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PubMed2003

A computational study of radical haloacetal cyclizations controlled by the acetal center.

The stereochemical outcome of the radical haloacetal cyclization reaction (Ueno-Stork reaction) has been examined by ab initio and other molecular orbital techniques. It was found that the stereochemistry of 5-exo- and 6-exo trig cyclizations can be accurately predicted from calculations using moderate levels of theory (UHF/6-311G** or B3LYP/6-311G**). A simplified computational procedure, easily run on a standard desktop computer, has been developed that provides excellent predictive ability for the stereochemical outcome for the reactions in question. Interestingly, a novel twist transition state has been identified for the first time in 5-exo-trig radical cyclization reactions.

Journal Article↗

PubMed2002

Studies on the synthesis of cyclic pentapeptides as LHRH antagonists and the factors that influence cyclization yield.

Six cyclic pentapeptides containing two or three non-protein amino acids have been synthesized by cyclization of linear precursors in dilute solution and characterized by TLC. HPLC, NMR, melting point. specific rotation etc. A total of 72 cyclization reactions were carried out to study the factors that influence head-to-tail cyclization: linear precursor sequence, coupling reagent, residue configuration, the proportion of DMAP additive, concentration, reaction temperature and reaction time. The cyclic pentapeptides will be modified by active moieties and evaluated as LHRH antagonists.

Amino Acid Sequence↗

PubMed1996

Conformational study of two linear hexapeptides by two-dimensional NMR and computer-simulated modeling: implication for peptide cyclization in solution.

Two linear peptides, D-leucyl-L-prolyl-L-isoleucyl-L-valyl-L-alanyl-beta-alanine (I) and D-leucyl-L-prolyl-L-isoleucyl-L-valyl-N-methyl-L-alanyl-beta-alanine (II), whose sequences were designed from protodestruxin and desmethyldestruxin B by replacing D-leucic acid with D-leucine, two cyclic hexadepsipeptides with insecticidal and immunodepressant activities, have been found to be cyclized in unusually high yields (>85%). In order to gain insight into the conformation and the relative flexibility of different constituent residues in these linear peptides, we have applied various techniques of 2D-NMR spectroscopy coupled with dynamic simulated annealing by computer modeling to establish the solution conformations of these two linear peptides. Based on the derived structures, it is found that the distances between N- and C-terminal residues of both peptides are short enough to facilitate the cyclization, thus collaborating the observation of favorable cyclization yields for both linear peptides.

Amino Acid Sequence↗

PubMed2000

Lanthanide Catalyzed Cyclization of Uridine 3'-p-Nitrophenyl Phosphate.

Steady state kinetics and (15)N isotope effects have been used to study the cyclization reaction of uridine 3'-p-nitrophenyl phosphate. The cyclization reaction is catalyzed by transition metal ions and lanthanides, as are substitution reactions of many phosphate esters. Kinetic analysis reveals that the erbium-catalyzed cyclization reaction involves the concerted deprotonation of the 2'-OH group and departure of the leaving group. The transition state is very late, with a very large degree of bond cleavage to the leaving group, which could be due to a large degree of polarization of the P&bond;O bonds by erbium. Copyright 2000 Academic Press.

Journal Article↗

PubMed1993

Antigenic analysis of bean pod mottle virus using linear and cyclized synthetic peptides.

The antigenic structure of the comovirus bean pod mottle virus (BPMV) was studied using synthetic peptides selected on the basis of the exposed location of certain regions of the viral protein. Three regions of domain A, four regions of domain B and two regions of domain C of BPMV coat protein were studied. Each of four regions were synthesized in the form of linear and cyclized peptides while the others were synthesized as linear peptides only. The peptides were tested for their ability to be recognized by antibodies directed against BPMV. The peptides were also used for producing rabbit antisera, which were tested for their ability to react with various BPMV antigens as well as with the linear and cyclized peptides. All the peptides were found to correspond to epitopes of BPMV coat protein. Several of the antigenic sites of BPMV located on exposed loops of the coat protein occupy positions which correspond to known epitopes in the structurally related picornaviruses. Only in some cases did cyclization sufficiently improve the level of conformational mimicry between peptides and the viral protein to allow cross-reactions between them to be observed.

Amino Acid Sequence↗

PubMed1994

Superoxide dismutase and catalase prevent the formation of reactive oxygen species during reduction of cyclized dopa ortho-quinone by DT-diaphorase.

Dopa was oxidized by Mn(3+)-pyrophosphate complex to the corresponding o-quinone, accompanied by the cyclization of the amino chain to form cyclized dopa ortho-quinone (cDoQ) with absorption maxima at wavelengths of 305 and 475 nm. The cyclization was found to proceed in a single step from DoQ to cDoQ without formation of cDoQH2 and oxygen consumption. DT-diaphorase catalyzes the reduction of cDoQ to the corresponding hydroquinone (cDoQH2), which was found to be unstable in the presence of oxygen. The autoxidation of the cDoQH2 was followed by recording the constant oxidation of NADH and oxygen consumption and reduction of cDoQ at a wavelength of 475 nm. It was found that three different oxidizing agents were involved in autoxidation of cDoQH2. The addition of DETAPAC resulted in a strong inhibition of NADH oxidation (65% inhibition) during the reduction of cDoQ by DT-diaphorase, suggesting that manganese was responsible for 65% of the autoxidation of cDoQH2. The addition of SOD to the incubation mixture resulted in the inhibition of NADH oxidation (79%) during the reduction of cDoQ by DT-diaphorase. In the presence of DETAPAC, the addition of SOD inhibited NADH oxidation during cDoQH2 autoxidation 75%, suggesting that superoxide radicals are responsible for 75% of the oxygen-dependent autoxidation. The remaining NADH oxidation, which was not inhibited by DETAPAC and SOD, was accompanied by a constant oxygen consumption, suggesting that this autoxidation of cDoQH2 proceeds by reducing oxygen to superoxide radical. The effect of SOD and catalase in the presence of DETAPAC was also studied. A nearly complete inhibition (90%) of oxygen consumption during the reduction of cDoQ by DT-diaphorase was observed when SOD alone or SOD and catalase were added to the incubation mixture containing DETAPAC. We conclude that SOD and catalase constitute a protective cellular system against formation of reactive oxygen species during reduction of cDoQ by DT-diaphorase.

Animals↗

PubMed1985

Reversibility of cyclization of the Tetrahymena rRNA intervening sequence: implication for the mechanism of splice site choice.

The Tetrahymena rRNA intervening sequence (IVS) excises itself from the pre-rRNA and then mediates its own cyclization. We now find that certain di- and trinucleotides with free 3' hydroxyl groups reopen the circular IVS at the cyclization junction, producing a linear molecule with the oligonucleotide covalently attached to its 5' end. This linear molecule recyclizes with release of the added oligonucleotide. Thus the IVS RNA, like an enzyme, lowers the activation energy for both forward and reverse cleavage-ligation reactions. Certain combinations of pyrimidines are required for circle reopening. The most reactive oligonucleotide is UCU. This sequence resembles those preceding the major and minor cyclization sites in the linear IVS RNA (UUU and CCU) and the 5' splice site in the pre-rRNA (UCU). We propose that an oligopyrimidine binding site within the IVS binds the sequences upstream of each of these target sites for cleavage-ligation.

Animals↗

PubMed1989

A spectrophotometric assay for glutaminyl-peptide cyclizing enzymes.

Current assays for the glutaminyl-peptide cyclizing enzyme, glutaminyl cyclase, have several shortcomings. In this report a rapid spectrophotometric assay for cyclization of glutaminyl-peptides to pyroglutamyl-peptides by glutaminyl cyclase is described which overcomes many of these shortcomings. This coupled assay utilizes glutamate dehydrogenase, alpha-ketoglutarate and NADH to measure the ammonia released during cyclization of the dipeptide substrate Gln-Gln. Glutaminyl cyclase from bovine pituitary, partially purified by ion exchange chromatography, exhibits a Km for this substrate of 0.6 mM and a Vmax of 9.6 nmol/min/mg protein. These values are comparable to ones previously reported using other glutaminyl-peptide substrates and either radioimmunoassay or high-performance liquid chromatography to measure glutaminyl cyclase activity.

Acyltransferases↗

PubMed1993

CD and FTIR studies of an immunogenic disulphide cyclized octadecapeptide, a fragment of a snake curaremimetic toxin.

In a previous paper, the systematic epitope screening of a snake curaremimetic toxin or toxin a was described by this group using a panel of synthetic octadecapeptides. The disulphide cyclized peptide (Cys-23,40)(23-40) corresponding to loop II of the native toxin was found to elicit, with no linkage to a carrier, neutralizing antisera against the toxin. We have now undertaken the conformational study of this immunogenic disulphide cyclized peptide by CD and FTIR. The CD study of the peptide was carried in aqueous solution under various conditions (pH, temperature, presence of micelles) and in trifluoroethanol solution. Low temperature, SDS micelles and trifluoroethanol were found to induce a beta-sheet formation (16 to 39%). FTIR spectra of the peptide in the solid state (dry film) and in D2O solution or deuterated-TFE solution (hydrated film) displayed some characteristic bands indicating the presence of beta-sheet (1623 cm-1) and beta-turn (1637 cm-1; 1694 cm-1). These studies indicate that the immunogenic disulphide cyclized peptide (23-40) can adopt in solution an ordered structure.

Amino Acid Sequence↗

PubMed1988

The cyclization of linear DNA in Escherichia coli by site-specific recombination.

The efficiency with which linearized plasmid DNA can transform competent Escherichia coli can be significantly increased by use of the Cre-lox site-specific recombination system of phage P1. Linear plasmid molecules containing directly repeated loxP sites (lox2 plasmids) are cyclized in Cre+ E. coli strains after introduction either by transformation or by mini-Mu transduction. Exonuclease V activity of the RecBC enzyme inhibits efficient cyclization of linearized lox2 plasmids after transformation. By use of E. coli mutants which lack exonuclease V activity, Cre-mediated cyclization results in transformation efficiencies for linearized lox2 plasmids identical to those obtained with covalently closed circular plasmid DNA. Moreover, Cre+ E. coli recBC strains allow the efficient recovery of lox2 plasmids integrated within large linear DNA molecules such as the 150-kb genome of pseudorabies virus.

Bacteriophages↗

PubMed1982

Effect of various acceptors on the rates of the cyclization and chain-shortening of amylose catalyzed by the cyclodextrin glycosyltransferase from Klebsiella pneumoniae M 5 al. Improvement of new photometric assay methods.

The effect of various acceptors on the cyclization and chain-shortening reaction of amylose catalyzed by cyclodextrin glycosyltransferase [(1 leads to 4)-alpha-D-glucan: [(1 leads to 4)-alpha-D-glycopyranosyl]transferase (cycling) EC 2.4.1.19] from Klebsiella pneumoniae M 5 al was studied by use of photometric-assay methods. The requirements for the acceptor were the same for both cyclization and chain-shortening, indicating the close relationship between both reactions. Maltose proved to be the most effective (2.48- and 5-fold acceleration of the cyclization and chain-shortening, respectively, in the presence of 584 micrometers maltose). The dependence of the chain-shortening reaction on the conformational state of the amylose molecules is discussed.

Amylose↗

PubMed2004

Chemo- and regioselective peptide cyclization triggered by the N-terminal fatty acid chain length: the recombinant cyclase of the calcium-dependent antibiotic from Streptomyces coelicolor.

Here we report the first biochemical characterization of a recombinant nonribosomal peptide cyclase of a streptomycete, the model actinomycete Streptomyces coelicolor A3(2). This bacterium produces the calcium-dependent antibiotic (CDA), which is a branched cyclic macrolactone belonging to the group of acidic lipopeptides. The recombinant CDA3 cyclase from CDA synthetase efficiently catalyzes ring formation of linear peptidyl thioester substrates based on a sequence analogous to natural CDA. Four leaving groups were attached to the C-terminus of the undecapeptide: coenzyme A (CoA), phosphopantetheine, N-acetylcysteamine (SNAC), and thiophenol. The best rates for cyclization were determined for the thiophenol substrate, revealing that chemical reactivity is more important than cofactor recognition. The cyclase catalyzes the formation of two regioisomeric macrolactones, which arise from simultaneous nucleophilic attack of the two adjacent Thr(2) and Ser(1) residues onto the C-terminus of the acyl-enzyme intermediate. This relaxed regioselectivity has not been observed for any other recombinant NRPS or PKS cyclases so far. Substitution of either Ser(1) or Thr(2) by alanine led to selective formation of a decapeptide or undecapeptide lactone ring. In contrast to that, CDA3 cyclase strictly retains stereoselectivity for both nucleophiles, accepting only l-configured Ser(1) and Thr(2) for cyclization. Further, our studies provide evidence for the crucial role of N-terminal fatty acyl groups of lipopeptides in controlling the regio- and chemoselectivity of enzyme-catalyzed macrocyclization. Elongation of the fatty acyl group of our thioester substrate from C(2) to C(6) as in CDA turned the relaxed regioselectivity into a strict regioselectivity, yielding solely the decapeptide lactone ring with a significantly improved cyclization-to-hydrolysis ratio.

Anti-Bacterial Agents↗

PubMed2005

Excision of the epothilone synthetase B cyclization domain and demonstration of in trans condensation/cyclodehydration activity.

The epothilones are potent anticancer natural products produced by a polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) hybrid involving proteins EpoA-F. The single NRPS module of the epothilone assembly line, EpoB, is a distinct subunit of approximately 160 kDa and consists of four successive domains: cyclization, adenylation, oxidation, and peptidyl carrier protein (Cy-A-Ox-PCP). The cyclization domain is responsible for introduction of the thiazoline heterocycle into the growing polyketide/nonribosomal peptide chain from the precursors malonyl-CoA and cysteine through the multiple steps of condensation, cyclization, and dehydration. This enzyme-bound thiazoline intermediate is subsequently oxidized to a thiazole by the EpoB Ox domain. The EpoB module was dissected to provide 57 kDa EpoB(Cy) and 102 kDa EpoB(A-Ox-PCP) as subunit fragments to evaluate Cy as a free-standing domain. EpoB was reconstituted by these fragments in trans to generate the methylthiazole product. Using this system, apparent kinetic constants for the upstream acyl donor EpoA(ACP) and EpoB(Cy) were determined, providing a measure of affinity for the naturally occurring interface of the amino terminus of EpoB and the EpoA carboxy terminus. Site-directed mutants in excised EpoB(Cy) were prepared and used to examine residues involved in condensation and heterocycle formation. This work demonstrates the ability to define a functional Cy domain by excision from its native NRPS module, and examine both its protein-protein interactions and mechanism of activity.

Amino Acid Sequence↗

PubMed1996

Purification and characterization of versicolorin B synthase from Aspergillus parasiticus. Catalysis of the stereodifferentiating cyclization in aflatoxin biosynthesis essential to DNA interaction.

The absolute configuration of the dihydrobisfuran ring system characteristic of aflatoxin B1 is essential to the covalent reaction of its metabolically activated form with double-stranded DNA. The biosynthesis of this potent mycotoxin proceeds through three configurationally labile intermediates to racemic versiconal hemiacetal. Subsequent enzymatic cyclization establishes the stereochemistry of this, critical ring fusion in (-)-versicolorin B and is catalyzed by versicolorin B synthase (VBS). The isolation and purification of VBS from Aspergillus parasiticus (SU-1, ATCC 56775) and its kinetic characterization and attempted inactivation are described. Initial purification trials were plagued both by a chromophoric impurity which was difficult to remove and by low recoveries of active protein. The discovery of a remarkably broad pH range of enzyme stability and catalytic activity led to an efficient procedure involving preparative isoelectric focusing and ion exchange FPLC chromatography. The enzyme behaved as a dimer upon gel filtration and migrated with M(r) 78000 Da during denaturing gel electrophoresis. The UV spectrum of pure VBS gave no evidence of a bound chromophore. Detailed kinetic analysis of VBS revealed that this protein selects from two equilibrating enantiomers of versiconal hemiacetal to cyclize the appropriate antipode to optically pure versicolorin B. By varying the amount of enzyme to a fixed concentration of substrate, the rate of enzymic cyclization could be limited by the intrinsic rate of enantiomerization of the substrate under the conditions of reaction. It was possible to quantitate the dynamics of this substrate enantiomerization/cyclization process, to establish the role played by VBS, and to evaluate the significance of each to the overall biosynthesis of aflatoxin. The potential role of an acidic residue of the enzyme in catalysis was supported by analysis of the pH-rate profile of VBS and chemical labeling studies. Successful demonstration of competitive inhibition of VBS by a simple substrate analogue led to the design and synthesis of a potential mechanism-based inactivator of the protein.

Aflatoxin B1↗

PubMedDate not supplied

Combinatorial synthetic design. Solution and polymer-supported synthesis of heterocycles via intramolecular aza Diels-Alder and imino alcohol cyclizations.

A flexible synthetic strategy for combinatorial chemical applications has been developed on the basis of an aldehyde-bridge-alkene motif as the key component in several intramolecular cycloaddition reactions. This strategy was explored most extensively with the formal aza Diels-Alder cyclization, which affords a series of configurationally and functionally diverse heterocyclic compounds. The substrates included substituted salicylaldehydes, glyoxylic esters and amides, and N-acyl-alpha-aminoaldehydes; all reacted with a variety of anilines to yield different tetrahydroquinoline products. The cyclization of the aminoaldehydes was also translated from solution and optimized for solid phase. The stepwise mechanism of this cycloaddition suggested that the cationic intermediate from initial ring closure could be trapped by a variety of nucleophiles. This suggestion was confirmed by cyclization of amino alcohols and related compounds.

Alcohols↗

PubMed2003

Rhenium(I)-induced cyclization of thiosemicarbazones derived from beta-keto esters.

The reactions of methylacetoacetate and ethyl 2-methylacetoacetate thiosemicarbazones (H(2)L(A) and H(2)L(B), respectively) with [ReX(CO)(5)] and [ReX(CO)(3)(CH(3)CN)(2)] (X = Cl, Br) were explored under various experimental conditions. Besides the adducts fac-[ReX(CO)(3)(H(2)L)], in which the rhenium is coordinated to three carbonyl groups, the X anion, and the N,S-bidentate thiosemicarbazone ligand, the following complexes were also isolated: fac-[ReBr(CO)(3)(Hpyz(B))], the tetrameric complexes fac-[Re(pyz(A))(CO)(3)](4) and fac-[Re(pyz(B))(CO)(3)](4), and fac-[Re(pyz(B))(CO)(3)(H(2)O)] (where Hpyz(A) and Hpyz(B) are pyrazolones derived by cyclization of H(2)L(A) and H(2)L(B), respectively). The cyclization reactions were monitored by (1)H NMR spectroscopy and the complexes isolated were identified by elemental analysis, mass spectrometry, IR and (1)H NMR spectroscopy, and in some cases by X-ray diffractometry. The isolation and the full structural identification of the rather unusual fac-[ReBr(CO)(3)(Hpyz(B))], which contains the enol form of the pyrazolone ligand, affords new insight into the cyclization of thiosemicarbazones derived from beta-keto esters.

Journal Article↗

PubMed2001

Electronic control of the Bergman cyclization: the remarkable role of vinyl substitution.

We report an ab initio study of the effect of vinyl substitution on the cycloaromatization of 3-ene-1,5-diynes (the Bergman cyclization). The majority of the calculations were conducted by using the BLYP version of Density Functional Theory, and higher level Brueckner orbital calculations were used for a few key compounds. In all, 46 enediynes, 44 cyclization transition states, 39 singlet p-benzynes, and 28 related triplet p-benzynes were studied, including simple vinyl-substituted and annulated examples. The data indicate that strongly electron-withdrawing groups increase the cyclization barrier, while sigma-donating groups decrease it; pi conjugation, especially donation, has little effect. Most annulations, including those involving heteroaromatic rings, lower the barrier slightly (6 MR) or raise it slightly (5 MR). Larger effects are seen for smaller rings or charged rings. Some previously observed apparent rate inhibitions are seen to be due to reversibility or forward reactivity of the intermediate p-benzynes, which are thereby inhibited from the H abstraction step that completes cycloaromatization. H abstraction reactivity, as judged from the p-benzyne singlet-triplet energy gap and from isodesmic equations, is also examined. Unexpected behavior is predicted for some heteroaromatic systems. Finally, we anticipate how these results may be applied to the design of prodrug candidates for subsequent biological application.

Chemistry, Organic↗

PubMed2002

A Ru catalyzed divergence: oxidative cyclization vs cycloisomerization of bis-homopropargylic alcohols.

During the course of investigating the development of catalytic reactions involving ruthenium vinylidene intermediates, a novel divergence of reactivity was discovered. The oxidative cyclization of bis-homopropargylic alcohols with Ru(+2) complexes as catalysts and N-hydroxysuccinimide as oxidant, which requires formation of a ruthenium vinylidene intermediate, is complicated by the simple electrophilically initiated direct attack of the hydroxyl group on a pi-complex of the alkyne and ruthenium. A catalytic system composed of CpRu[(p-CH(3)O(6)H(4))(3)P](2)Cl and excess (p-CH(3)O-C(6)H(4))(3)P directs the reaction toward the oxidative cyclization to form delta-lactones in good yields. Significantly, a simple switch of catalyst to CpRu[(p-FC(6)H(4))(3)P](2)Cl redirects the reaction to a cycloisomerization to form dihydropyrans in good yields. The synthetic utility of the oxidative cyclization is illustrated by the synthesis of oviposition attractant pheromone of the mosquito Culex pipens. The utility of the cycloisomerization to dihydropyrans is demonstrated by an iterative process leading to the antiviral agent narbosine B. A rationale for this dramatic switch by simple ligand modification is proposed.

Alkynes↗