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PubMed1982

High-resolution proton nuclear magnetic resonance analysis of conformational properties of biosynthetic actinomycin analogues.

High-resolution proton nuclear magnetic resonance (1H NMR) has been used to study the conformation and dynamics of biosynthetic analogues of actinomycin D that have been substituted at one or both of the 3'-amino acids with azetidine-2-carboxylic acid, pipecolic acid, or 4-ketoproline for one or both of the prolines. The results of measurements made in organic solvents indicate that the amino acid residues on the alpha and beta pentapeptide lactone rings experience different magnetic environments in all the analogues studied. Analysis of the J alpha NH coupling constants and temperature coefficients for the valine and threonine amide protons indicates that substitution at the 3' position has little effect on the conformational and hydrogen-bonding properties of the amino acids at the 1' or 2' position. Examination of the low-field position of the H alpha proton of the 3'-amino acid reveals that the biosynthetic substitutions were made at a unique site on either the alpha or the beta pentapeptide ring and that only one conformation of proline, azetidine-2-carboxylic acid, or pipecolic acid is observed. In D2O, the dynamics of the prolines appear to differ; one remains in a preferred conformation while the other fluctuates at a rate that is intermediate on the NMR time scale. A possible relationship between the conformational and dynamic properties and the DNA binding and kinetic properties is discussed.

Dactinomycin↗
PubMed1995

7-Azetidinylquinolones as antibacterial agents. 3. Synthesis, properties and structure-activity relationships of the stereoisomers containing a 7-(3-amino-2-methyl-1-azetidinyl) moiety.

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.

Animals↗
PubMed2006

Design, synthesis, and biological evaluation of 4-alkyliden-beta lactams: new products with promising antibiotic activity against resistant bacteria.

The design, synthesis, and antibacterial activity of 4-alkyliden-azetidin-2-ones as new antimicrobial agents against multidrug-resistant pathogens is reported. 4-Alkyliden-azetidin-2-ones were easily obtained using an original protocol starting from 4-acetoxy-azetidinones and diazoesters. Parent compounds were further elaborated to obtain a small library of 4-alkylidene derivatives. A molecular modeling approach using GRID descriptors based on the concept of VRS identified attractive drug candidates and contributed to the rationalization of functional group effects in QSARs. The in vitro antibacterial activity of the new agents was evaluated against 43 recent clinical isolates of antibiotic-susceptible and -resistant Gram-positive and Gram-negative pathogens by determining their minimum inhibitory concentrations (MICs). The most active compound showed MIC values ranging from 0.25 to 32 mg/L against some of the bacterial species tested. Interestingly, some compounds demonstrated similar activity against methicillin-susceptible and -resistant strains of Staphylococcus aureus suggesting possible alternative mechanisms of action of these agents, supported by citotoxicity and preliminary scanning electron microscopy studies.

Alkylation↗
PubMed2003

Selective ring contraction of 5-spirocyclopropane isoxazolidines mediated by acids.

Thermolysis of 3,4-cis ring-fused 5-spirocyclopropane isoxazolidines 16, 18-21, 33, 34, 38a, and 61, in the presence of a protic acid at 70-110 degrees C, yielded 3,4-cis ring-fused azetidin-2-ones 22-26,41, 42, 46, and 62 with concomitant extrusion of ethylene, in good yields. So far, the collected evidences strongly support a mechanism started by a homolytic cleavage of the protonated N-O bond for the rearrangement of 5-spirocyclopropane isoxazolidines to beta-lactams. Some different competitive pathways can then follow depending on the stability or the stereoelectronic properties of cationic diradical intermediates. The two-step process, intramolecular 1,3-dipolar cycloaddition/thermal rearrangement under acidic conditions, represents a general synthesis of a new class of 3,4-cis-fused bicyclic azetidin-2-ones starting from easily available compounds such as amino acids, hydroxy acids, and dicarbonyl or amino alcohol derivatives.

Journal Article↗
PubMed2006

High nucleophilicity of cyclic amidocarbene toward aryl isocyanates, new approach to spiro[azetidinone-4,3'-indolinone] derivatives.

The nucleophilic addition of beta-lactam-4-ylidenes 2, a type of ambiphilic cyclic amidocarbene, to aryl isocyanates has been studied and their application in organic synthesis has been demonstrated. Thermolysis of spiro[beta-lactam-4,2'-oxadiazolines] 1 in the presence of aryl isocyanates afforded both N-lactam and O-lactam substituted spiro[azetidine-2-one-4,3'-indole-2'-one] derivatives 5 and 6 in the total yield of 65-86%. Upon hydrolysis, products 5 and 6 were converted into spiro[azetidine-2-one-4,3'-indole-2'-one] 9 that was analogous to known biologically active compounds.

Journal Article↗
PubMed2003

Cu(I)-catalyzed enantioselective [2 + 2] cycloaddition of 1-methoxyallenylsilane with alpha-imino ester: chiral synthesis of alpha,beta-unsaturated acylsilanes.

[reaction: see text] The catalytic, enantioselective [2 + 2] cycloaddition reaction of 1-methoxyallenylsilanes with alpha-imino ester has been achieved by means of the [Cu(MeCN)(4)]BF(4)/(R)-Tol-BINAP catalyst to afford 3-methylene-azetidine 2-carboxylates in good yields and with excellent enantiomeric excesses. The acid-catalyzed ring opening of the azetidines afforded chiral acylsilanes quantitatively.

Journal Article↗
PubMed2003

Intracellular localization of a group II chaperonin indicates a membrane-related function.

Chaperonins are protein complexes that are believed to function as part of a protein folding system in the cytoplasm of the cell. We observed, however, that the group II chaperonins known as rosettasomes in the hyperthermophilic archaeon Sulfolobus shibatae, are not cytoplasmic but membrane associated. This association was observed in cultures grown at 60 degrees C and 76 degrees C or heat-shocked at 85 degrees C by using immunofluorescence microscopy and in thick sections of rapidly frozen cells grown at 76 degrees C by using immunogold electron microscopy. We observed that increased abundance of rosettasomes after heat shock correlated with decreased membrane permeability at lethal temperature (92 degrees C). This change in permeability was not seen in cells heat-shocked in the presence of the amino acid analogue azetidine 2-carboxylic acid, indicating functional protein synthesis influences permeability. Azetidine experiments also indicated that observed heat-induced changes in lipid composition in S. shibatae could not account for changes in membrane permeability. Rosettasomes purified from cultures grown at 60 degrees C and 76 degrees C or heat-shocked at 85 degrees C bind to liposomes made from either the bipolar tetraether lipids of Sulfolobus or a variety of artificial lipid mixtures. The presence of rosettasomes did not significantly change the transition temperature of liposomes, as indicated by differential scanning calorimetry, or the proton permeability of liposomes, as indicated by pyranine fluorescence. We propose that these group II chaperonins function as a structural element in the natural membrane based on their intracellular location, the correlation between their functional abundance and membrane permeability, and their potential distribution on the membrane surface.

Archaeal Proteins↗
PubMed1978

Effects of amino acid analogues on protein synthesis and degradation in isolated cells.

1. Naturally-occurring and synthetic analogues of phenylalanine, tyrosine, histidine, arginine, proline, tryptophan and the sulphur amino acids have beeen tested in rat reticulocytes and in the Reuber H35 hepatoma for effects on protein synthesis and protein degradation and on the heat lability of phosphoenolpyruvate carboxykinase (EC 4.1.1.32) in the hepatoma cells. The experiments were designed to test whether the analogues could be incorporated into mammalian proteins and whether the resultant proteins would be degraded at an accelerated rate. 2. Several analogues, including thiazolylanine, triazolalanine and selenocystine both stimulated protein synthesis and produced labile protein in reticulocytes. Other analogues, such as dihydroxyphenylalanine, thioproline and pipecolic acid accelerated protein breakdown but probably indirectly via an inhibition of protein synthesis. Azetidine-2-carboxylic acid had the largest effect on protein breakdown in reticulocytes. 3. Labile protein was produced in hepatoma cells incubated in the presence of azetidine-2-carboxylic acid, canavanine, indospicine, triazolalanine, 2-, 3- and 4-fluorophenylalanine. These same analogues, together with 3,4-dehydroproline, beta-2-thienylalanine, dihydroxyphenylalanine, histidinol, 5- and 6-fluorotryptophan, selenocystine and selenomethionine produced heat-labile phosphoenolpyruvate carboxykinase. Enzyme induced in the presence of selenomethionine or indospicine showed the largest increases in heat lability, and for these analogues equimolar concentrations of methionine and arginine respectively were needed to nullify the enzyme abnormality. 4. The toxicity of the same naturally-occurring analogues has been discussed in terms of their ability to be incorporated into cell proteins.

Amino Acids↗
PubMed1991

Adenine photodimerization in deoxyadenylate sequences: elucidation of the mechanism through structural studies of a major d(ApA) photoproduct.

The mechanism of the photodimerization of adjacent adenine bases on the same strand of DNA has been elucidated by determining the structure of one of the two major photoproducts that are formed by UV irradiation of the deoxydinucleoside monophosphate d(ApA). The photoproduct, denoted d(ApA)*, corresponds to a species of adenine photodimer first described by Pörschke (Pörschke, D. (1973) J.Am.Chem.Soc. 95, 8440-8446). From a detailed examination of its chemical and spectroscopic properties, including comparisons with the model compound N-cyano-N1-(1-methylimidazol-5-yl)formamidine, it is deduced that d(ApA)* contains a deoxyadenosine unit covalently linked through its C(8) position to C(4) of an imidazole N(1) deoxyribonucleoside moiety bearing an N-cyanoformamidino substituent at C(5). On treatment with acid, d(ApA)* is degraded with high specificity to 8-(5-amino-imidazol-4-yl)adenine whose identity has been confirmed by independent chemical synthesis. It is concluded that the primary event in adenine photodimerization entails photoaddition of the N(7)-C(8) double bond of the 5'-adenine across the C(6) and C(5) positions of the 3'-adenine. The azetidine species thus generated acts as a common precursor to both types of d(ApA) photoproduct which are formed from it by competing modes of azetidine ring fission.

Adenine↗
PubMed1984

Precardiac mesoderm differentiation in vitro. Actin-isotype synthetic transitions, myofibrillogenesis, initiation of heartbeat, and the possible involvement of collagen.

The differentiation of precardiac mesoderm into beating heart tissue was examined during explant culture. Explanted tissue forms tubular heart-like vesicles and initiates rhythmic contractility within 18-24 h in vitro, a developmental time-course approximating that observed during in vivo development. Electron-microscopic observations reveal that beating heart cells are rich in cytoplasmic myofibrils in varying degrees of order, with some regions containing highly organized myofibrillar arrays. The analysis of actin-isotype biosynthesis, using metabolic labeling with [35S]-methionine and isoelectric-focusing resolution of the synthesized radioactive polypeptides, demonstrates that the initiation of cardiac alpha-actin synthesis and the pattern of transition in the synthesis of alpha-, beta-, and gamma-actin isotypes is equivalent to the initiation time and pattern observed in vivo. A possible collagen involvement in the differentiation process was investigated by assessing the effects of collagen-synthesis inhibitors on the development of the explant cultures. Two different agents, alpha, alpha'-dipyridyl and L-azetidine-2-carboxylic acid, exhibited a dose-dependent ability to inhibit the formation of beating heart tissue. When examined by electron microscopy, the nonbeating tissue exhibited a drastic depression of myofibrillogenesis, but otherwise appeared healthy. Further examination of the effect of L-azetidine-2-carboxylic acid demonstrated that the inhibition of myofibril formation and heartbeat was correlated with a 60% inhibition of native collagen synthesis; however, the time-course and pattern of actin-isotype biosynthesis was completely unaffected. The data suggest a possible involvement in heart differentiation that is necessary for either the synthesis of non-actin cardiac contractile proteins or the assembly of cardiac contractile proteins into myofibrils.

Actins↗
PubMed1985

Biochemical and ultrastructural study of the effects of proline analogues on collagen synthesis in 3T6 fibroblasts.

The effects of proline analogues, L-3,4-dehydroproline and L-azetidine-2-carboxylic acid, on collagen synthesis by cultured 3T6 fibroblasts have been studied. Prolyl hydroxylase activity was partially inhibited in cells cultured with dehydroproline for 24 h, resulting in the synthesis of collagen in which the proline was underhydroxylated. Azetidine had no effect on prolyl hydroxylase and less effect on the degree of hydroxylation of proline. Fibroblasts grown in the presence of either analogue and fixed in-situ contained greatly distended cisternae of the rough endoplasmic reticulum. Proline analogues otherwise caused few ultrastructural changes in the cells. Treated cells which had been handled more roughly during preparation for electron microscopy contained many large cytoplasmic vacuoles in addition to dilated cisternae. Our results indicate that the major effect of the proline analogues was the inhibition of prolyl hydroxylation. However, electron microscopy of the treated cells revealed hitherto unreported cytoplasmic damage.

Cell Division↗
PubMed1976

Production, isolation, and properties of azetomycins.

Streptomyces antibioticus synthesizes five actinomycins that differ in the "proline site" of the molecule. When cultured in the presence of azetidine-2-carboxylic acid (AzC), antibiotic synthesis was stimulated 40 to 50%, synthesis of actinomycin IV was inhibited, and one or both prolines were replaced by AzC. AzC incorporation could not be reversed by concomitant supplementation with proline or sarcosine, and only pipecolic acid affected a minor reversal of AzC incorporation. AzC-containing actinomycins were isolated and designated azet-I and azet-II; a third unresolved component or mixture was called azet-III. The molar ratio of AzC to proline was: azet-I, 1:1; azet-II, 2:0. Azet-III was equivocal. These azetidine actinomycins (azetomycins) were found to be potently inhibitory to the growth of selected gram-positive but not as potent to the growth of gram-negative organisms. The relative inhibitory affect against growth and ribonucleic acid synthesis in Bacillus subtilis was: actinomycin IV =/> azet-I > azet-II >>> azet-III. Protein synthesis was affected similarly; however, kinetic studies with B. subtilis revealed that ribonucleic acid synthesis was inhibited rapidly followed by an inhibition of protein synthesis. At concentrations less than 1 mug/ml, deoxyribonucleic acid synthesis was stimulated by these actinomycins.

Amino Acids↗
PubMed1972

Effects of proline analogues on the formation of alkaline phosphatase in Escherichia coli.

Two of the four proline analogues tested for their effect on the formation and activity of Escherichia coli alkaline phosphatase were able to substitute for proline in protein synthesis in a proline auxotroph. One of these, 3,4-dehydroproline, effectively replaced proline and led to formation of an active enzyme under conditions where no proline was present in the polypeptides. Substitution of azetidine-2-carboxylate for proline prevented active enzyme formation, producing instead altered monomeric forms of the alkaline phosphatase. These were detected with antibodies specific to denatured forms of the enzyme, and they were also characterized, together with cellular proteins, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Alkaline phosphatase, as well as several other proteins, is localized exterior to the bacterial cell cytoplasm in the periplasmic space. In the presence of azetidine-2-carboxylate, a substantial number of these periplasmic proteins retain their specific site of localization, and the denatured subunits of alkaline phosphatase were only detected in the periplasmic fraction of the cell. Thus, secretion of these proteins does not appear to require a high degree of specificity in the native structure of the polypeptide chain. The analogues 4-allohydroxyproline and 4-thiazolidine carboxylate were unable to substitute for proline in protein synthesis but they inhibited growth of E. coli.

Alkaline Phosphatase↗
PubMed1981

Production of amino acids by analog-resistant mutants of the cyanobacterium Spirulina platensis.

Mutants of Spirulina platensis resistant to 5-fluorotryptophan, beta-3-thienyl-alanine, ethionine, p-fluorophenylalanine, or azetidine-2-carboxylic acid were isolated. Some of these mutants appeared to be resistant to more than one analog and to overproduce the corresponding amino acids. A second group was composed of mutants that were resistant to one analog only. Of the latter mutants, one resistant to azetidine-2-carboxylic acid was found to overproduce proline only, whereas one resistant to fluorotryptophan and one resistant to ethionine did not overproduce any of the tested amino acids.

Alanine↗
PubMed2004

Strategies for the stereocontrolled formation of oxygen analogues of penicillins and cephalosporins.

The synthesis of oxacephalotin and oxacephamandol, which are more active than natural, sulfur-containing congeners, and the isolation of clavulanic acid, a potent inhibitor of beta-lactamase enzymes, directed attention of many academic and industrial laboratories the synthesis of oxygen analogues of penicillins and cephalosporins. The present review focuses attention on the problem of stereocontrol in the formation of a desired configuration of the bridgehead carbon atom in the title compounds. Five feasible synthetic methods leading to the basic skeletons of clavams and 5-oxacephams are discussed. Three of them involve the nucleophilic substitution at C-4 of the azetidin- 2-ones performed as inter- or intramolecular process and the remaining two involve cycloaddition reactions between ketenes and iminoethers, or between vinyl ethers and isocyanates. Owing to the general application, stereospecificity and high asymmetric induction, the last method seems to be most advantageous. The weak point of the nucleophilic substitution methodology is that a nucleophile approaches the 3-substituted azetidin-2-one ring preferentially anti to the existing substituent and in the case where there is no substituent at C-3, that the stereoselectivity of formation of the new chirality center at C-4 is low. All discussed methods are illustrated by the examples taken from the literature.

Anti-Bacterial Agents↗
PubMed2002

[Reactions of derivatives of beta-lactam antibiotics with non-antibacterial biological activity].

Beyond the well-known antibacterial and beta-lactamase enzyme inhibiting properties of the different beta-lactam antibiotics and their modified derivatives there are a number of beta-lactam (azetidine-2-one) compounds possessing different biological activities. Most of them have been shown to inhibit a variety of cysteine or serine protease enzymes comprising plants, viruses, protozoa, bacteria and mammalian species. This review article covers the biologically active beta-lactam compounds but beta-lactam antibiotics or beta-lactamase inhibitors, and including a few chemically related gamma- or delta-lactams or azetidines presumably having the same site and mechanism of action. These include viral protease inhibitors, protozoan enzymes (e.g. cruzain, falcipain), plant enzymes (papain). Of the mammal enzymes the most important ones are cholesterol absorption inhibitors and human leucocyte (neutrophyle) elastase inhibitors, but mention must be made on thrombin, chymotrypsin, cathepsin, prostata specific antigen and tumor necrosis factor inhibitors, as potential future remedies of cardio vascular and inflammatory diseases.

Anti-Bacterial Agents↗
PubMed2002

Water-assisted alkaline hydrolysis of monobactams: a theoretical study.

A theoretical study of the water-assisted alkaline hydrolysis of 2-azetidinone, 3-formylamino-2-azetidinone and 3-formylamino-2-azetidine-1-sulfonate ion is carried out at the B3LYP/6-31+G* level. The effect of bulk solvent is taken into account using the PCM solvation model while specific solvent effects are represented by the inclusion of an ancillary water molecule along the reaction profile. The calculated free energy barriers in solution are in reasonable agreement with experimental values. The observed substituent effects due to the presence of the 3-formylamino and the SO(3) groups attached to the beta-lactam ring are crucial factors determining the hydrolysis of monobactam antibiotics.

Azetidines↗
PubMed2000

beta-Lactam derivatives as enzyme inhibitors: 1-peptidyl derivatives of 4-phenylazetidin-2-one as inhibitors of elastase and papain.

N-Peptidyl substituted azetidin-2-ones were synthesized and evaluated as inhibitors of the serine protease elastase, and the cysteine protease papain. All compounds were synthesized from 4-phenylazetidin-2-one, either from the racemate or from the pure enantiomers. The (S)-enantiomer was prepared by enantioselective synthesis from (S)-beta-phenyl-beta-alanine, while the (R)-enantiomer was obtained by enzymatic resolution with alpha-chymotrypsin. N-Alkylation with bromoacetates introduced a spacer group which, after hydrolysis to the free acid, was acylated with amino acid esters or di- or tripeptide esters. The enzymatic assays proved some derivatives to be effective inhibitors of PPE and/or papain. N-BOC protected amino acid derivatives without a spacer group inhibited PPE reversibly, while derivatives with spacer group showed either weak or no inhibitory properties. On the other hand, papain was inactivated irreversibly by ethyl (RS)-2-oxo-4-phenylazetidin-1-acetate. The highest inhibitory activity against papain was found for the diastereomers of N-(2-oxo-4-phenylazetidin-1-acetyl)-L-alanyl-L-valine benzyl ester, a compound with a spacer group.

Amino Acids↗