therapies represent novel strategies for manipulating the expression and function of target proteins and are undergoing clinical evaluation for the treatment of viral diseases and malignancies. However, poor biological stability and cellular delivery represent potential limitations to the therapeutic development of oligonucleotides. Conjugation of oligonucleotides to lipophilic groups can improve delivery to cells but the enhanced cellular binding may also facilitate nonspecific interactions. In this report, we show that phosphorothioate oligonucleotides conjugated to lipophilic groups, either tocopherol (Vitamin E) or 2-Di-O-hexadecyl-3-glycerol, can significantly inhibit the functioning of the dipeptide transporter system (DTS) in cultured Caco-2 intestinal cells. Because the DTS mediates the binding and absorption of nutrient peptides and important drugs, such as the cephalosporin and penicillin antibiotics, this finding has important implications in relation to the potential toxicity of lipophilic conjugates in vivo. It also suggests a potential drug interaction with lipophilic oligonucleotide-conjugates if they were to be delivered orally.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1982

Synthesis and immunoadjuvant activities of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan and of some carbohydrate analogs.

The repeating disaccharide-dipeptide units of the bacterial, cell-wall peptidoglycan, one being O-(N-acetyl-beta-muramoyl-L-alanyl-D-isoglutamine)-(1 leads to 4)-2-acetamido-2-deoxy-D-glucose, and the other, O-(2-acetamido-2-deoxy-beta-D-glucosyl)-(1 leads to 4)-N-acetyl-muramoyl-L-alanyl-D-isoglutamine, have been synthesized. Some carbohydrate analogs, such as O-(N-acetyl-beta-muramoyl-L-alanyl-D-isoglutamine)-(1 leads to 4)-N-acetylmuramoyl-L-alanyl-D-isoglutamine, O-beta-D-glucosyl-(1 leads to 4)-N-acetylmuramoyl-L-alanyl-D-isoglutamine, and O-(6-acetamido-6-deoxy-beta-D-glucosyl)-(1 leads to 4)-N-acetylmuramoyl-L-alanyl-D-isoglutamine, were also synthesized. Their immunoadjuvant activities were examined in guinea-pigs.

Adjuvants, Immunologic↗
PubMed2003

Synthesis and solid state 13C and 1H NMR analysis of new oxamide derivatives of methyl 2-amino-2-deoxy-alpha-D-glucopyranoside and ester of amino acids or dipeptides.

The syntheses of new oxamide derivatives of methyl 2-amino-2-deoxy-alpha-D-glucopyranoside and amino acid or peptide esters are presented. The reaction of methyl 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-alpha-D-glucopyranoside and oxalyl chloride gave N-(methyl 3,4,6-tri-O-acetyl-2-deoxy-alpha-D-glucopyranosid-2-yl) oxamic acid chloride which on reaction with the ester of Gly, L-Ala, L-Phe, GlyGly, Gly-L-Phe and Gly-L-Ala afforded N-(methyl 3,4,6-tri-O-acetyl-2-deoxy-alpha-D-glucopyranosid-2-yl), N'-oxalyl-amino acid or dipeptide esters. The structure of the oxamides was studied using 1H, 13C NMR in solution and solid state.

Amino Acids↗