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PubMed2006

Ring transformation of 2-(haloalkyl)azetidines into 3,4-disubstituted pyrrolidines and piperidines.

[reaction: see text] Reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane (AlH(2)Cl) afforded new 2-(haloalkyl)azetidines in high yields. The latter compounds proved to be very useful starting materials for rearrangements toward stereospecifically defined five- and six-membered azaheterocycles, such as 3,4-cis-disubstituted pyrrolidines and piperidines. During these reactions, bicyclic azetidinium intermediates were formed which were ring opened by a variety of nucleophiles. Hereby, reactions proceeding via 1-azoniabicyclo[2.2.0]hexanes are reported for the first time.

Journal Article↗
PubMed2006

Reaction of azetidines with chloroformates.

The reaction of an azetidine with a chloroformate can give either the dealkylated heterocycle or the ring-opened product (gamma-chloroamine), which can further cyclize to the oxazinanone. A general study of this underrated reaction was conducted and revealed that azetidines can undergo smooth nucleophilic ring-opening reactions to highly functionalized gamma-chloroamines in the presence of a variety of alkyl chloroformates under mild reaction conditions. Yields are usually good, and parameters governing this reaction were evaluated. [reaction: see text].

Journal Article↗
PubMed2005

Efficient route to (S)-azetidine-2-carboxylic acid.

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.

Amino Acids, Cyclic↗
PubMed1999

[Determination of the azetidine-2-carboxylic acid from lily of the valley].

This paper reports the separation and determination of the azetidine-2-carboxylic acid in lily of the valley by high performance liquid chromatography (HPLC) with post-column derivatization and fluorescence detection. The operating conditions were cation exchange resin column (30 cm x 0.4 cm i.d.) with buffer solution A [1.96% (mass fraction) sodium citrate solution pH 3.10 +/- 0.02] and B [2.1% (mass fraction) sodium nitrate solution pH 9.60 +/- 0.02] as mobile phase at flow-rate of 0.4 mL/min, gradient elution, column temperature 65 degrees C, detection wavelength lambda ex = 338 nm and lambda em = 425 nm. The retention time of azetidine-2-carboxylic acid was 5.86 minutes. The recovery was 96.4% and coefficient of variation was 0.94%. This method is simple, rapid and sensitive.

Azetidinecarboxylic Acid↗
PubMed1975

[The effect of an L-proline analogue, L-azetidine-2-carboxylic acid, on the phenotypic differentiation of the somite mesenchyme of chick embryos].

L-azetidine has been utilized in vivo and in vitro. In vivo, the substance is injected into the yolk sac of young embryos. It inhibits the secretion of the periaxial extracellular material resulting in a lack of several vertebrae. In young vertebral primordia, cultured on L-azetidine, the myotome cells differentiate into myoblasts whereas the sclerotome cells remain undifferentiated. In older primordia, the sclerotome cells give rise to abnormal cartilage but the myotome cells seldom differentiate.

Age Factors↗
PubMed2002

A novel one-step approach for the preparation of alpha-amino acids, alpha-amino amides, and dipeptides from azetidine-2,3-diones.

A remarkable reaction of azetidine-2,3-diones with primary as well as secondary amines, and water is presented. Simply by varying the nucleophile, an unprecedented one-step synthesis of alpha-amino acids, alpha-amino amides, and dipeptides, was developed in both the racemic and optically pure forms. The current mechanistic hypothesis invokes a concerted process involving CO extrusion. However, a stepwise pathway can also account for these novel transformations.

Amines↗
PubMed1984

In the search for new anticancer drugs. VII. Platinum complexes of diaziridines and azetidine.

Three new diaziridine platinum(II) complexes (4a)-(4c), and a new azetidine platinum(II) complex (3b) were synthesized and tested against the lymphocytic leukemia P388 in mice. (formula; see text) Moderate to good activity was found for all compounds as evidenced by a T/C value of 162 at a dose of 32 mg/kg for (3b), 190 at a dose of 32 mg/kg for (4a), 139 at a dose of 4 mg/kg for (4b), and 142 at a dose of 20 mg/kg for (4c).

Animals↗
PubMed1976

Biochemical characterization of azetidine carboxylic acid-resistant Chinese hamster cells.

We have isolated variants of Chinese hamster lung (CHL) fibroblasts with decreased sensitivity to the toxic proline analog, L-azetidine-2-carboxylic acid (AZCA). Resistance to AZCA is a stable characteristic of these cell lines since it is maintained after 40 generations in nonselective medium. Two AZCA-resistant cell lines overproduce and excrete more proline than wild-type cells. Furthermore, AZCA rapidly inhibits the synthesis of proline from glutamic acid in wild-type but not the resistant cell lines. These studies suggest that resistance to AZCA in these cell lines is due to an alteration in some component of the proline biosynthetic pathway, possibly a regulatory site that is inhibited by AZCA.

Azetidines↗
PubMed1995

Azetidin-2-one derivatives as inhibitors of thrombin.

A series of 3-(3-guanidinopropyl)-azetidin-2-one derivatives was prepared and evaluated as inhibitors of cleavage of synthetic substrates in vitro by the serine proteases thrombin, trypsin and plasmin. The N-unsubstituted, 4-phenethyl derivative 9a demonstrated weak inhibition of these enzymes but acetylation of the beta-lactam N atom afforded 9b, an effective, time-dependent inhibitor of thrombin and a potent inhibitor of plasmin. Variation of the 4-position of the beta-lactam ring was examined in conjunction with different N-substituents to provide a series of potent, time-dependent inhibitors of thrombin. A C-4 substituent was essential for good inhibitory properties and, in general, polar C-4 substituents enhanced the selectivity of inhibition for thrombin compared to plasmin. A trans relationship between the C-4 and C-3 substituents was found to be superior to a cis disposition whilst homologation of the guanidinopropyl side chain to that of a guanidinobutyl moiety reduced activity. Several compounds were effective inhibitors of thrombin-induced clot formation in human plasma in vitro but activity in this assay did not correlate well with inhibition of thrombin-induced cleavage of a synthetic substrate, presumably a consequence of inherent chemical instability and degradation in plasma.

Antithrombins↗
PubMed2003

4-alkylidene-azetidin-2-ones: novel inhibitors of leukocyte elastase and gelatinase.

In addition to their antibiotic potency, beta-lactams have recently been investigated as inhibitors of serine proteinase such as leukocyte elastase (LE), released by inflammatory cells. We describe the synthesis of a series of 4-alkylidene-beta-lactams, and investigate how substitutions on C-3, C-4, and N-1 of the beta-lactam ring affect the activity of human LE and gelatinases MMP-2 and MMP-9. LE activity was measured using a chromogenic substrate, while gelatin-zymography assay was used to evaluate gelatinase activity. We demonstrate that C-4 unsaturation on the beta-lactam ring determines the degree of biological activity, with a selectivity over LE by 3-[1-(tert-butyldimethylsilyloxy)-ethyl] derivatives (lowest IC(50) was 4 microM), and over gelatinase MMP-2 by C-3-unsubstituted 4-[1-ethoxycarbonyl]-ethylidene-beta-lactams (lowest IC(50) was 60 microM). (3S)-3-[(1R)-1-hydroxyethyl]-4-(1-ethoxycarbonyl)-ethylidene-azetidin-2-one inhibits gelatinase MMP-9. The compounds tested showed no cytotoxicity against NIH-3T3 murine fibroblasts. This is the first example of beta-lactams inhibiting metallo-proteinases instrumental in cancer invasion and angiogenesis. These molecules are good candidates for prototype drugs showing selective antibiotic, anti-inflammatory, and anti-invasion properties.

3T3 Cells↗
PubMed2005

New fluorinated pyrrolidine and azetidine amides as dipeptidyl peptidase IV inhibitors.

Cyclohexylglycine amides of various fluorinated pyrrolidines and azetidines were prepared and tested for activity against dipeptidyl peptidase IV and in vivo in the KK mouse model of type 2 diabetes. The tetrafluoropyrrolidide, cis-3,4-difluoropyrrolidide and the fluorinated azetidides displayed unexpectedly strong activity.

Adenosine Deaminase Inhibitors↗
PubMed2006

N/C-4 substituted azetidin-2-ones: synthesis and preliminary evaluation as new class of antimicrobial agents.

A series of 3-chloro-4-(3-methoxy-4-acetyloxyphenyl)-1-[3-oxo-3-(phenylamino)propanamido] azetidin-2-ones 3a-g and 3-chloro-4-[2-hydroxy-5-(nitro substituted phenylazo)phenyl]-1-phenylazetidin-2-ones 6a-h were synthesized using appropriate synthetic route. Structures of all the synthesized compounds were established on the basis of elemental analysis and spectroscopic data. The antimicrobial activity of the synthesized compounds was screened against several microbes. Several of these molecules showed potent antimicrobial activity against Bacillus anthracis, Staphylococcus aureus and Candida albicans and significant structure-activity relationship (SAR) trends.

Anti-Bacterial Agents↗
PubMedDate not supplied

Interaction of the nicotinic agonist (R,S)-3-pyridyl-1-methyl-2-(3-pyridyl)-azetidine (MPA) with nicotinic acetylcholine receptor subtypes expressed in cell lines and rat cortex.

The interaction of the nicotinic agonist (R,S)-3-pyridyl-1-methyl-2-(3-pyridyl)-azetidine (MPA) with different nicotinic acetylcholine receptor (nAChR) subtypes was studied in cell lines and rat cortex. MPA showed an affinity (Ki = 1.21 nM) which was higher than anatoxin-a > (-)-nicotine > (+)-[R]nornicotine > (-)-[S]nornicotine > and (+)-nicotine, but lower than cytisine (Ki = 0.46 nM) in competing for (-)-[3H]nicotine binding in M10 cells, which stably express the recombinant alpha4beta2 nAChR subtype. A one-binding site model was observed in all competing experiments between (-)-[3H]nicotine binding and each of the agonists studied in M10 cells. MPA showed a 13-fold higher affinity for (-)-[3H]nicotine binding sites compared to the [3H]epibatidine binding sites in rat cortical membranes. In human neuroblastoma SH-SY5Y cells, which predominantly express the alpha3 nAChR subunit mRNA, MPA displaced [3H]epibatidine binding from a single population of the binding sites with an affinity in the same nM range as that observed MPA in displacing [3H]epibatidine binding in rat cortical membranes. Chronic treatment of M10 cells with MPA significantly up-regulated the number of (-)-[3H]nicotine binding sites in a concentration dependent manner. Thus MPA appears to have higher affinity to alpha4-subunit containing receptor subtype than alpha3-subunit containing receptor subtype of nAChRs. Furthermore MPA binds to alpha4beta2 receptor subtype with higher affinity than (-)-nicotine and behaves, opposite to cytisine, as a fult agonist in up-regulating the number of nAChRs.

Alkaloids↗
PubMed2003

3-Acylamino-azetidin-2-one as a novel class of cysteine proteases inhibitors.

A new class of inhibitors for cysteine proteases cathepsin B, L, K and S is described. These inhibitors are based on the beta-lactam ring designed to interact with the nucleophilic thiol of the cysteine in the active site of cysteine proteases. Some 3-acylamino-azetidin-2-one derivatives showed very potent inhibition activities for cathepsins L, K and S at the nanomolar or subnanomolar IC(50) values.

Azetidines↗
PubMed2003

Synthesis and biological evaluation of 4-deacetoxy-1,7-dideoxy azetidine paclitaxel analogues.

Three novel 4-deacetoxy-1,7-dideoxy azetidine paclitaxel analogues were synthesized through a convenient route that employed hydroboration-amination and intramolecular S(N)2-type substitution reaction from a natural taxoid taxinine. All analogues have been tested for cytotoxicity against three human tumor cell lines. None of them showed remarkable cytotoxicity compared to paclitaxel against tested tumor cell lines.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Structure-activity studies related to ABT-594, a potent nonopioid analgesic agent: effect of pyridine and azetidine ring substitutions on nicotinic acetylcholine receptor binding affinity and analgesic activity in mice.

Analogs of A-98593 (1) and its enantiomer ABT-594 (2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays.

Alkaloids↗
PubMed1994

7-azetidinylquinolones as antibacterial agents. 2. Synthesis and biological activity of 7-(2,3-disubstituted-1-azetidinyl)-4-oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids. Properties and structure-activity relationships of quinolones with an azetidine moiety.

A series of 7-(2,3-disubstituted-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 study the effects on potency and physicochemical properties of the substituent at position 2 of the azetidine moiety. The activity of the title compounds was determined in vitro against Gram-positive and Gram-negative bacteria, and the in vivo efficacy of selected derivatives was determined using a mouse infection model. The X-ray crystal structures of 6b, 6c, and 6d were found to be in reasonable agreement with the corresponding AM1 calculated geometries. Correlations between antibacterial potency of all the synthesized 7-azetidinylquinolones and naphthyridines and their calculated electronic properties and experimental capacity factors were established. Antibacterial efficacy and pharmacokinetic and physicochemical properties of selected derivatives were compared to the relevant 7-(3-amino-1-azetidinyl) and 7-(3-amino-3-methyl-1-azetidinyl) analogues (for Part 1, see: J. Med. Chem. 1993, 36, 801-810). A combination of a cyclopropyl or a substituted phenyl group at N-1 and a trans-3-amino-2-methyl-1-azetidinyl group at C-7 conferred the best overall antibacterial, pharmacokinetic, and physicochemical properties to the azetidinylquinolones studied.

4-Quinolones↗
PubMed2006

A one-pot preparation of 1,3-disubstituted azetidines.

A straightforward synthesis of 1,3-disubstituted azetidines has been accomplished via the alkylation of a primary amine with the bis-triflate of a 2-substituted-1,3-propanediol species. This transformation is carried out in one reaction vessel, and elimination of the alkylating reagent is generally not a major byproduct. The scope of this methodology has been investigated using a variety 2-substituted-1,3-propanediols and amine nucleophiles.

Alkylation↗