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PubMed1999

Cofactor requirements and reconstitution of microcin B17 synthetase: a multienzyme complex that catalyzes the formation of oxazoles and thiazoles in the antibiotic microcin B17.

In the maturation of the Escherichia coli antibiotic Microcin B17 (MccB17), the McbA prepro-antibiotic is modified post-translationally by the multimeric microcin synthetase complex (composed of the McbB, -C, and -D proteins), which cyclizes four cysteines and four serines to thiazoles and oxazoles, respectively. Herein, we report the purification of individual subunits of MccB17 synthetase as fusions to maltose binding protein (MBP), and the in vitro reconstitution of heterocyclization activity. Preliminary characterization of each subunit reveals McbB to be a zinc-containing protein that may catalyze the initial cyclodehydration step, and McbC to contain flavin, consistent with an anticipated role for a dehydrogenase. We have previously demonstrated that McbD is a regulated ATPase/GTPase that may function as a conformational switch. Photolabeling experiments with the McbA propeptide now identify McbD as the initial site of substrate recognition. Heterocyclization activity was reconstituted only by combining all three subunits, demonstrating that each protein is required for heterocycle formation. Titration assays indicate that the subunits bind to each other with at least micromolar affinities, although McbD affords activity only after the MBP tag is proteolytically removed. Subunit competition assays with an McbDD147A mutant, which yields a catalytically deficient synthetase in vivo, show it to be defective in complex formation, whereas the McbBC181A/C184A double mutant, which is also inactive, competitively inhibits reconstitution by native McbB. Addition of the HtpG chaperone (originally shown to copurify with MccB17 synthetase), does not stimulate synthetase reconstitution or heterocyclization activity in vitro. A model for synthetase activity is proposed.

Amino Acid Sequence↗
PubMedDate not supplied

Trifluoroacetic anhydride-mediated solid-phase version of the Robinson-Gabriel synthesis of oxazoles.

A traceless solid-phase synthesis of oxazoles 4 via Robinson-Gabriel reaction of solid-supported alpha-acylamino ketones 2 has been achieved. The reaction requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and that trifluoroacetic anhydride be used as the cyclodehydrating agent. The solvent has a dramatic effect on the latter reaction, which goes to completion and follows a cyclative-type mechanism only when an ethereal solvent is used. Different synthetic routes have been investigated toward assembling compounds 2. The most straightforward one, which we have validated more extensively, comprises the reaction of Merrifield alpha-methoxyphenyl (MAMP) resin with an alpha-amino ketone to form compounds 1, which are, in turn, acylated. Other methodologies and strategies allowing for the synthesis of compounds 1 that have been investigated include direct alkylation of Rink amide resin; reductive amination of the latter with alpha-keto aldehydes; reaction of MAMP resin with alpha-amino alcohols, followed by oxidation; and protection of Rink amide resin with either 2,4-dinitrosulfonyl or allyl group, followed by alkylation and removal of protecting group. In addition, we disclose a novel variant of the Ugi four-component reaction that allows for the preparation of compounds 2 in a single synthetic step.

Acetic Anhydrides↗
PubMedDate not supplied

Four-dimensional quantitative structure-activity relationship analysis of a series of interphenylene 7-oxabicycloheptane oxazole thromboxane A2 receptor antagonists.

A series of 39 (a training set of 29 and a test set of 10) interphenylene 7-oxabicyclo [2.2.1]heptane oxazole thromboxane A2 (TXA2) receptor antagonists were studied using four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis. Two thousand conformations of each analogue were sampled to generate a conformational energy profile (CEP) from a molecular dynamic simulation (MDS) of 100,000 trajectory states. Each conformation was placed in a grid cell lattice for each of six trial alignments. Cubic grid cell sizes of 1 and 2 A were considered. The frequency of occupation of each grid cell was computed for each of seven types of pharmacophoric group classes of atoms of each compound. These grid cell occupancy descriptors (GCODs) were then used as independent variables in constructing three-dimensional (3D)-QSAR models after data reduction. The types of data reduction included doing no reducing, reduction based on individual GCOD correlation with activity, and reduction from minimum variance constraints over the GCOD population. The 3D-QSAR models were generated and evaluated by a scheme that combines a genetic algorithm (GA) optimization with partial least squares (PLS) regression. The 3D-QSAR models were evaluated by cross-validation using the leave-one-out technique. The cross-validated correlation coefficient, Q2, ranged from 0.27 to 0.86. The models are not from chance correlation because a scrambled data set was generated and evaluated (Q2 = 0.25-0.37). A composite 3D-QSAR model was constructed using the best models derived from GCODs of both 1 and 2 A grid cell size lattices. The 3D-QSAR models provide detailed 3D pharmacophore requirements in terms of atom types and corresponding locations needed for high TXA2 inhibition activity. Specific sites in space that should not be occupied by an active inhibitor are also specified. The GCOD measures for the compounds in the training set permit reference points regarding which pharmacophore sites can provide the largest boosts in inhibition activity relative to the existing analogues.

Drug Design↗
PubMed2003

Synthesis of [L-Ala-1]RA-VII, [D-Ala-2]RA-VII, and [D-Ala-4]RA-VII by epimerization of RA-VII, an antitumor bicyclic hexapeptide from Rubia plants, through oxazoles.

Three epimers of a natural cyclic hexapeptide RA-VII were prepared via formation of oxazoles from thioamides or thioimidates of RA-VII followed by hydrolysis. They are the epimers at l-Ala-1, d-Ala-2, and d-Ala-4, respectively. The one having l-Ala-1 adopted trans-cis-trans-trans-trans-trans (t-c-t-t-t-t) amide configurations in the crystal, a type-VI beta-turn for residues 1-4 stabilized by one intramolecular hydrogen bond between Ala-4 NH and l-Ala-1 C = O, and in CDCl(3) existed as a mixture of six conformers, of which the major conformer was very similar to that in the crystal, but quite different from that of RA-VII in solution. The second epimer, having d-Ala-2 had in the crystalline state t-t-t-t-c-t amide configurations, a gamma-turn at Tyr-3 stabilized by two intramolecular hydrogen bonds between d-Ala-2 NH and Ala-4 C = O and between Ala-4 NH and d-Ala-2 C = O, and existed in CDCl(3) as a single conformer, the structure of which was very similar to its crystal structure, and to the crystal structure of peptide 25 except for the backbone and the side chains at residues 1 and 2. The third epimer, having d-Ala-4 had t-c-t-t-c-t amide configurations in the crystal, a type-VI beta-turn for residues 1-4 as observed in the first epimer, and in CDCl(3) existed in three conformers, of which the major one was similar to that in the crystal but different from that of RA-VII in solution. The three epimers showed very weak cytotoxicity on P-388 leukemia cells, which may be because of their conformational differences from the active conformation of RA-VII.

Alanine↗
PubMed2004

5H-oxazol-4-ones as building blocks for asymmetric synthesis of alpha-hydroxycarboxylic acid derivatives.

5H-Alkyl-2-phenyl-oxazol-4-ones, a little-known heterocyclic ring system, are readily available via a microwave-assisted, sodium fluoride catalyst cyclization of mono-alpha-haloimides, which in turn are accessed by N-acylation of benzamides with alpha-bromo acid halides. Terminally substituted allyl systems serve as excellent substrates for Mo-catalyzed asymmetric allylic alkylation. The resultant products are formed with excellent ees involving a catalyst derived from N,N'-bis-picolinamide of trans-1,2-diaminocyclohexane and cycloheptatriene molybdenum tris(carbonyl). In addition to benzenoid, nonbenzenoid aromatic and vinyl substituents on the allyl carbonate moiety provide good to excellent regio- and diastereoselectivity as well as excellent enantioselectivity. Substituents on the heterocycle include methyl, n-butyl, allyl, isobutyl, isopropyl, and cyclohexyl. The presence of a double bond in the product allows them to be further modified via the chemistry of the double-bond, including metathesis. The products are hydrolyzed under basic conditions to provide alpha-hydroxyamides.

Alcohols↗
PubMed2005

Structural mimicry of two cytochrome b(562) interhelical loops using macrocycles constrained by oxazoles and thiazoles.

A major chemical challenge is the structural mimicry of discontinuous protein surfaces brought into close proximity through polypeptide folding. We report the design, synthesis, and solution structure of a highly functionalized saddle-shaped macrocyclic scaffold, constrained by oxazoles and thiazoles, supporting two short peptide loops projecting orthogonally from the same face of the scaffold. This structural mimetic of two interhelical loops of cytochrome b(562) illustrates a promising approach to structurally mimicking discontinuous loops of proteins.

Biomimetic Materials↗
PubMed2006

Oxazole-based peptide macrocycles: a new class of G-quadruplex binding ligands.

Herein we report on the synthesis and DNA binding properties of a new class of water soluble oxazole-based peptide macrocycles that bind selectively to quadruplex DNA, with no detectable binding to duplex DNA. We have recently identified one quadruplex in the proto-oncogene c-kit that is suspected to act as a regulatory element for the expression of the c-kit gene. Here we provide the first example of a ligand binding to and stabilizing the c-kit quadruplex. Moreover, we show that these macrocycles show a preference for the c-kit quadruplex as compared to the human telomeric quadruplex.

Base Sequence↗
PubMed1994

Synthesis of 2-methyl-(Z)-4-(phenylimino)naphth[2,3-d]oxazol-9-one , a monoimine quinone with selective cytotoxicity toward cancer cells.

A regio and stereospecific synthesis of 2-methyl-(Z)-4-(phenylimino)naphth[2,3-d]oxazol-9-one (1) was achieved by using titanium tetrachloride in methylene chloride in the preparation of the imine. The regiochemistry was assigned by single-crystal X-ray analysis. In vitro tests showed that this diastereomer is selectively active for some solid cancer tumors.

Antineoplastic Agents↗
PubMed1993

Nonprostanoid prostacyclin mimetics. 4. Derivatives of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid substituted alpha to the oxazole ring.

The 4,5-diphenyloxazole derivatives 2-4 were previously identified as nonprostanoid prostacyclin (PGI2) mimetics. A series of derivatives of 2-4 bearing substitutents at the carbon atom alpha to the oxazole ring were synthesized and evaluated as inhibitors of ADP-induced aggregation of human platelets in vitro. In the unsaturated series, the alpha-carbethoxy derivative 10a, evaluated as an equal mixture of geometrical isomers, inhibited platelet aggregation with an IC50 of 0.36 microM. Evaluation of the individual methyl ester derivatives (E)-9a and (Z)-9a revealed that (E)-9a was 10-fold more potent than (Z)-9a. In the saturated series, the alpha-carbomethoxy-substituted compound 12a inhibited platelet aggregation with an IC50 of 0.08 microM, 15-fold more potent than the unsubstituted prototype 2. The potency of 12a was found to be sensitive to variation of the methoxy moiety. The ethyl (12b) and isopropyl (12d) esters were less effective as were the acid 12e and a series of amides (12f-h). Other substituents introduced at this site of the pharmacophore included P(O)(OEt)2 (25), SCH3 (31a), S(O)CH3 (31b), SO2CH3 (31c), isopropyl (31d), phenyl (31f), and CH2OH (31i). However, none were significantly more potent inhibitors of platelet function than the parent compound 2. The results indicate the presence of a pocket in the PGI2 receptor protein that preferentially recognizes small, polar but uncharged substituents. The structure-activity correlates are suggestive of a hydrogen-bond interaction between a donor moiety on the PGI2 receptor and the methoxycarbonyl functionality of 12a that is sensitive to both the size of the substituent and its stereochemical presentation in this structural class of PGI2 mimetic. The ethyl ester 12b dose-dependently displaced [3H]iloprost from human platelet membranes and stimulated adenylate cyclase. However, the maximal stimulation was less than that recorded for iloprost, indicating that 12b functions as a partial agonist at the PGI2 receptor.

Adenosine Diphosphate↗
PubMed1979

Antianaphylactic agents. 1. 2-(Acylamino)oxazoles.

The synthesis and biological properties of 35 2-(acylamino)oxazoles are described. The majority of the compounds inhibit the release of slow-reacting substance of anaphylaxis (SRS-A) in vitro from sensitized guinea pig chopped lung. In addition, several of the compounds inhibited the release of SRS-A from passively sensitized human chopped lung and protected guinea pigs from the effects of anaphylaxis in a modified Herxheimer test.

Anaphylaxis↗
PubMed2006

Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles.

In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv (MIC = 0.006 microg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships of these new compounds are presented.

Antitubercular Agents↗
PubMed1996

The chemistry of Pseudomonic acid. 15. Synthesis and antibacterial activity of a series of 5-alkyl, 5-alkenyl, and 5-heterosubstituted oxazoles.

The synthesis of a range of 5-alkyl, 5-alkenyl, and 5-heterosubstituted 2-(1-normon-2-yl) oxazoles is described. The antibacterial activity was determined as the minimum inhibitory concentration against a range of Gram-positive and Gram-negative organisms using a standard Agar dilution procedure. Compounds possessing an acid functionality directly on, or close to, the ring were found to be of greatly decreased potency, while increasing lipophilicity with greater chain length led to increased potency of these derivatives.

Anti-Bacterial Agents↗
PubMed1998

Substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones as hypoglycemic agents.

A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.

Animals↗
PubMed1999

Alpha(2) adrenoceptor agonists as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -thiazoles.

A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53 displayed alpha(2) receptor binding in the 10-20 nM range and also had significant antinociceptive activity in the mouse abdominal irritant test (MAIT).

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

Oxazolium-derived azomethine ylides. External oxazole activation and internal dipole trapping in the synthesis of an aziridinomitosene.

Intermolecular alkylation of the aziridinyl oxazole 20 using PhSO(2)CH(2)CH(2)OTf is possible despite the presence of potentially nucleophilic aziridine nitrogen. The resulting oxazolium salt 22 reacts with BnNMe(3)(+)CN(-) to produce the azomethine ylide 24b via electrocyclic ring opening of an oxazoline 23b. Internal cycloaddition affords 26 in 66% yield. After saponification and base-induced cleavage of the N-phenylsulfonylethyl group, conventional cyclization provides access to 33. Deprotection and DDQ oxidation completes the synthesis of the aziridinomitosene derivative 9b. The starting cis-disubstituted aziridine ester 16 can be prepared by the aza-Darzens reaction of 15 with tert-butyl chloroacetate.

Aziridines↗
PubMed2002

Metalation of 4-oxazolinyloxazole derivatives. A convenient route to 2,4-bifunctionalized oxazoles.

The synthesis of an array of 5-phenyloxazole derivatives bearing a variety of hydroxyalkyl groups at the C-2 position of the heterocyclic nucleus and possessing a formyl or a carboxyl function at C-4 is reported. These bifunctionalized compounds have been efficiently prepared by addition of carbonylated electrophiles to the 2-lithio derivative of 5-phenyloxazole preliminarily equipped with an oxazoline unit at the 4-position of the oxazole nucleus. It is demonstrated that this protocol offers a double advantage since it suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline ring system.

Enzyme Inhibitors↗
PubMed2003

Total synthesis of dendroamide a: oxazole and thiazole construction using an oxodiphosphonium salt.

The total synthesis of dendroamide A (1), a multidrug-resistance reversing bistratamide-type peptide-derived macrocycle, has been accomplished in 19% yield. Fmoc-protected amino acids were condensed into appropriately protected dipeptides which were treated with bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate to afford oxazoles and thiazolines (oxidized to thiazoles) with high chemo- and stereoselectivity. The convergent condensation of three heterocyclic amino acids followed by macrocyclization afforded the natural product.

Amino Acids↗