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1.
Nucl Med Biol ; 94-95: 98-105, 2021.
Article in English | MEDLINE | ID: mdl-33621898

ABSTRACT

OBJECTIVE: Studies have confirmed that tumorigenesis is related to an imbalance of polyamine metabolism and over-expression of oncogenes resulting in the up-regulation of ornithine decarboxylase (ODC, the first rate-limiting enzyme for regulating intracellular polyamines biosynthesis), which has become a target for anti-tumor therapy. In this study, an ornithine derivative, N5-(2-[18F]fluoropropionyl) ornithine (N5-[18F]FPO), has been prepared and its potential utility for tumor PET imaging evaluated. METHODS: N5-[18F]FPO was successfully prepared via a nucleophilic fluorination reaction and a subsequent efficient deprotection step. The in vitro and in vivo stability were determined by HPLC conducted in fetal bovine serum, saline and rat urine. Cellular uptake studies were conducted in HepG2 cells and the biodistribution and micro-PET/CT imaging performed in normal ICR mice and three tumor-bearing mice models, respectively. RESULTS: Total synthesis time of N5-[18F]FPO was about 80 min with a radiochemical yield of 15% ± 6% (uncorrected, based on 18F-, n = 6) and a high radiochemical stability can be seen in vitro and vivo. The N5-[18F]FPO exhibited fast uptake in HepG2 cells and the cellular uptake ability of N5-[18F]FPO can be inhibited by L-ornithine and DFMO, which indicated that the transport pathway of N5-[18F]FPO is similar to that of L-ornithine, interacting with ODC after being transported into the cell. The biodistribution and micro-PET/CT images demonstrate that N5-[18F]FPO was excreted by the urinary system, and excellent tumor visualization with high tumor-to-background ratios can be observed in the three tumor-bearing mice models studied. CONCLUSION: All the above results suggest that N5-[18F]FPO has the potential to be a novel radiotracer for imaging ODC expression in solid tumors.


Subject(s)
Fluorine Radioisotopes/chemistry , Ornithine/chemistry , Ornithine/chemical synthesis , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Animals , Cell Line, Tumor , Mice , Ornithine/pharmacokinetics , Radiochemistry , Rats , Tissue Distribution
2.
Eur J Med Chem ; 178: 30-38, 2019 Sep 15.
Article in English | MEDLINE | ID: mdl-31173969

ABSTRACT

Several studies that have identified agents that potentiate the antimicrobial activity of antibiotics, but there are limited insights into their structure-activity relationships (SAR). The SAR associated with select N-alkylaryl amide derivatives of ornithine was performed to establish those structural features that were associated with potentiation of the antimicrobial activity of clarithromycin against E. coli ATCC 25922. The data indicate that the N-propyl derivative was slightly more active in reducing the effective MIC of clarithromycin against E. coli ATCC 25922. In addition, the S-enantiomer of compound 9 was somewhat more potent than the R-enantiomer in potentiating clarithromycin activity. No significant enhancement in potentiation activity was observed with the conversion of these secondary amides to their N-methyl tertiary amides. Formation of the N-methyl or N,N-dimethyl derivatives of the primary amine of 9 was associated with the loss of potentiation activity. Conversion of this primary amine to a guanidine was also not associated with an increase in potentiation activity. Among the isomeric diamino pentamides, 15 potentiated the antibacterial activity of clarithromycin to the greatest extent. In addition to these amide derivatives, the desoxy derivatives 16 and 18 were the more potent potentiators within this triamine series. The relative location of the primary amines, as indicated by the relative differences in the potentiation observed with 16 compared to 14, appears to be a critical factor in determining potentiation activity. Cell-based membrane permeabilization and efflux inhibition studies in E. coli ATCC 25922 suggest that the potentiation of clarithromycin activity by 16 reflects its ability to inhibit efflux pump activity and to a lesser extent its actions as a permeabilizer of the outer leaflet of the outer cell membrane.


Subject(s)
Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Clarithromycin/pharmacology , Escherichia coli/drug effects , Ornithine/pharmacology , Amides/chemical synthesis , Amides/chemistry , Cell Membrane Permeability/drug effects , Drug Synergism , Membrane Transport Proteins/drug effects , Microbial Sensitivity Tests , Molecular Structure , Ornithine/analogs & derivatives , Ornithine/chemical synthesis , Structure-Activity Relationship
3.
Org Biomol Chem ; 13(25): 7020-6, 2015 Jul 07.
Article in English | MEDLINE | ID: mdl-26030164

ABSTRACT

We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-Gln-OtBu derivatives, leading to innovative unnatural α,ß or γ-amino acids functionalized with tertiary amines. Rapid and scalable, this process allowed us to build a library of basic unnatural amino acids at the gram-scale and directly usable for liquid- or solid-phase peptide synthesis. The diversity of available tertiary amines allows us to modulate the physicochemical properties of the resulting amino acids, such as basicity or hydrophobicity.


Subject(s)
Amines/chemistry , Amino Acids/chemical synthesis , Arginine/analogs & derivatives , Lysine/analogs & derivatives , Ornithine/analogs & derivatives , Solid-Phase Synthesis Techniques/methods , Amides/chemistry , Amines/chemical synthesis , Amino Acids/chemistry , Arginine/chemical synthesis , Catalysis , Lysine/chemical synthesis , Ornithine/chemical synthesis , Oxidation-Reduction , Ruthenium/chemistry , Solid-Phase Synthesis Techniques/economics
4.
J Enzyme Inhib Med Chem ; 30(3): 345-53, 2015 Jun.
Article in English | MEDLINE | ID: mdl-24939101

ABSTRACT

Many cancer cells have high expression of ornithine decarboxylase (ODC) and there is a concerted effort to seek new inhibitors of this enzyme. The aim of the study was to initially characterize the inhibition properties, then to evaluate the cytotoxicity/antiproliferative cell based activity of N-ω-chloroacetyl-l-ornithine (NCAO) on three human cancer cell lines. Results showed NCAO to be a reversible competitive ODC inhibitor (Ki = 59 µM) with cytotoxic and antiproliferative effects, which were concentration- and time-dependent. The EC50,72h of NCAO was 15.8, 17.5 and 10.1 µM for HeLa, MCF-7 and HepG2 cells, respectively. NCAO at 500 µM completely inhibited growth of all cancer cells at 48 h treatment, with almost no effect on normal cells. Putrescine reversed NCAO effects on MCF-7 and HeLa cells, indicating that this antiproliferative activity is due to ODC inhibition.


Subject(s)
Antineoplastic Agents/pharmacology , Ornithine Decarboxylase Inhibitors/pharmacology , Ornithine Decarboxylase/metabolism , Ornithine/analogs & derivatives , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Activation/drug effects , HeLa Cells , Hep G2 Cells , Humans , Liver/drug effects , Liver/enzymology , Liver/metabolism , MCF-7 Cells , Male , Molecular Structure , Ornithine/chemical synthesis , Ornithine/chemistry , Ornithine/pharmacology , Ornithine Decarboxylase Inhibitors/chemical synthesis , Ornithine Decarboxylase Inhibitors/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Vero Cells
5.
ChemMedChem ; 9(4): 792-7, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24574257

ABSTRACT

Inhibitors of the human enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH-1) can raise endogenous levels of asymmetric dimethylarginine (ADMA) and lead to a subsequent inhibition of nitric oxide synthesis. In this study, N(5) -(1-imino-2-chloroethyl)-L-ornithine (Cl-NIO) is shown to be a potent time- and concentration-dependent inhibitor of purified human DDAH-1 (KI =1.3±0.6 µM; kinact =0.34±0.07 min(-1) ), with >500-fold selectivity against two arginine-handling enzymes in the same pathway. An activity probe is used to measure the "in cell" IC50 value (6.6±0.2 µM) for Cl-NIO inhibition of DDAH-1 artificially expressed within cultured HEK293T cells. A screen of diverse melanoma cell lines reveals that a striking 50/64 (78 %) of melanoma lines tested showed increased levels of DDAH-1 relative to normal melanocyte control lines. Treatment of the melanoma A375 cell line with Cl-NIO shows a subsequent decrease in cellular nitric oxide production. Cl-NIO is a promising tool for the study of methylarginine-mediated nitric oxide control and a potential therapeutic lead compound for other indications with elevated nitric oxide production, such as septic shock and idiopathic pulmonary fibrosis.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Melanoma/enzymology , Ornithine/analogs & derivatives , Amidohydrolases/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , HEK293 Cells , Humans , Melanoma/metabolism , Molecular Conformation , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Ornithine/chemical synthesis , Ornithine/chemistry , Ornithine/pharmacology , Structure-Activity Relationship , Up-Regulation/drug effects
6.
Bioorg Med Chem ; 20(22): 6655-61, 2012 Nov 15.
Article in English | MEDLINE | ID: mdl-23043725

ABSTRACT

Streptococcus agalactiae is an important agent in the infection of neonates in the first world. One of the most extended methods for its identification is based on the detection of a characteristic red pigment in the patient samples, named [12]-granadaene (1). In this article, we present a modular and flexible approach to simple analogues of this ornithine rhamno-polyene 1 and the elucidation of the most important features of its structure: the absolute configuration at C-27, the stereochemistry of the anomeric center and the link of the amino acid ornithine to the rest of the structure.


Subject(s)
Ornithine/analogs & derivatives , Polyenes/chemistry , Streptococcus agalactiae/chemistry , Magnetic Resonance Spectroscopy , Molecular Conformation , Ornithine/chemical synthesis , Ornithine/chemistry , Polyenes/chemical synthesis , Stereoisomerism
7.
Molecules ; 17(7): 7709-21, 2012 Jun 25.
Article in English | MEDLINE | ID: mdl-22732884

ABSTRACT

A key saggitamide intermediate corresponding to a rare sugar framework has been obtained. This approach should help to establish the overall configuration of more complex structures of the sagittamide family.


Subject(s)
Carbohydrates/chemistry , Ornithine/analogs & derivatives , Valine/analogs & derivatives , Alkenes/chemical synthesis , Alkenes/chemistry , Esters/chemical synthesis , Esters/chemistry , Magnetic Resonance Spectroscopy , Molecular Conformation , Ornithine/chemical synthesis , Ornithine/chemistry , Stereoisomerism , Valine/chemical synthesis , Valine/chemistry
8.
Bioorg Med Chem ; 20(8): 2651-5, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22405596

ABSTRACT

Synthesis of Fmoc-protected N(δ)-acetyl-N(δ)-(tert-butoxy)-l-ornithine has revealed it to be a metal-chelating amino-acid precursor. This protected amino acid was compatible with the preparation of ferrichrome peptides by standard Fmoc-based solid-phase peptide synthesis. Evaluation of deferriferrichrysin for metal ion chelation revealed that zirconium(IV) and titanium(IV) formed complexes with deferriferrichrysin.


Subject(s)
Ferrichrome/chemistry , Organometallic Compounds/chemical synthesis , Ornithine/analogs & derivatives , Ornithine/pharmacology , Peptides, Cyclic/chemistry , Titanium/chemistry , Zirconium/chemistry , Ferrichrome/analogs & derivatives , Molecular Structure , Organometallic Compounds/chemistry , Ornithine/chemical synthesis , Ornithine/chemistry
9.
ACS Chem Biol ; 7(1): 160-5, 2012 Jan 20.
Article in English | MEDLINE | ID: mdl-22004374

ABSTRACT

Protein arginine deiminase activity (PAD) is increased in cancer, rheumatoid arthritis, and ulcerative colitis. Although the link between abnormal PAD activity and disease is clear, the relative contribution of the individual PADs to human disease is not known; there are 5 PAD isozymes in humans. Building on our previous development of F- and Cl-amidine as potent pan-PAD irreversible inhibitors, we describe herein a library approach that was used to identify PAD-selective inhibitors. Specifically, we describe the identification of Thr-Asp-F-amidine (TDFA) as a highly potent PAD4 inactivator that displays ≥15-fold selectivity for PAD4 versus PAD1 and ≥50-fold versus PADs 2 and 3. This compound is active in cells and can be used to inhibit PAD4 activity in cellulo. The structure of the PAD4·TDFA complex has also been solved, and the structure and mutagenesis data indicate that the enhanced potency is due to interactions between the side chains of Q346, R374, and R639. Finally, we converted TDFA into a PAD4-selective ABPP and demonstrated that this compound, biotin-TDFA, can be used to selectively isolate purified PAD4 in vitro. In total, TDFA and biotin-TDFA represent PAD4-selective chemical probes that can be used to study the physiological roles of this enzyme.


Subject(s)
Amidines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Hydrocarbons, Fluorinated/chemical synthesis , Hydrolases/antagonists & inhibitors , Ornithine/analogs & derivatives , Small Molecule Libraries/chemical synthesis , Amidines/pharmacology , Biotinylation , Enzyme Inhibitors/pharmacology , Humans , Hydrocarbons, Fluorinated/pharmacology , Hydrolases/chemistry , Hydrolases/metabolism , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Isoenzymes/metabolism , Kinetics , Models, Molecular , Molecular Probes/chemical synthesis , Ornithine/chemical synthesis , Ornithine/pharmacology , Protein Structure, Tertiary , Protein-Arginine Deiminase Type 4 , Protein-Arginine Deiminases , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Small Molecule Libraries/pharmacology , Substrate Specificity
10.
J Med Chem ; 54(19): 6919-35, 2011 Oct 13.
Article in English | MEDLINE | ID: mdl-21882827

ABSTRACT

Protein arginine deiminase (PAD) activity is upregulated in a number of human diseases, including rheumatoid arthritis, ulcerative colitis, and cancer. These enzymes, there are five in humans (PADs 1-4 and 6), regulate gene transcription, cellular differentiation, and the innate immune response. Building on our successful generation of F- and Cl-amidine, which irreversibly inhibit all of the PADs, a structure-activity relationship was performed to develop second generation compounds with improved potency and selectivity. Incorporation of a carboxylate ortho to the backbone amide resulted in the identification of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine), as PAD inactivators with improved potency (up to 65-fold) and selectivity (up to 25-fold). Relative to F- and Cl-amidine, the compounds also show enhanced potency in cellulo. As such, these compounds will be versatile chemical probes of PAD function.


Subject(s)
Amidines/chemical synthesis , Hydrolases/antagonists & inhibitors , Ornithine/analogs & derivatives , Amidines/chemistry , Amidines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biological Availability , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Drug Synergism , Humans , Hydrolases/chemistry , Kinetics , Molecular Structure , Ornithine/chemical synthesis , Ornithine/chemistry , Ornithine/pharmacology , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 21(8): 2351-3, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21421312

ABSTRACT

A scalable four-step synthesis of the ornithine transcarbamylase inhibitor N(5)-phosphonoacetyl-l-ornithine (PALO) is achieved through boroxazolidinone protection of ornithine. Investigations in the model organism Saccharomyces cerevisiae found that, in contrast to a previous report, PALO did not influence growth rate or expression of genes involved in arginine metabolism.


Subject(s)
Arginine/metabolism , Ornithine/analogs & derivatives , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Gene Expression Regulation , Ornithine/chemical synthesis , Ornithine/chemistry , Ornithine/pharmacology , Ornithine Carbamoyltransferase/antagonists & inhibitors , Ornithine Carbamoyltransferase/metabolism , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae Proteins/genetics
12.
Carbohydr Res ; 345(11): 1533-40, 2010 Jul 19.
Article in English | MEDLINE | ID: mdl-20478556

ABSTRACT

Conformationally constrained amino acid analogs are widely used to probe the bioactive conformation of peptides. In this paper we report on the synthesis of hexafunctional allose-templated L- and D-hydroxyornithine and L- and D-hydroxyarginine analogs in which the allose-based polyol scaffold constrains the side chain of hydroxyornithine and hydroxyarginine in an extended conformation. The partially protected building blocks were selected for future use in solid-phase peptide synthesis using the Fmoc-strategy. The synthesis starts from a previously prepared C-glucosyl glycine analog. Multiple chemical protection-deprotection steps and an oxidation are used to prepare 3-keto-C-glucosyl analogs that serve as a precursor to install an amino function via reductive amination. Guanidinylation of the amino group provides access to allose-templated hydroxyarginine analogs. Both hexafunctional building blocks are further chemically modified to provide suitable protection for solid-phase peptide synthesis using the Fmoc-strategy.


Subject(s)
Arginine/analogs & derivatives , Glucose/chemistry , Ornithine/analogs & derivatives , Ornithine/chemical synthesis , Arginine/chemical synthesis , Arginine/chemistry , Molecular Conformation , Peptides/chemical synthesis , Peptides/chemistry
13.
Amino Acids ; 39(2): 515-21, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20108009

ABSTRACT

Synthesis of 6-amino-2-azaspiro[3.3]heptane-6-carboxylic acid and 2-azaspiro[3.3]heptane-6-carboxylic acid was performed. Both four-membered rings in the spirocyclic scaffold were constructed by subsequent ring closure of corresponding 1,3-bis-electrophiles at 1,1-C- or 1,1-N-bis-nucleophiles. The two novel amino acids were added to the family of the sterically constrained amino acids for the use in chemistry, biochemistry, and drug design.


Subject(s)
Aza Compounds/chemical synthesis , Ornithine/analogs & derivatives , Spiro Compounds/chemical synthesis , gamma-Aminobutyric Acid/analogs & derivatives , Ornithine/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis
14.
Amino Acids ; 38(3): 691-700, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19283444

ABSTRACT

Sulfamoylation of the L-ornithine methyl ester side-chain generates a non-natural arginine isostere which can be coupled with N-Fmoc-L-proline to synthesize analogues which maintain the structural characteristics of the biologically important Pro-Arg dipeptide sequence. As a probe of its biological importance, the sulfamoylated amino acid derivative was also incorporated as P1 residue in tripeptide structures matching the C-terminal subsequence of fibrinogen. The reported results demonstrate that the functionalization of L-ornithine side-chain with a neutral sulfamoyl group can generate an arginine bioisostere which can be used for the synthesis of prototypes of a new class of human thrombin inhibitors.


Subject(s)
Arginine/analogs & derivatives , Ornithine/analogs & derivatives , Sulfonamides/chemical synthesis , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Dipeptides/chemistry , Drug Design , Humans , Hydrogen Bonding , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/pharmacology , Ornithine/chemical synthesis , Ornithine/chemistry , Partial Thromboplastin Time , Sulfonamides/chemistry , Thrombin/antagonists & inhibitors , Thrombin Time
15.
Amino Acids ; 38(4): 1155-64, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19649769

ABSTRACT

A series of N (alpha)-acyl (alkyl)- and N (alpha)-alkoxycarbonyl-derivatives of L- and D-ornithine were prepared, characterized, and analyzed for their potency toward the bacterial enzyme N (alpha)-acetyl-L-ornithine deacetylase (ArgE). ArgE catalyzes the conversion of N (alpha)-acetyl-L-ornithine to L-ornithine in the fifth step of the biosynthetic pathway for arginine, a necessary step for bacterial growth. Most of the compounds tested provided IC(50) values in the muM range toward ArgE, indicating that they are moderately strong inhibitors. N (alpha)-chloroacetyl-L-ornithine (1g) was the best inhibitor tested toward ArgE providing an IC(50) value of 85 microM while N (alpha)-trifluoroacetyl-L-ornithine (1f), N (alpha)-ethoxycarbonyl-L-ornithine (2b), and N (alpha)-acetyl-D-ornithine (1a) weakly inhibited ArgE activity providing IC(50) values between 200 and 410 microM. Weak inhibitory potency toward Bacillus subtilis-168 for N (alpha)-acetyl-D-ornithine (1a) and N (alpha)-fluoro- (1f), N (alpha)-chloro- (1g), N (alpha)-dichloro- (1h), and N (alpha)-trichloroacetyl-ornithine (1i) was also observed. These data correlate well with the IC(50) values determined for ArgE, suggesting that these compounds might be capable of getting across the cell membrane and that ArgE is likely the bacterial enzymatic target.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Escherichia coli Proteins/antagonists & inhibitors , Ornithine/analogs & derivatives , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Chromatography, High Pressure Liquid , Drug Design , Enzyme Inhibitors/pharmacology , Kinetics , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Molecular Weight , Ornithine/chemical synthesis , Ornithine/chemistry , Ornithine/pharmacology , Phosgene/analogs & derivatives , Phosgene/chemistry , Polystyrenes/chemistry , Spectrometry, Mass, Electrospray Ionization
16.
Eur J Pharmacol ; 593(1-3): 30-5, 2008 Sep 28.
Article in English | MEDLINE | ID: mdl-18692042

ABSTRACT

Argpyrimidine, the product of non-enzymatic protein glycation by methylglyoxal, has been implicated in the pathophysiology of diabetes mellitus and neurodegenerative diseases. Chemically, argpyrimidine is a substituted pyrimidinol with structural features common to known antioxidants. The objective of this study was to investigate the antioxidant properties of argpyrimidine. Argpyrimidine was synthesized by mixing L-arginine with 3-acetoxypentane-2,4-dione under acidic conditions and purified by chromatography. Argpyrimidine inhibited lipid peroxidation of rat brain homogenates catalyzed by hydroxyl radicals, metal ions, and autooxidation in a concentration- and time-dependent manner. In addition, argpyrimidine scavenged superoxide anion, 1,1-diphenyl 2-picryl-hydrazyl-stable free radical, intracellular-hydrogen peroxide, and inhibited free-radical-mediated nicking of plasmid-DNA. Taken together, our data suggest that argpyrimidine has antioxidant properties and may therefore have biological relevance in pathophysiologies associated with diabetes mellitus and neurodegenerative diseases.


Subject(s)
Antioxidants , Free Radical Scavengers , Ornithine/analogs & derivatives , Pyrimidines/pharmacology , Ascorbic Acid/antagonists & inhibitors , Ascorbic Acid/pharmacology , Biphenyl Compounds , Cell Line, Tumor , DNA/drug effects , Ferric Compounds/chemistry , Ferrous Compounds/chemistry , Humans , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/pharmacology , In Situ Nick-End Labeling , Lipid Peroxidation/drug effects , Ornithine/chemical synthesis , Ornithine/pharmacology , Oxidants/pharmacology , Oxidation-Reduction , Oxidative Stress/drug effects , Picrates/chemistry , Plasmids/genetics , Pyrimidines/chemical synthesis , Superoxides/metabolism
17.
Protein Pept Lett ; 15(4): 353-5, 2008.
Article in English | MEDLINE | ID: mdl-18473946

ABSTRACT

The sheep skins unhairing process with preliminary alkaline treatment of the wool leads to two unnatural dipeptide mimetics lysinoalanine (Lys(*) - Ala) and ornithinoalanine (Orn(*)- Ala) obtaining. They are result from the keratin hydrolysis process. The changes of wool keratin make it resistant to sulphide degradation. We synthesized and characterized these unnatural dipeptides under the experimental conditions. The structures and mechanism of Lys(*) - Ala and Orn(*)- Ala obtaining were elucidated. The using of newly synthesized products as markers for control of wool's keratin changes during skin unhairing process was demonstrated. The developments have also been the result of economic and environmental pressures to meet environmental regulations.


Subject(s)
Alanine/chemical synthesis , Dipeptides/chemical synthesis , Keratins/chemistry , Lysinoalanine/chemical synthesis , Ornithine/chemical synthesis , Wool/chemistry , Alanine/analysis , Alanine/chemistry , Animals , Dipeptides/analysis , Dipeptides/chemistry , Lysinoalanine/analysis , Lysinoalanine/chemistry , Ornithine/analysis , Ornithine/chemistry , Sheep , Skin
18.
Biosci Biotechnol Biochem ; 72(2): 568-71, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18256486

ABSTRACT

Three major glyceraldehyde-related advanced glycation end products (AGEs) were formed from a mixture of N(alpha)-acetyllysine, N(alpha)-acetylarginine, and glyceraldehyde. Two of the compounds were MG-H1 and GLAP, as previously reported, and the other compound was identified as N(alpha)-acetyl-N(delta)-(5-hydroxy-4,6-dimethyl-pyrimidin-2-yl)-ornithine, argpyrimidine (APN). APN is a modification product of arginine residue, but it did not form from glyceraldehyde with arginine residue. The coexistence of lysine residue was necessary to APN formation.


Subject(s)
Glucose/chemistry , Glyceraldehyde/chemistry , Ornithine/analogs & derivatives , Pyrimidines/chemical synthesis , Magnetic Resonance Spectroscopy , Ornithine/chemical synthesis , Spectrometry, Fluorescence , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Ultraviolet
19.
J Org Chem ; 73(3): 1025-30, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18179234

ABSTRACT

Nomega-Methylated arginines such as asymmetric dimethyl-L-arginine (ADMA) and monomethyl-l-arginine (NMMA) are known as potent physiological inhibitors of nitric oxide synthases (NOSs). To explore a possible physiological and pharmaceutical relevance of N(delta)-methylated analogues, a synthetic scheme had to be developed that would not lead to N(delta)-methyl-L-arginine only but also to its presumed metabolites of NOS catalysis. Two basic synthetic approaches have been pursued to obtain N(delta)-methylated derivatives of L-ornithine, L-citrulline, L-arginine, and N(omega)-hydroxy-L-arginine. A first attempt utilized conventionally protected L-ornithine, i.e., the tert-butyl ester and Boc-amine, and led to three end compounds in excellent yields. Simultaneous protection of the alpha-amino acid moiety by formation of boroxazolidinones, particularly by employing 9-borabicyclo[3.3.1]nonane (9-BBN-H), proved to be a convenient option to perform side chain modifications and led to all of the desired end compounds. Additionally, enantiomeric excess (ee, %) of crucial synthetic intermediates and end compounds was determined by chiral HPLC.


Subject(s)
Arginine/analogs & derivatives , Citrulline/chemical synthesis , Ornithine/analogs & derivatives , Arginine/chemical synthesis , Arginine/chemistry , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Citrulline/chemistry , Molecular Structure , Ornithine/chemical synthesis , Ornithine/chemistry , Oxazolone/analogs & derivatives , Oxazolone/chemical synthesis , Oxazolone/chemistry
20.
J Med Chem ; 50(3): 550-65, 2007 Feb 08.
Article in English | MEDLINE | ID: mdl-17266207

ABSTRACT

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.


Subject(s)
Bradykinin B2 Receptor Antagonists , Bronchodilator Agents/chemical synthesis , Ornithine/analogs & derivatives , Sulfonamides/chemical synthesis , Animals , Blood Pressure/drug effects , Bronchoconstriction/drug effects , Bronchodilator Agents/chemistry , Bronchodilator Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Drug Design , Guinea Pigs , Humans , Ileum/drug effects , Ileum/physiology , In Vitro Techniques , Inositol Phosphates/biosynthesis , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Ornithine/chemical synthesis , Ornithine/chemistry , Ornithine/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology
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