ABSTRACT
This work reports on the concise total synthesis of eight natural products of the mugineic acid and avenic acid families (phytosiderophores). An innovative "east-to-west" assembly of the trimeric products resulted in a high degree of divergence enabling the formation of the final products in just 10 or 11â steps each with a minimum of overall synthetic effort. Chiral pool starting materials (l-malic acid, threonines) were employed for the outer building blocks while the middle building blocks were accessed by diastereo- and enantioselective methods. A highlight of this work consists in the straightforward preparation of epimeric hydroxyazetidine amino acids, useful building blocks on their own, enabling the first synthesis of 3''-hydroxymugineic acid and 3''-hydroxy-2'-deoxymugineic acid.
Subject(s)
Azetidinecarboxylic Acid/analogs & derivatives , Biological Products/chemistry , Biological Products/chemical synthesis , Plants/chemistry , Siderophores/chemical synthesis , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/chemistry , Malates/chemistry , Siderophores/chemistry , Threonine/chemistryABSTRACT
Thirteen new sphingosine-1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized by replacing azetidine-3-carboxylic acid moiety of compound 4 with new polar groups. The in vitro binding potency of these new analogs toward S1PR1 was determined. Out of 13 new compounds, four compounds 9a, 10c, 12b, and 16b displayed high S1PR1 binding potency with IC50 values of 13.2⯱â¯3.2, 14.7⯱â¯1.7, 9.7⯱â¯1.6, and 6.3⯱â¯1.3â¯nM, respectively; further binding studies of these four ligands toward S1PR2-5 suggested they are highly selective for S1PR1 over other S1PRs. The radiosynthesis of the lead radiotracer [18F]12b was achieved with good radiochemical yield (â¼14.1%), high radiochemical purity (>98%), and good specific activity (â¼54.1 GBq/µmol, decay corrected to the end of synthesis, EOS). Ex vivo autoradiography and initial biodistribution studies in rodents were performed, suggesting that [18F]12b was able to penetrate the blood-brain barrier (BBB) with high brain uptake (0.71% ID/g at 60â¯min post-injection) and no defluorination was observed. In vitro autoradiography study in brain slices of lipopolysaccharides (LPS)-induced neuroinflammation mice indicated that SEW2871, a specific S1PR1 ligand was able to reduce the uptake of [18F]12b, suggesting [18F]12b has S1PR1 specific binding. These initial results suggested that [18F]12b has potential to be an F-18 labeled radiotracer for imaging S1PR1 in the brain of the animal in vivo.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Azetidinecarboxylic Acid/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Receptors, Lysosphingolipid/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/chemistry , Dose-Response Relationship, Drug , Fluorine Radioisotopes , Inflammation/chemically induced , Inflammation/drug therapy , Ligands , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Mice , Molecular Structure , Positron-Emission Tomography , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistry , Receptors, Lysosphingolipid/chemistry , Sphingosine-1-Phosphate Receptors , Structure-Activity Relationship , Tissue DistributionABSTRACT
The straightforward syntheses of enantiopure (2R)-2-trifluoromethyl-2-carboxyazetidine and (R)- and (S)-trifluoromethylhomoserines are reported. The key step is a Strecker-type reaction on a common chiral CF3-containing bicyclic oxazolidine intermediate obtained by a condensation reaction of (R)-phenylglycinol and ethyl-4,4,4-trifluoroacetoacetate (ETFAA).
Subject(s)
Acetoacetates/chemistry , Amino Alcohols/chemical synthesis , Azetidinecarboxylic Acid/chemical synthesis , Azetidines/chemical synthesis , Homoserine/chemical synthesis , Amino Alcohols/chemistry , Azetidinecarboxylic Acid/chemistry , Azetidines/chemistry , Catalysis , Homoserine/chemistry , Molecular Structure , Oxazoles/chemistry , StereoisomerismABSTRACT
The phytosiderophore 2'-deoxymugineic acid (DMA) is exuded via the root system by all grasses (including important crop plants like rice, wheat and barley) to mobilize Fe(III) from soil and improve plant Fe nutrition, crucial for high crop yields. Elucidation of the biogeochemistry of 2'-deoxymugineic acid in the rhizosphere requires its quantification in minute amounts. To this end, (13)C4-DMA was synthesized for the first time, from cheap isotopically labeled starting materials. The synthetic route utilizes L-allyl((13)C2)glycine and L-(2-(13)C)azetidine ((13)C)carboxylic acid as versatile labeled building blocks. The title compound was recently used as an internal standard for analysis of soil and plant samples allowing the first accurate quantification of DMA in these matrices by means of LC-MS/MS. It is furthermore used in tracer experiments investigating biodegradation of DMA in soil.
Subject(s)
Azetidinecarboxylic Acid/analogs & derivatives , Azetidinecarboxylic Acid/analysis , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/chemistry , Carbon Isotopes/chemistry , Isotope Labeling , Soil/chemistryABSTRACT
The formation from D-glucose of both enantiomers of 2,4-dideoxy-2,4-iminoribonic acid is the first chemical synthesis of unprotected 3-hydroxyazetidine carboxylic acids. The long-term stability of 3-hydroxyazetidine amides is established at acidic and neutral pH and implies their value as non-proteinogenic amino acid components of peptides, providing medicinal chemists with a new class of peptide isosteres. The structure of N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid was established by X-ray crystallographic analysis. An N-methylazetidine amide derivative is a specific inhibitor of ß-hexosaminidases at the micromolar level, and is only the second example of potent inhibition of any glycosidase by an amide of a sugar amino acid related to an iminosugar.
Subject(s)
Amino Acids/chemistry , Azetidinecarboxylic Acid/chemistry , Azetidines/chemistry , Amides/chemistry , Animals , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/metabolism , Azetidines/chemical synthesis , Azetidines/metabolism , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Hexosaminidases/antagonists & inhibitors , Hexosaminidases/metabolism , Humans , Imino Sugars/chemistry , Molecular Conformation , Protein Binding , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A short and efficient synthesis of the previously unknown N-aminoazetidinecarboxylic acid has been established using a photochemical [2 + 2] cycloaddition strategy starting from 6-azauracil. Chiral derivatization with a nonracemic oxazolidinone provided access to both enantiomers of the title product.
Subject(s)
Azetidinecarboxylic Acid/chemistry , Azetidinecarboxylic Acid/chemical synthesis , Hydrazines/chemistry , Hydrazines/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Structure , Oxazolidinones/chemistry , Stereoisomerism , Uracil/analogs & derivatives , Uracil/chemistryABSTRACT
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC(50)<3 nM and inhibit the release of TNFalpha (IC(50)<0.3 microM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC(50)=0.05-0.23 microM), less potent in cells (IC(50)<1.1 microM), but show good oral absorption. Compound 13E (100mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score.
Subject(s)
Azetidinecarboxylic Acid/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/pharmacology , Azetidines/chemistry , Binding Sites , Cell Line , Crystallography, X-Ray , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , HSP27 Heat-Shock Proteins/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Spiro Compounds/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Six new endomorphin analogues, incorporating constrained amino acids in place of native proline have been synthesized. Residues of (S)-azetidine-2-carboxylic acid (Aze), 3,4-dehydro-(S)-proline (Delta(3)Pro), azetidine-3-carboxylic acid (3Aze) and dehydro-alanine (DeltaAla) have been used to prepare [Delta(3)Pro(2)]EM-2 (1), [Aze(2)]EM-1 (2), [Aze(2)]EM-2 (3), [3Aze(2)]EM-1 (4), [3Aze(2)]EM-2 (5) and [DeltaAla(2)]EM-2 (6). Binding assays and functional bioactivities for mu- and delta-receptors are reported. The highest affinity, bioactivity and selectivity are shown by peptides 2 and 3 containing the Aze residue.
Subject(s)
Azetidinecarboxylic Acid/chemical synthesis , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Proline/chemistry , Alanine/chemistry , Animals , Azetidinecarboxylic Acid/pharmacology , Binding Sites , Brain/metabolism , Cell Membrane/metabolism , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Peptides/chemistry , Rats , Receptors, Opioid, mu/chemistryABSTRACT
The four stereoisomers of azetidine-2,3-dicaroxylic acid (L-trans-ADC, L-cis-ADC, D-trans-ADC, and D-cis-ADC) were synthesized in a stereocontrolled fashion following two distinct strategies: one providing the two cis-ADC enantiomers and one giving access to the two trans-ADC enantiomers. The four azetidinic amino acids were characterized in a radioligand binding assay ([(3)H]CGP39653) at native NMDA receptors: L-trans-ADC showed the highest affinity (K(i)=10 microM) followed by the D-cis-ADC stereoisomer (21 microM). In contrast, the two analogues L-cis-ADC and D-trans-ADC were low-affinity ligands (>100 and 90 microM, respectively). Electrophysiological characterization of the ADC compounds at the four NMDA receptor subtypes NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D expressed in Xenopus oocytes showed that L-trans-ADC displayed the highest agonist potency at NR1/NR2D (EC(50)=50 microM), which was 9.4-, 3.4-, and 1.9-fold higher than the respective potencies at NR1/NR2A-C. D-cis-ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium-range micromolar potencies (EC(50)=720 and 230 microM, respectively). A subsequent in silico ligand-protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site.
Subject(s)
Azetidinecarboxylic Acid/analogs & derivatives , Receptors, N-Methyl-D-Aspartate/agonists , Animals , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/chemistry , Azetidinecarboxylic Acid/pharmacology , Computer Simulation , Dicarboxylic Acids/chemical synthesis , Dicarboxylic Acids/chemistry , Dicarboxylic Acids/pharmacology , Models, Molecular , Oocytes/drug effects , Protein Structure, Tertiary , Receptors, N-Methyl-D-Aspartate/chemistry , Stereoisomerism , Structure-Activity Relationship , XenopusABSTRACT
The effect of the media (achiral and chiral ionic liquids) on the stereochemistry of intramolecular 1,3-dipolar cycloaddition reactions of D-galactose-derived omega-unsaturated nitrones, leading to bicyclic isoxazolidines, has been investigated.
Subject(s)
Acetates/chemical synthesis , Azetidinecarboxylic Acid/analogs & derivatives , Bridged Bicyclo Compounds/chemical synthesis , Galactose/chemistry , Nitrogen Oxides/chemistry , Peptide Nucleic Acids/chemical synthesis , Azetidinecarboxylic Acid/chemical synthesis , Oxazoles/chemistry , StereoisomerismABSTRACT
To study the structure-activity relationship of mugineic acid (MA), a phytosiderophore isolated from Hordeum velugare L. var. Minorimugi, several 2-deoxymugineic acid (DMA) analogues were synthesized. 1H-NMR spectra of DMA analogues and their Co(III) complexes were first measured and analyzed to elucidate the structures of metal complexes. CD spectra of the Co(III) and Fe(III) complexes of DMA analogues were then measured and compared with those of MA. Furthermore, the interaction between the Fe(III) complexes of DMA analogues and the phytosiderophore-Fe(III) complex transporter found in maize was examined.
Subject(s)
Azetidinecarboxylic Acid/analogs & derivatives , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/chemistry , Azetidinecarboxylic Acid/pharmacology , Cobalt , Ferric Compounds/metabolism , Hordeum/chemistry , Membrane Transport Proteins , Nuclear Magnetic Resonance, Biomolecular , Siderophores , Structure-Activity Relationship , Zea maysABSTRACT
[reaction: see text] Facile and straightforward syntheses of both enantiomers of azetidine-2-carboxylic acid are described. The syntheses depart from inexpensive chemicals and allow for the production, in five to six steps, of practical quantities of each enantiomer. Synthetic highlights include the construction of the azetidine ring using an intramolecular alkylation and the use of optically active alpha-methylbenzylamine as chiral auxiliary.
Subject(s)
Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/analogs & derivatives , Azetidinecarboxylic Acid/chemistry , Molecular Structure , StereoisomerismABSTRACT
A new and efficient route to (S)-azetidine-2-carboxylic acid (>99.9% ee) in five steps and total yield of 48% via malonic ester intermediates was established. As the key step, efficient four-membered ring formation (99%) was achieved from dimethyl (S)-(1'-methyl)benzylaminomalonate by treating with 1,2-dibromoethane (1.5 eq) and cesium carbonate (2 eq) in DMF. Krapcho dealkoxycarbonylation of dimethyl (1'S)-1-(1'-methyl)benzylazetidine-2,2-dicarboxylate, the product of this cyclization procedure, proceeded with preferential formation (2.7:1, 78% total yield) of the desired (2S,1'S)-monoester, with the help of a chiral auxiliary which was introduced on the nitrogen atom. The undesired (2R,1'S)-isomer could be converted to that with proper stereochemistry, by a deprotonation and subsequent re-protonation step. Finally, lipase-catalyzed preferential hydrolysis of the (2S,1'S)-monoester and subsequent deprotection provided enantiomerically pure (S)-azetidine-2-carboxylic acid in a 91% yield from the mixture of (2S,1'S)- and (2R,1'S)-isomers.
Subject(s)
Azetidinecarboxylic Acid/chemical synthesis , Amino Acids, Cyclic/chemical synthesis , Cyclization , StereoisomerismABSTRACT
A new synthetic method for the preparation of allyl amines has been developed. The key steps of this method are enantioselective addition of diethylzinc and [1,3]-chirality transfer through the [3.3] sigmatropic rearrangement of allyl cyanates. Stereocontrolled syntheses of lentiginosine (1) and polyoxamic acid derivative 2 from a common intermediate 7 derived from D-tartaric acid (8), have been accomplished.
Subject(s)
Alkaloids/chemical synthesis , Allyl Compounds/chemical synthesis , Amines/chemical synthesis , Azetidinecarboxylic Acid/analogs & derivatives , Organometallic Compounds/chemistry , Oxamic Acid/chemical synthesis , Alkaloids/chemistry , Allyl Compounds/chemistry , Amines/chemistry , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/chemistry , Molecular Structure , Oxamic Acid/analogs & derivatives , Oxamic Acid/chemistry , StereoisomerismABSTRACT
The non-natural enantiomer of polyoxamic acid was synthesized in six steps from 2,3-aziridino-gamma-lactone 7 with an overall yield of 10%. The key step of the strategy is a deprotection-protection sequence on the nitrogen atom of the aziridine ring required for aziridine activation toward nucleophilic ring opening.
Subject(s)
Azetidinecarboxylic Acid/analogs & derivatives , Azetidinecarboxylic Acid/chemical synthesis , Chemistry, Organic/methods , Lactones/chemistry , Azetidinecarboxylic Acid/chemistry , Models, Chemical , Molecular Structure , StereoisomerismABSTRACT
Enantiopure L-azetidine-2-carboxylic acid, the (3R)-phenyl, (3R)-naphthyl and (3S)-isopropyl analogs were prepared based on a zinc-mediated asymmetric addition of allylic halides to the camphor sultam derivative of glyoxylic acid O-benzyl oxime.
Subject(s)
Alanine/analogs & derivatives , Azetidinecarboxylic Acid/chemical synthesis , Leucine/chemistry , Phenylalanine/chemistry , Alanine/chemistry , Azetidinecarboxylic Acid/chemistry , Molecular StructureABSTRACT
A formal asymmetric synthesis of Mugineic acid was accomplished from cis-2-butene-1,4-diol through catalytic Sharpless epoxidation oxidations and coupling reaction.
Subject(s)
Azetidinecarboxylic Acid/analogs & derivatives , Oxazoles/chemistry , Amino Acids/chemistry , Azetidinecarboxylic Acid/chemical synthesis , Epoxy Compounds/chemistry , Homoserine/chemistryABSTRACT
A series of stereochemically pure 7-(3-amino-2-methyl-1-azetidinyl)-1,4- dihydro-6-fluoro-4-oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, was prepared to determine the effects of chirality on potency and in vivo efficacy relative to the racemic mixtures (for part 2, see: J. Med. Chem. 1994, 37, 4195-4210). A series of chiral 9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-(substituted-1- azetidinyl)-7H-pyrido[1,2,3- de]-1,4-benzoxazine-6-carboxylic acids was synthesized to study the effect of the azetidine moiety on tricyclic quinolone antibacterial agents. A series of amino acid prodrugs of chiral naphthyridines 24a and 24b and quinolone 33a (cetefloxacin) was prepared and evaluated for antibacterial activity, solubility, and pharmacokinetic behavior. The absolute configuration of the new azetidinylquinolones was established by X-ray analysis of one of the diastereomeric salts of the resolved azetidinols (15) and of compound 25a (E-4767), which showed the best in vitro and in vivo overall profile. Structure-activity relationship studies indicated that the absolute stereochemistry at the asymmetric centers of both the azetidine and the oxazine rings was critical to increase in vitro activity and oral efficacy. The 3S configuration in the pyridobenzoxazine series and the (2S,3R) configuration of the 3-amino-2-methylazetidine moiety for all new compounds conferred the best antibacterial activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Azetidinecarboxylic Acid/analogs & derivatives , Quinolones/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Azetidinecarboxylic Acid/chemical synthesis , Azetidinecarboxylic Acid/chemistry , Azetidinecarboxylic Acid/pharmacokinetics , Chemical Phenomena , Chemistry, Physical , Crystallography, X-Ray , Escherichia coli Infections/drug therapy , Mice , Microbial Sensitivity Tests , Molecular Structure , Pseudomonas Infections/drug therapy , Quinolones/chemical synthesis , Quinolones/chemistry , Quinolones/pharmacokinetics , Staphylococcal Infections/drug therapy , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Azetidine-2-carboxylic acid, the 4-membered ring noranalogue of proline, is regularly used in the study of proline metabolism as well as the study of protein conformation. We prepared D,L-[2,3-3H]azetidine-2-carboxylic acid with an optimized 10% yield from commercially available 4-amino-[2,3-3H]butyric acid. Purification was performed by fast-protein liquid chromatography. The biological activity was checked in both Arabidopsis thaliana and Escherichia coli. The obtained specific activity of 10 mCi/mmol was sufficient for most uptake and incorporation studies.