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PubMed2006

Reduction of 4-(haloalkyl)azetidin-2-ones with LiAlH4 as a powerful method for the synthesis of stereodefined aziridines and azetidines.

[reaction: see text] A new synthesis of stereodefined aziridines and azetidines, starting from 4-(1- or 2-haloalkyl)azetidin-2-ones, is described. Treatment of the latter compounds with LiAlH(4) gave 1,2-fission of the beta-lactam, followed by an intramolecular nucleophilic substitution of the halogen, giving rise to the formation of 2-(1-alkoxy-2-hydroxyethyl)aziridines in the case of 4-(1-haloalkyl)azetidin-2-ones and of 2-(1-alkoxy-2-hydroxyethyl)azetidines in the case of 4-(2-haloalkyl)azetidin-2-ones. The resulting 2-(1-alkoxy-2-hydroxyethyl)aziridines were transformed into the corresponding trans-3,4-substituted oxolanes via an intramolecular nucleophilic ring opening, triggered by AlCl(3).

Journal Article↗
PubMed2005

Amino acid-azetidine chimeras: synthesis of enantiopure 3-substituted azetidine-2-carboxylic acids.

Azetidine-2-carboxylic acid (Aze) analogs possessing various heteroatomic side chains at the 3-position have been synthesized by modification of 1-9-(9-phenylfluorenyl) (PhF)-3-allyl-Aze tert-butyl ester (2S,3S)-1. 3-Allyl-Aze 1 was synthesized by regioselective allylation of alpha-tert-butyl beta-methyl N-(PhF)aspartate 13, followed by selective omega-carboxylate reduction, tosylation, and intramolecular N-alkylation. Removal of the PhF group and olefin reduction by hydrogenation followed by Fmoc protection produced nor-leucine-Aze chimera 2. Regioselective olefin hydroboration of (2S,3S)-1 produced primary alcohol 23, which was protected as a silyl ether, hydrogenated and N-protected to give 1-Fmoc-3-hydroxypropyl-Aze 26. Enantiopure (2S,3S)-3-(3-azidopropyl)-1-Fmoc-azetidine-2-carboxylic acid tert-butyl ester 3 was prepared as a Lys-Aze chimera by activation of 3-hydroxypropyl-Aze 26 as a methanesulfonate and displacement with sodium azide. Moreover, orthogonally protected azetidine dicarboxylic acid 4 was synthesized as an alpha-aminoadipate-Aze chimera by oxidation of alcohol 26. These orthogonally protected amino acid-Aze chimeras are designed to serve as tools for studying the influence of conformation on peptide activity.

Amino Acids↗
PubMed2002

Unexpected formation of an azetidine-carborane derivative by dehydration of N-(1,12-dicarba-closo-dodecaboran-1-yl)formamide. The first X-ray structure of a 2,3-bis(imino)azetidine.

Efforts to dehydrate (1,12-dicarba-closo-dodecaboran(12)-1-yl)formamide (a = 6.685(2) A, b = 12.877(4) A, c = 12.547(4) A, alpha = gamma = 90 degrees, beta = 90.724(11) degrees, V = 1080.8(6) A(3), Z = 4) resulted in the formation of a series of unexpected products. Addition of the Burgess reagent to the formamide, for example, led to the isolation of the corresponding methyl carbamate (a = 11.529(8) A, b = 11.529(8) A, c = 11.402(12) A, alpha = beta = gamma = 90 degrees, V = 1516(2) A(3), Z = 4), while treatment with triphosgene, a well-known dehydrating agent, resulted in the formation of a highly unusual 2,3-bis(p-carboranylimino)azetidine derivative. This particular compound, in the presence of Re(I), was hydrolyzed to give the corresponding amide, which is the first example of a 2,3-bis(imino)azetidine that has been characterized crystallographically (a = 38.496(13) A, b = 11.920(4) A, c = 27.523(10) A, beta = 127.050(5) degrees, V = 10079(6) A(3), Z = 8).

Journal Article↗
PubMed1975

Incorporation of L-azetidine-2-carboxylic acid into hemoglobin in rabbit reticulocytes in vitro.

L-Azetidine-2-carboxylic acid is the naturally occurring lower homologue of L-proline. Reticulocytes from anemic rabbits incubated with DL-[14-C]azetidine-2-carboxylic acid synthesized radiolabeled hemoglobin, which when isolated from cell lysates co-chromatographed with unlabeled hemoglobin on Sephadex G-100 columns. Amino acid analysis of hemoglobin from reticulocytes incubated with DL-[14-C]-azetidine-2-carboxylic acid suggested that the homologue was incorporated into hemoglobin intact and unaltered. Alternatively, another amino acid analogue, 1-aminocyclopentane-[1-14-C]carboxylic acid, which is purported to be a valine antagonist, was not incorporated into hemoglobin under these conditions. Incubation of reticulocytes with 1, 5, and 10 mM L-azetidine-2-carboxylic acid reduced L-[U-14-C]proline (0.10 mM) incorporation into hemoglobin by 25, 58, and 72%, respectively. Conversely, 1.45 and 145 muM L-proline reduced radiolabeled azetidine-2-carboxylic acid (0.8 mM) in corporation into hemoglobin by 45 and 92%, respectively. Incorporation of L-[U-14-C]leucine and L-[U-14-C]lysine (0.1 mM each) into hemoglobin was unaffected at these concentrations of L-azetidine-2-carboxylic acid. These results suggest that L-azetidine-2-carboxylic acid is incorporated into hemoglobin without reducing the rate of globin synthesis in rabbit reticulocytes in vitro. The alpha and beta chains of hemoglobin into which [14-C]azetidine-2-carboxylic acid had been incorporated in rabbit reticulocytes in vitro were resolved electrophoretically on sodium dodecyl sulfate-polyacrylamide gels. The ratio of total radioactivity in the alpha and beta chains separately extracted from gels was in good agreement with the known 7:4 ratio of prolyl residues in the respective chains. Autoradiograms of two-dimensional tryptic peptide maps of rabbit globin into which either [14-C]azetidine-2-carboxylic acid or [14-C]proline had been incorporated showed nearly identical patterns of radioactivity. These results suggest that azetidine-2-carboxylic acid substitutes specifically for prolyl residues during in vitro hemoglobin synthesis in rabbit reticulocytes.

Amino Acids↗
PubMedDate not supplied

Heat shock response by cells treated with azetidine-2-carboxylic acid.

The purpose of this study is to reinvestigate the heat shock response in cells treated with the antimetabolite azetidine-2-carboxylic acid (azetidine), an analogue of proline. Previous studies could not clearly discriminate between the progressive thermosensitization caused by amino acid analogues and a parallel induction of thermotolerance by heat shock. Incubation of H35 cells with 2.5 mm azetidine causes an increasing thermosensitization which achieves a maximum after approximately 18-22 h. At this point, azetidine does not prevent the development of acute thermotolerance following a heat shock at 42.5 degrees C, or the simultaneous induction of chronic thermotolerance during mild hyperthermia at 38-41 degrees C. However, for both the acute and chronic heating conditions thermotolerance levels are reduced in proportion with azetidine-thermosensitization. Incorporation of azetidine causes an apparent downward temperature shift of approximately 1 degree C relative to the time-temperature relationships for normal, or following heat shocks, for thermotolerant cells. After 18 h of incubation with azetidine, protein synthesis is reduced by a factor of 4 and cells show a preferential synthesis of heat shock proteins (hsp). A heat shock then, although inducing thermotolerance, is not followed by any noticeable effect on the synthesis of hsps. It is shown that the combination of prolonged azetidine treatment and heat shock causes a persistent inhibition of protein synthesis. This is hypothesized to result in the development of hsp synthesis independent thermotolerance. Additional treatment following heat shock in azetidine-treated cells with the protein synthesis inhibitor cycloheximide does not affect the induction of thermotolerance. In contrast to the heat shock response, no thermotolerance induction is observed in azetidine-treated cells after an exposure to sodium arsenite.

Animals↗
PubMed1976

Incorporation of L-azetidine-2-carboxylic acid into hemoglobin S in sickle erythrocytes in vitro.

L-Azetidine-2-carboxylic acid, the naturally occurring lower homologue of L-proline, is incorporated into hemoglobin S (sickle hemoglobin) in vitro. Sickle erythrocytes from patients with sickle cell anemia incubated with L-[3H] azetidine-2-carboxylate synthesized radiolabeled hemoglobin which when isolated from cell lysates, co-chromatographed with hemoglobin S on DEAE-cellulose columns. The alpha/beta ratio of azetidine carboxylate incorporation into the globin chains of sickle hemoglobin was 0.94, which is consistent with the presence of four proline residues in each polypeptide chain. Incorporation of azetidine carboxylate into hot trichloroacetic acid-insoluble material in sickle erythrocytes indicated that the homologue was present in the polypeptide backbone of the globin chains of sickle hemoglobin. Amino acid analysis of the hot trichloroacetic acid-insoluble material from sickle erythrocytes which had been incubated with radiolabeled azetidine carboxylate indicated that 75% of the radioactivity could be accounted for as intact homologue while 20% of the radioactivity co-chromatographed with alanine. These results suggest that azetidine carboxylate is incorporated unaltered into hemoglobin S in addition to being metabolized to alanine in sickle erythrocytes prior to incorporation into protein. The kinetics of thermal precipitation of hemoglobin S (oxygen ligand) into which radioactive azetidine carboxylate or radioactive proline had been incorporated in vitro is identical. This observation, together with the behavior of hemoglobin S and the globin chains from hemoglobin S containing azetidine carboxylate during ion-exchange chromatography, indicates that homologue replacement of prolyl residues does not significantly alter the overall charge or stability of the hemoglobin S tetramer. Azetidine carboxylate did not inhibit uptake of radiolabeled proline by sickle erythrocytes suggesting that the homologue does not adversely affect amino acid transport in these cells.

Amino Acids↗
PubMed1996

Physiological and pharmacological profile of trans-azetidine-2,4-dicarboxylic acid: metabotropic glutamate receptor agonism and effects on long-term potentiation.

In this study, we biochemically analysed the effects of the novel metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid and examined its role in hippocampal long-term potentiation. In cell lines expressing metabotropic receptor 1 or 5 subtypes, the compound stimulated phosphoinositide hydrolysis with EC50 values of 189.4 +/- 6.4 and 32.2 +/- 8.3 microM, respectively. In hippocampal slices, trans-azetidine-2,4-dicarboxylic acid also increased phosphoinositide hydrolysis, yet failed to show any effect on forskolin-stimulated formation of cyclic AMP, even if 1 mM azetidine was applied. Since trans-azetidine-2,4-dicarboxylic acid (20 mM in 5 microliters) injected cerebroventricularly prolongs long-term potentiation induced by weak tetanization, a possible interaction with N-methyl-D-aspartate receptors was investigated using patch-clamp techniques. Neither facilitation of N-methyl-D-aspartate (500 microM) currents nor induction of non-specific currents was observed in the presence of 50 and 500 microM azetidine. Strong tetanus-induced long-term potentiation in the dentate gyrus of freely moving rats was not influenced by azetidine. In combination with the antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (200 mM in 5 microliters), however, the potentiation was attenuated and returned to baseline within 90 min. Blockade of N-methyl-D-aspartate receptors using 2-amino-5-phosphonopentanoate (20 mM in 5 microliters) prevented the potentiation in controls, but not in the azetidine group, where normal potentiation was observed for both the population spike amplitude and the excitatory postsynaptic potential. These data suggest that (i) trans-azetidine-2,4- dicarboxylic acid is an agonist at glutamate metabotropic receptors; (ii) a facilitation of induction and maintenance of long-term potentiation via N-methyl-D-aspartate receptors seems unlikely; and (iii) pharmacological activation of metabotropic receptors prior to tetanization appears to bypass the N-methyl-D-aspartate receptor dependence of the potentiation. In conclusion, a role for metabotropic glutamate receptors in both short-term and long-term potentiation is indicated by these data.

Animals↗
PubMed2005

Azetidinic amino acids: stereocontrolled synthesis and pharmacological characterization as ligands for glutamate receptors and transporters.

A set of ten azetidinic amino acids, that can be envisioned as C-4 alkyl substituted analogues of trans-2-carboxyazetidine-3-acetic acid (t-CAA) and/or conformationally constrained analogues of (R)- or (S)-glutamic acid (Glu) have been synthesized in a diastereo- and enantiomerically pure form from beta-amino alcohols through a straightforward five step sequence. The key step of this synthesis is an original anionic 4-exo-tet ring closure that forms the azetidine ring upon an intramolecular Michael addition. This reaction was proven to be reversible and to lead to a thermodynamic distribution of two diastereoisomers that were easily separated and converted in two steps into azetidinic amino acids. Azetidines 35-44 were characterized in binding studies on native ionotropic Glu receptors and in functional assays at cloned metabotropic receptors mGluR1, 2 and 4, representing group I, II and III mGlu receptors, respectively. Furthermore, azetidine analogues 35, 36, and 40 were also characterized as potential ligands at the glutamate transporter subtypes EAAT1-3 in the FLIPR Membrane Potential (FMP) assay. The (2R)-azetidines 35, 37, 39, 41 and 43 were inactive in iGlu, mGlu and EAAT assays, whereas a marked change in the pharmacological profile at the iGlu receptors was observed when a methyl group was introduced in the C-4 position, compound 36 versus t-CAA. At EAAT1-3, compound 35 was inactive, whereas azetidines 36 and 40 were both identified as inhibitors and showed selectivity for the EAAT2 subtype.

Amino Acid Transport System X-AG↗
PubMed1999

Effects of azetidine-2-carboxylic acid on treatments of hepatoma cells with single or fractionated X-ray irradiations and on thermal radiosensitization in normal and thermotolerant cells.

The amino acid analog azetidine-2-carboxylic acid (azetidine) is a potent sensitizer to both hyperthermia and ionizing radiation. Incubation of H35 hepatoma cells with 2.5 mM azetidine before or after treatments with X-rays causes a time- and sequence-dependent enhancement of cell killing. Exposure of cells to 1-1.5 mM azetidine for 96 h in combination with repeated doses of 3 Gy X-rays at 24 h intervals causes an enhanced reduction of the surviving cell population due to both radiosensitization and an additional growth inhibition. Azetidine does not prevent the induction of thermotolerance after a heat shock. This thermotolerance proportionally reduces thermal radiosensitization but does not seem to affect azetidine radiosensitization. It is suggested that thermal radiosensitization and azetidine radiosensitization operate by different mechanisms.

Animals↗
PubMed1995

Profiling of trans-azetidine-2,4-dicarboxylic acid at the human metabotropic glutamate receptors mGlu1b, -2, -4a and -5a.

We have tested the two enantiomers of trans-azetidine-2,4-dicarboxylic acid, (2S,4S)-azetidine-2,4-dicarboxylic acid ((2S,4S)-ADA) and (2R,4R)-azetidine-2,4-dicarboxylic acid ((2R,4R)-ADA) for activity at the human metabotropic glutamate receptors mGlu1b, mGlu2, mGlu4a and mGlu5a expressed in mammalian cells. In Chinese hamster ovary (CHO) cells expressing human mGlu2 receptors, 500 microM (2S,4S)-ADA inhibited forskolin-stimulated cAMP accumulation by 33 +/- 3% while 100 microM (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid induced an inhibition by 66 +/- 5%. The (2R,4R)-ADA enantiomer was inactive at human mGlu2 receptors. In CHO cells expressing human mGlu4a receptors, 10 microM L-AP4 inhibited forskolin-stimulated cAMP levels by 37 +/- 4% whereas both ADA enantiomers of trans-azetidine-2,4-dicarboxylic acid (500 microM) had no such effect. In CHO cells expressing human mGlu1b receptors and L cells expressing human mGlu5a receptors, both enantiomers, applied at 500 microM or 1 mM, were ineffective in stimulating inositolmonophosphate accumulation and did not affect quisqualate-stimulated inositolmonophosphate accumulation. We conclude that (2S,4S)-azetidine-2,4-dicarboxylic acid is a weak human mGlu2 receptor agonist and that (2R,4R)-azetidine-2,4-dicarboxylic acid is inactive at human mGlu2 receptors. Trans-azetidine-2,4-dicarboxylic acid has no significant agonistic effect on human mGlu4a receptors and neither agonistic nor antagonistic effects on human mGlu1b and mGlu5a receptors.

Animals↗
PubMed2006

Synthesis and structure of novel conformationally constrained 1',2'-azetidine-fused bicyclic pyrimidine nucleosides: their incorporation into oligo-DNAs and thermal stability of the heteroduplexes.

[structures: see text] The synthesis of novel 1',2'-aminomethylene bridged (6-aza-2-oxabicyclo[3.2.0]heptane) "azetidine" pyrimidine nucleosides and their transformations to the corresponding phosphoramidite building blocks (20, 39, and 42) for automated solid-phase oligonucleotide synthesis is reported. The novel bicyclonucleoside "azetidine" monomers were synthesized by two different strategies starting from the known sugar intermediate 6-O-benzyl-1,2:3,4-bis-O-isopropylidene-D-psicofuranose. Conformational analysis performed by molecular modeling (ab initio and MD simulations) and NMR showed that the azetidine-fused furanose sugar is locked in a North-East conformation with pseudorotational phase angle (P) in the range of 44.5-53.8 degrees and sugar puckering amplitude (phi(m)) of 29.3-32.6 degrees for the azetidine-modified T, U, C, and 5-Me-C nucleosides. Thermal denaturation studies of azetidine-modified oligo-DNA/RNA heteroduplexes show that the azetidine-fused nucleosides display improved binding affinities when compared to that of previously synthesized North-East sugar constrained oxetane fused analogues.

Azetidines↗
PubMed1990

Synthesis and peptide bond orientation in tetrapeptides containing L-azetidine-2-carboxylic acid and L-proline.

The role of the amino acid proline in influencing the secondary and tertiary structure of proteins and polypeptides has been an area of active study for many years. We have investigated this problem by incorporating the four-membered ring amino acid, azetidine-2-carboxylic acid, into some proline polypeptides. An adjunct to the synthesis of the peptides was the synthesis of azetidine-2-carboxylic acid and its resolution. We developed an improved synthesis of N-benzhydryl-2-carbobenzyloxy azetidine, an essential intermediate required for the synthesis of L-azetidine-2-carboxylic acid. This amino acid was subsequently obtained via the partial hydrogenation of the N-benzhydryl compound, under mild conditions. Our ability to isolate the intermediate N-benzhydryl-2-carboxylic acid demonstrated that the rate of cleavage of the O-benzyl ester group in this molecule is faster than the cleavage of the N-benzhydryl group. The tetrapeptides, Boc-(L-Pro)3-L-Aze-Opcp, and Boc-(L-Aze-L-Pro)2-Opcp (Boc: t-butoxycarbonyl; Pro: proline; Aze: azetidine-2-carboxyl acid; Opcp: pentachlorophenyl), were prepared using traditional solution peptide synthesis. They were characterized by direct chemical ionization-mass spectrometry, CD spectra, and 13C- and 1H-nmr spectroscopy. The assessment of the secondary structure of the two peptides using the methods noted above has led us to conclude that the compound Boc-(L-Aze-L-Pro)2-Opcp, in trifluoroethanol, has an all-cis peptide bond conformation with phi and psi torsion angles compatible with a left-handed helix. The secondary structure assessment of the peptide Boc-(L-Pro)3-L-Aze-Opcp, in chloroform or trifluoroethanol, leads to an assignment of both cis and trans peptide bonds as being present in the peptide. We have interpreted this latter finding as indicating that the introduction of the azetidine group into a peptide containing three consecutive proline residues in a linear sequence perturbs the normal proline peptide secondary structure in this tetrapeptide.

Azetidinecarboxylic Acid↗
PubMed1985

Structural changes of hair after incorporation of the proline analogue L-azetidine-2-carboxylic acid. A model of hair disease by alteration of primary structure.

In order to correlate biochemical changes of the hair with physical properties we present a model for the examination techniques. L-azetidine was incorporated into the hair keratin complex and the resulting mechanoelastic properties were determined using the ultramicrohardness testing system on scanning electron microscopy. Structure was investigated by X-ray diffraction and incorporation of L-azetidine was detected by thin-layer chromatography. This system could possibly be introduced for examination of hair changes in humans. 8 white mice, 3 weeks of age, were given L-azetidine-2-carboxylic acid in water (0.1 g/100 ml) as only source of fluid over a period of 5 weeks. They had free access to dry mouse cake only. 8 animals of the same strain, who had free access to tap water and mouse cake and were kept under the same conditions, served as controls. After 5 weeks, the animals were sacrificed and hair was obtained for analyses. 2 dimensional thin-layer chromatography of hair hydrolyzed with 6N HCl at 105 degrees C for 12 hours revealed 2 additional spots in the chromatographic pattern in the experimental animals in comparison with the control group. 1 of the spots was identified as L-azetidine-2-carboxylic acid, while the second spot was possibly a degradation product of L-azetidine on acid hydrolysis at a high temperature. Hair of the animals was put into Mark capillaries and subjected to X-ray diffraction, which showed a markedly disordered orientation of keratin. Impression studies using scanning electron microscopy revealed a remarkably reduced elasticity of hair with incorporated L-azetidine. These findings may be explained on the basis of qualitative or quantitative changes in the helical structure of the keratin complex of hair, which is responsible for the elastic properties, whereas the globular matrix is responsible for the firmness of the hair.

Animals↗
PubMed1997

Reactions of N-(Ethoxycarbonyl)-3-halo-3-(halomethyl)azetidines with DBU. The Halogen Dance.

Reaction of N-(ethoxycarbonyl)-3-(bromomethyl)-3-chloroazetidine (3) with DBU results in the formation of two haloalkenes, i.e., N-(ethoxycarbonyl)-3-(bromomethylene)azetidine and N-(ethoxycarbonyl)-3-(chloromethylene)azetidine (4a and 4b, respectively). The results of control experiments suggest that Cl(-) is capable of promoting nucleophilic displacement of bromine in the CH(2)Br groups of both 3 and N-(ethoxycarbonyl)-3-bromo-3-(bromomethyl)azetidine (8), but Br(-) is incapable of displacing chlorine in the CH(2)Cl groups of both N-(ethoxycarbonyl)-3-chloro-3-(chloromethyl)azetidine (7) and N-carbethoxy-3-bromo-3-(chloromethyl)azetidine (10). Thus, it is suggested that the formation of 4b via reaction of 3 with DBU is a result of DBU-promoted elimination of HCl from 7, a key reaction intermediate. The observations reported herein can be explained without invoking the intermediacy of any bridged halonium ion.

Journal Article↗
PubMed1998

Alkyne-Co(2)(CO)(6) Complexes in the Synthesis of Fused Tricyclic beta-Lactam and Azetidine Systems(,)(1).

A synthetic approach to racemic and enantiomerically pure, fused tricyclic 2-azetidinones and azetidines has been developed by using a Pauson-Khand (P-K) reaction on monocyclic enyne-beta-lactams as the key synthetic step. The access to cyclization precursors, monocyclic beta-lactams 1-7, was achieved by Staüdinger reaction of enyne imines 8 and 9 and D-glyceraldehyde imines 10 and (benzyloxy)- or phenoxyacetyl chlorides. Enyne imines 8 and 9 formed cis-2-azetidinones 1 and 2 having the required enyne moiety. cis-2-Azetidinones 11 were obtained as single diastereomers and transformed to enyne-2-azetidinones 3 and 5 by standard methodology. Alternatively, 4-formyl-2-azetidinones 14 were prepared by cyclization of p-anisyl glyoxal diimine and (benzyloxy)acetyl chloride and converted to racemic enyne-beta-lactams 4 and 6 by standard reactions. Enyne-2-azetidinones 1-7 were reacted with Co(2)(CO)(8) to quantitatively yield the corresponding alkyne-Co(2)(CO)(6) complexes. Reaction of such complexes with different promoters, especially heat and TMANO, formed tricyclic 2-azetidinones 15-19 with the ring system fused to the C3-C4 and C4-N1 lactam bonds. Yields were usually high, and the processes were highly diastereoselective. The exceptions were enyne-2-azetidinones 2 and 3a bearing N-propargyl moieties. These products decomposed to mixtures of unidentifiable products. Inhibition of the amide resonance was postulated as responsible for the failure of beta-lactams 2 and 3a to form tricyclic systems. In fact, the analogous enyne-azetidines 20a,b smoothly cyclized to form the corresponding tricyclic systems. This approach to tricyclic azetidines was extended to prepare different products. A new, unprecedented, N1-C2 bond breakage was also observed in the azetidine ring. The results described show that the P-K reaction is a suitable approach to tricyclic 2-azetidinones and azetidines. These are the first examples reported for a P-K reaction in with the enyne system is tethered to a strained heterocyclic four-membered ring.

Journal Article↗
PubMed1975

Effect of L-azetidine 2-carboxylic acid on growth and proline metabolism in Escherichia coli.

The effects of L-azetidine 2-carboxylic acid on growth and proline metabolism in a proline-requiring auxotroph of Escherichia coli are described. The homologue inhibited growth of the wild type and it, alone, did not substitute effectively for proline as a growth supplement for the mutant. In medium containing 0.05 mM proline, the addition of increasing amounts of homologue progressively inhibited growth of the wild type but stimulated growth of the mutant at homologue: proline ratios of 10 : 1 and 50 : 1. This suggested that the homologue exerted a "sparing effect" on proline in the mutant. The incorporation of L-[U-14C]proline and L-[3H]azetidine 2-carboxylic acid into hot trichloroacetic acid-insoluble material in the mutant was measured. Amino acid analysis of the insoluble material from cells incubated with radiolabeled proline alone revealed that proline was partially degraded and metabolized to other amino acids prior to incorporation into protein. The addition of unlabeled homologue to the incubation medium significantly reduced proline catabolism, suggesting that the homologue exerted a sparing effect on proline in this mutant. In medium containing unlabeled proline and radiolabeled L-azetidine 2-carboxylic acid, the homologue was incorporated both intact and partially degraded prior to incorporation into protein. Alanine was the major L-azetidine 2-carboxylic acid catabolite.

Amino Acids↗
PubMed1976

Effect of L-azetidine-2-carboxylic acid on glycosylations of collagen in chick-embryo tendon cells.

The glycosylations of hydroxylysine during collagen biosynthesis in isolated chick-embryo tendon cells were studied by using pulse-chase labelling experiments with [14C]-lysine. The hydroxylation of lysine and the glycosylations of hydroxylysine continued after a 5 min pulse label for up to about 10 min during the chase period. These data differ from those obtained previously in isolated chick-embryo cartilage cells, in which, after a similar 5 min pulse label, these reactions continued during the chase period for up to about 20 min. The collagen synthesized by the isolated chick-embryo tendon cells differed markedly from the type I collagen of adult tissues in its degree of hydroxylation of lysine residues and glycosylations of hydroxylysine residues. When the isolated tendon cells were incubated in the presence of L-azetidine-2-carboxylic acid, the degree of glycosylations of hydroxylysine during the first 10 min of the chase period was identical with that in cells incubated without thcarboxylic acid for at least 60 min, whereas no additional glycosylations took place in the control cells after the 10 min time-point. As a consequence, the collagen synthesized in the presence of this compound contained more carbohydrate than did the collagen synthesized by the control cells. Additional experiments indicated that azetidine-2-carboxylic acid did not increase the collagen glycosyltransferase activities in the tendon cells or the rate of glycosylation reactions when added directly to the enzyme incubation mixture. Control experiments with colchicine indicated that the delay in the rate of collagen secretion, which was observed in the presence of azetidine-2-carboxylic acid, did not in itself affect the degree of glycosylations of collagen. The results thus suggest that the increased glycosylations were due to inhibition of the collagen triple-helix formation, which is known to occur in the presence of azetidine-2-carboxylic acid.

Animals↗
PubMed1987

Receptor binding characteristics of a 3H-labeled azetidine analogue of nicotine.

A new radioligand, (+/-)-[3H]-1-methyl-2-(3-pyridyl)-azetidine, which is an analogue of nicotine, has been used to investigate the binding characteristics of the nicotine receptor in rat brain membranes. By Scatchard analysis, the azetidine analogue yielded a curvilinear plot with Kd values of 7 X 10(-11) and 1.7 X 10(-9) M and Bmax values of 0.3 X 10(-14) and 2.5 X 10(-14) mol/mg protein respectively. Thermodynamic analyses yielded negative free enthalpy values for both sites, a decrease in the Bmax of only the lower affinity site, and no effect on either Kd. The psychotropic potency (prostration in rats following intraventricular injection) of the azetidine analogue was about 5-fold greater than (-)-nicotine, being among the greatest of any known nicotine analogues tested to date. Since only the higher affinity Kd differed from that of (-)-nicotine, 3-fold greater, the psychotropic potency appears to be correlated with the higher affinity site. Insofar as [3H]methylcarbamylcholine, a nicotinic ligand resembling acetylcholine, exhibits a linear Scatchard with a Kd of 1 X 10(-9) M, the higher affinity site appears to be characteristic of nicotine analogues.

Animals↗