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PubMed1993

Two potentially angiostatic factors, a steroid and L-azetidine-2-carboxylic acid, antagonize one another.

The proline analogue L-azetidine-2-carboxylic acid (LACA) systemically suppressed mast-cell-mediated angiogenesis, as measured by the rat mesenteric-window method. Dexamethasone and methylprednisolone at very low and non-toxic s.c. doses also somewhat inhibited the angiogenesis. Most interestingly, the co-administration of either of these steroids with LACA paradoxically stimulated angiogenesis. These findings suggest that in the future search for candidates for clinically-useful systemic angiostatic remedies, one may have to focus not only on the effect of individual drugs or agents, but also on the effect of such putative anti-angiogenic agents when co-administered. The fact that two potentially angiostatic agents can antagonize one another has not previously been reported.

Animals↗
PubMed1993

The proline analog L-azetidine-2-carboxylic acid modifies the neovascularization pattern by inhibiting branching or tortuosity and stimulating spatial expansion in the rat mesentery.

The L-proline analog L-azetidine-2-carboxylic acid, LACA, systemically inhibited autogenous mast-cell-mediated angiogenesis in normal rats. LACA was injected s.c. at a dose of 100 mg/kg/day and the angiogenic response was assessed in the mesenteric windows. Angiogenesis was induced by the i.p. injection of a highly-selective activator of the mast cells in situ. At these concentrations, LACA appeared to be non-toxic since it affected neither the physiologic body-weight gain nor the mast-cell secretory capacity in the test tissue. The LACA-treatment markedly reduced (p < or = 0.01) microvascular formation in terms of the number of vessels per unit length of tissue (No/mm) but, at the same time, tended to stimulate the spatial expansion of the newly-formed vasculature in terms of the vascularized area (VA). Since No/mm is a measure that reflects the degree of branching, the degree of tortuosity and VA, the findings suggest that LACA inhibited branching/tortuosity and simultaneously stimulated the spatial expansion of the new microvasculature. The difference in response to LACA in terms of No/mm and VA was highly statistically-significant (p < or = 0.0001). The fact that an agent may affect neovascular branching/tortuosity and spatial extension in a distinctly contradictory fashion has not been reported previously.

Animals↗
PubMed1995

In vitro activity of E-4868, a new fluoroquinolone with a 7-azetidin ring, compared with ciprofloxacin, ofloxacin and fleroxacin.

E-4868, (-)-7[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-1-(2,4- difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid, is a new fluoroquinolone with a 7-azetidin ring substituent. The in vitro activity against clinical isolates was compared with that of ciprofloxacin, ofloxacin and fleroxacin. In general, activity of E-4868 against aerobic and facultative anaerobic Gram-negative bacilli was equal to or slightly less active than ciprofloxacin with the exception of Morganella morganii and Proteus spp., E-4868 MIC90, 1 and 0.5 microgram/ml, respectively. E-4868 activity was two- to eight-fold higher than ciprofloxacin against Gram-positive cocci. For anaerobic species, E-4868 activity was comparable to that of ciprofloxacin, although against the Bacteroides fragilis group E-4868 was four-fold more active than ciprofloxacin.

Anti-Infective Agents↗
PubMed1994

Kinetic resolution of substituted 1,3-4H-5,6-dihydrooxazines with carboxylesterase NP: synthesis of (3S,1'R)-3-(1'-hydroxyethyl)-azetidin-2-one.

The kinetic resolution of oxazinyl-ethyl carboxylates 4, is reported employing carboxylesterase NP as biocatalyst. Starting from the anti racemic stereoisomers 4c-d, the unreacted ester is obtained in 40% yield and 93% e.e. The enantiomeric acid is obtained in the open form. Cyclization of the latter and base equilibration allows recycling of the undesired stereoisomer. Compound 4d has the absolute configuration required in the azetidinone 3d, an intermediate in the synthesis of penems and carbapenems.

Azetidines↗
PubMed1988

N-aryl 3-halogenated azetidin-2-ones and benzocarbacephems, inhibitors of beta-lactamases.

N-(3-Carboxy-6-methylphenyl)-3-fluoroazetidin-2-one and a series of related N-aryl-3-halo- and -3,3-dihaloazetidinones 3, in which the halo substituent is a fluorine or a bromine atom, were prepared by using the Wasserman procedure of cyclization of beta-bromopropionamides as a key step. Their affinities for the TEM-1 beta-lactamase were determined and compared with those of a series of tricyclic azetidinones, the benzocarbacephems 2, and known beta-lactamase inhibitors. The beta-lactams 2 and 3 behave as competitive inhibitors and not as substrates of the enzyme; neither halogen substitution (series 3) nor ring strain (series 2) induces enzymatic hydrolysis.

Azetidines↗
PubMed2004

Kinetics and mechanism of hydrolysis of N-acyloxymethyl derivatives of azetidin-2-one.

The pH-independent, acid-catalyzed and base-catalyzed hydrolyses of N-acyloxymethylazetidin-2-ones all occur at the ester function. The pH-independent hydrolysis involves rate-limiting alkyl C-O fission and formation of an exocyclic beta-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the beta-lactam carbonyl carbon atom, to form the corresponding N-hydroxymethylazetidin-2-ones. Calculations carried out at the B3LYP/6-31+G(d) level of theory also support that nucleophilic attack by water takes place at the exocyclic carbon rather than at the beta-lactam carbonyl carbon of the iminium ion. The mechanism for the acid-catalyzed pathway involves a preequilibrium protonation, probably at the beta-lactam nitrogen, followed by rate-limiting alkyl C-O fission with formation of an exocyclic iminum ion. The base-catalyzed hydrolysis involves rate-limiting hydroxide attack at the ester carbonyl carbon. These results imply formation of a beta-lactam system containing a positively charged amide nitrogen atom that hydrolyzes via a pathway that preserves the beta-lactam structure in the product and provide further evidence that cleavage of the beta-lactam C-N bond is not as facile as is commonly imagined.

Acids↗
PubMed2005

An intramolecular 1,3-dipolar cycloaddition reaction towards the synthesis of chiral azetidine nucleoside analogues: the D-gluco case.

The diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of unsaturated nitrones, derived from methyl alpha-D-glucopyranoside with 2-furaldehyde and 2-(benzyloxy)acetaldehyde has been studied In our pevious studies with 2-furaldehyde, the cycloaddition resulted 3 diastereoisomers in a 3:1:1 ratio. In this article, how the number of the possible isomers generated by 1,3-cycloaddition could be reduced from 4 to 1 when 2-(benzyloxy)acetaldehyde was employed as an aldehyde is shown.

Aldehydes↗