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PubMed1996

Protonation sites in gaseous pyrrole and imidazole: a neutralization-reionization and ab initio study.

Mild gas-phase acids C4H9+ and NH4+ protonate pyrrole at C-2 and C-3 but not at the nitrogen atom, as determined by deuterium labeling and neutralization-reionization mass spectrometry. Proton affinities in pyrrole are calculated by MP2/6-311G(2d,p) as 866, 845 and 786 kJ mol-1 for protonation at C-2, C-3 and N, respectively. Vertical neutralization of protonated pyrrole generates bound radicals that in part dissociate by loss of hydrogen atoms. Unimolecular loss of hydrogen atom from C-2- and C-3-protonated pyrrole cations is preceded by proton migration in the ring. Protonation of gaseous imidazole is predicted to occur exclusively at the N-3 imine nitrogen to yield a stable aromatic cation. Proton affinities in imidazole are calculated as 941, 804, 791, 791 and 724 for the N-3, C-4, C-2, C-5 and N-1 positions, respectively. Radicals derived from protonated imidazole are only weakly bound. Vertical neutralization of N-3-protonated imidazole is accompanied by large Franck-Condon effects which deposit on average 183 kJ mol-1 vibrational energy in the radicals formed. The radicals dissociate unimolecularly by loss of hydrogen atom, which involves both direct N-H bond cleavage and isomerization to the more stable C-2 H-isomer. Potential energy barriers to isomerizations and dissociations in protonated pyrrole and imidazole isomers and their radicals were investigated by ab initio calculations.

Imidazoles↗
PubMed2005

Acyl transfer in clorobiocin biosynthesis: involvement of several proteins in the transfer of the pyrrole-2-carboxyl moiety to the deoxysugar.

Clorobiocin is an aminocoumarin antibiotic containing a pyrrole-2-carboxyl moiety, attached through an ester bond to a deoxysugar. The pyrrole moiety is important for the binding of the antibiotic to its biological target, gyrase. The complete biosynthetic gene cluster for clorobiocin has been cloned and sequenced from the natural producer, Streptomyces roseochromogenes DS 12.976. In this study, the genes cloN1 and cloN7 were deleted separately from a cosmid containing the complete clorobiocin cluster. The modified cosmids were introduced into the genome of the heterologous host Streptomyces coelicolor M512 by using the integration functions of the PhiC31 phage. While a heterologous producer strain harbouring the intact clorobiocin biosynthetic gene cluster accumulated clorobiocin, the cloN1- and cloN7-defective integration mutants accumulated a clorobiocin derivative that lacked the pyrrole-2-carboxyl moiety, while also producing free pyrrole-2-carboxylic acid. The structures of these metabolites were confirmed by NMR and MS analysis. These results showed that CloN1 and CloN7, together with the previously investigated CloN2, are involved in the transfer of the pyrrole-2-carboxyl moiety to the deoxysugar of clorobiocin. A possible mechanism for the role of these three proteins in the acyl-transfer process is suggested.

Acylation↗
PubMed1992

Chemistry of sulphur-bound pyrrolic metabolites in the blood of rats given different types of pyrrolizidine alkaloid.

Rats were injected with the pyrrolizidine alkaloids heliotrine, indicine, or anacrotine, and killed after 20 hr. Alkaloid metabolites conjugated to haemoglobin thiol groups were recovered in the form of pyrrolic monoethyl ethers, by treating blood samples with ethanolic silver nitrate under "buffered" conditions. Chemically prepared putative toxic metabolites of the alkaloids--dehydroheliotrine, dehydroindicine, and dehydroanacrotine--were also allowed to react in vitro with blood and with an immobilized thiol, thiol-Sepharose, and subsequently the S-conjugated pyrroles were again recovered as ethyl ethers. The recovered pyrrolic ethers were identified by comparing them with reference compounds prepared from ethanol and the dehydro-alkaloids, and the structures of the S-bound pyrroles were deduced. Blood from rats given the 9-monoester alkaloids heliotrine or indicine contained pyrrolic residues, S-bound at their 9-position. Anacrotine-treated rats yielded two diastereomeric 7-ethers, showing that dehydrocrotanecine 7-conjugates had been present in the blood. The products from alkaloid-treated rats were identical with those from blood or thiol-Sepharose treated with the corresponding dehydro-alkaloids in vitro. This supported the view that proximal metabolites leading to S-binding in vivo were the dehydro-derivatives of the alkaloids. In each case the thiols were attacked by the most reactive centre of the dehydro-alkaloid: the 9-ester in dehydroheliotrine and dehydroindicine, and the 7-ester in dehydroanacrotine. Accordingly, simple chemical reactions could account for the products formed in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Detection of sulphur-conjugated pyrrolic metabolites in blood and fresh or fixed liver tissue from rats given a variety of toxic pyrrolizidine alkaloids.

Rats were given single injections of hepatotoxic pyrrolizidine alkaloids and killed after 30 h. Sulphur-bound pyrrolic metabolites from the alkaloids in samples of their blood or liver tissue were converted to extractable ethyl ethers of low molecular weight for detection and identification using TLC, HPLC or GC-MS. Liver samples were also preserved as an acetone-washed powder or in formalin-based fixative before being later subjected to similar analyses. S-Bound pyrrolic metabolites were identified in samples from rats given all the types of alkaloid tested, which included mono-esters (heliotrine, indicine), a diester (lasiocarpine), and macrocyclic diesters (retrorsine, senecionine). The pattern of pyrrolic metabolites from the crotanecine-based alkaloid anacrotine differed and could be distinguished from retronecine- or heliotridine-based alkaloids. Whereas the alkaloids tested ranged widely in toxicity, single doses of 0.25 x acute LD50 or more led to detectable metabolites. Liver pyrroles remained detectable in fixed or powdered samples preserved for long periods. Similar tests on rats given monocrotaline continuously in their drinking water (20 mg/l) led to detectable pyrroles in blood after 12 days (total intake approx. 27 mg/kg) and in liver after 25 days. The metabolites remained detectable in rats killed 17 days after the alkaloid exposure was discontinued. The simple procedures described are applicable to the diagnosis of pyrrolizidine alkaloid exposure in livestock, using fresh or dried blood or fresh or preserved liver samples. They bring to pyrrolizidine toxicology for the first time the capability to demonstrate chemically that livestock (or people) have been exposed to these alkaloids many days or weeks previously.

Animals↗
PubMed1999

Four-Coordinate, Low-Spin (S = 0) and Six-Coordinate, High-Spin (S = 1) Nickel(II) Complexes of Tetraphenylporphyrins with beta-Pyrrole Electron-Withdrawing Substituents: Porphyrin-Core Expansion and Conformation.

To examine the porphyrin-core expansion and the conformational variations induced by a change in the coordination sphere of nickel(II) from four-coordinate, low-spin (S = 0) to six-coordinate, high-spin (S = 1), several nickel(II) derivatives of tetraphenylporphyrins, substituted in their beta-pyrrole positions with electron-withdrawing groups, were isolated and studied by X-ray crystallography. The four-coordinate nickel(II) complex studied, Ni(TPP(Br)(4)(CN)(4)) (1), is a derivative of the antipodal beta-pyrrole brominated and cyanated macrocycle, 2,3,12,13-tetrabromo-7,8,17,18-tetracyano-5,10,15,20-tetraphenylporphyrin. One of the six-coordinate species is the bis-pyridine nickel(II) adduct, Ni(TPP(Br)(4)(CN)(4))(py)(2) (2), of this antipodal beta-pyrrole brominated and cyanated ring, whereas the second six-coordinate complex is the bis-1-methylimidazole nickel(II) adduct, Ni(TPP(CN)(4))(1-MeIm)(2) (3), of the antipodal tetracyanated macrocycle, 7,8,17,18-tetracyano-5,10,15,20-tetraphenylporphyrin. This study confirms that, upon conversion of a four-coordinate, low-spin nickel(II) derivative of a beta-pyrrole-substituted tetraphenylporphyrin into a six-coordinate, high-spin complex, a radial expansion of the porphyrin core also takes place. This radial expansion flattens the porphyrin core, inducing more planarity in the conformations of the six-coordinate nickel(II) porphyrin species. The X-ray structure of 1 reveals an average Ni-N(p) bond distance of 1.920(2) Å, similar to that present in tetragonal Ni(OEP) [(Ni-N(p))(av) = 1.929(3) Å], the ruffled low-spin nickel(II) (S = 0) porphyrin derivative, and many other low-spin nickel(II) complexes of distorted porphyrins. The conformation of the macrocycle present in 1 is severely saddle-shaped with a small ruffling and a minor doming. The structures of 2 and 3 indicate a clear expansion of the porphyrin cores with two sets of (Ni-N(p))(av) bond lengths of 2.040(2) and 2.073(2) Å in 2 and 2.037(2) and 2.068(2) Å in 3, which differ significantly from the average Ni-N(p) distance occurring in 1. Relative to the conformation of the porphyrin ring present in 1, the high-spin complex 2 is less saddle-shaped, but more ruffled. In 3, in which only two opposite pyrrole rings of the porphyrin are substituted by cyano groups, the macrocycle adopts a slightly waved conformation. Crystal data: Ni(TPP(Br)(4)(CN)(4)).2.5(1,2-Cl(2)C(2)H(4)), [1.2.5(1,2-Cl(2)C(2)H(4))], triclinic, space group P&onemacr;, a = 13.741(1) Å, b = 14.029(2) Å, c = 15.201(2) Å, alpha = 89.037(9) degrees, beta = 70.829(8) degrees, gamma = 67.607(8) degrees, V = 2539.4(5) Å(3), T = 20 degrees C, Z = 2, R(F)() = 0.047 and R(wF) = 0.067 based on 5341 reflections with I > 3sigma(I); Ni(TPP(Br)(4)(CN)(4))(py)(2).2.5(1,2-Cl(2)C(2)H(4)), [2.2.5(1,2-Cl(2)C(2)H(4))], triclinic, space group P&onemacr;, a = 11.9472(9) Å, b = 14.3651(7) Å, c = 19.556(1) Å, alpha = 87.049(5) degrees, beta = 73.181(6) degrees, gamma = 70.613(5) degrees, V = 3026.8(4) Å(3), T = 173 K, Z = 2, R(F)() = 0.036, R(wF) = 0.041 based on 6846 reflections with I > 3sigma(I); Ni(TPP(CN)(4))(1-MeIm)(2).2CH(2)Cl(2), [3.2(CH(2)Cl(2))], monoclinic, space group C2/c, a = 26.804(8) Å, b = 10.948(3) Å, c = 19.453(5) Å, beta = 113.13(2) degrees, V = 5251.5 Å(3), T = 20 degrees C, Z = 4, R(F)() = 0.047, R(wF) = 0.067 based on 4384 reflections with I > 3sigma(I).

Journal Article↗
PubMed2006

Synthesis, structure, anion binding, and sensing by calix[4]pyrrole isomers.

The synthesis, structure, and anion binding properties of chromogenic octamethylcalix[4]pyrroles (OMCPs) and their N-confused octamethylcalix[4]pyrrole isomers (NC-OMCPs) containing an inverted pyrrole ring connected via alpha'- and beta-positions are described. X-ray diffraction analyses proved the structures of two synthesized isomeric pairs of OMCPs and NC-OMCPs. The addition of anions to solutions of chromogenic OMCPs and NC-OMCPs resulted in different colors suggesting different anion-binding behaviors. The chromogenic NC-OMCPs showed significantly stronger anion-induced color changes compared to the corresponding chromogenic OMCP, and the absorption spectroscopy titrations indicated that chromogenic OMCPs and NC-OMCPs also possess different anion binding selectivity. Detailed NMR studies revealed that this rather unusual feature stems from a different anion-binding mode in OMCPs and NC-OMCPs, one where the beta-pyrrole C-H of the inverted pyrrole moiety participates in the hydrogen-bonded anion-NC-OMCP complex. Preliminary colorimetric microassays using synthesized chromogenic calixpyrroles embedded in partially hydrophilic polyurethane matrices allow for observation of analyte-specific changes in color when the anions are administered in the form of their aqueous solutions and in the presence of weakly competing anions.

Journal Article↗
PubMed2005

Formation process of silver-polypyrrole coaxial nanocables synthesized by redox reaction between AgNO3 and pyrrole in the presence of poly(vinylpyrrolidone).

We have recently demonstrated a one-step process to fabricate silver-polypyrrole (PPy) coaxial nanocables (Chen, A.; Wang, H.; Li, X. Chem. Commun. 2005, 14, 1863). The formation process of silver-PPy coaxial nanocables is discussed in this article. It was found from the results of TEM and SEM images that large numbers of silver atoms were formed when AgNO3 was added to a pyrrole solution. Then silver atoms transform to silver-PPy nanosheets with regular morphology, which will connect together to be more stable. Silver-PPy nanocables will be able to grow at the expense of the silver-PPy nanosheets. Poly(vinylpyrrolidone) (PVP) plays crucial roles in this process: as a capping agent to form silver nanowires, and as a dispersant of pyrrole monomers, which can influence the site at which pyrrole monomer exists. On the basis of experimental analysis, the possible mechanism was proposed. Because of the effect of PVP, silver ions and pyrrole monomers are apt to be adsorbed at the [111] and [100] facets of silver nanosheets, respectively. Obvious polymerization will take place on the boundary of the [111] and [100] facets. The PPy layer stays stable on the [100] facets. Meanwhile, newly formed silver atoms and silver nanosheets will further ripen and grow on the [111] facets. In a word, the morphology of final products and the formation process are determined by the reaction site between AgNO3 and the pyrrole monomer, which is influenced by PVP.

Journal Article↗
PubMed1998

Pyrrole-2-carboxylate decarboxylase from Bacillus megaterium PYR2910, an organic-acid-requiring enzyme.

Inducible pyrrole-2-carboxylate decarboxylase, which catalyzes the decarboxylation of pyrrole-2-carboxylate to pyrrole and CO2 in stoichiometric amounts, was purified from Bacillus megaterium PYR2910. The purity of the enzyme was shown by SDS/PAGE and gel-permeation HLPC. The enzyme has a molecular mass of approximately 98 kDa and consists of two identical subunits. It is highly specific for pyrrole-2-carboxylate, and also catalyzes the reverse reaction, the carboxylation of pyrrole. A unique feature of this enzyme is its requirement of an organic acid, such as acetate, propionate, butyrate or pimelate. A possible catalytic mechanism including a cofactor function of organic acid is discussed.

Acetates↗
PubMed2005

Photochemistry of pyrrole: time-dependent quantum wave-packet description of the dynamics at the 1pi sigma*-S0 conical intersections.

The photoinduced hydrogen-elimination reaction in pyrrole via the conical intersections of the two (1)pi sigma(*) excited states with the electronic ground states [(1)B(1)(pi sigma(*))-S(0) and (1)A(2)(pi sigma(*))-S(0)] have been investigated by time-dependent quantum wave-packet calculations. Model potential-energy surfaces of reduced dimensionality have been constructed on the basis of accurate multireference ab initio electronic-structure calculations. For the (1)B(1)-S(0) conical intersection, the model includes the NH stretching coordinate as the tuning mode and the hydrogen out-of-plane bending coordinate as the coupling mode. For the (1)A(2)-S(0) conical intersection, the NH stretching coordinate and the screwing coordinate of the ring hydrogens are taken into account. The latter is the dominant coupling mode of this conical intersection. The electronic population-transfer processes at the conical intersections, the branching ratio between the dissociation channels, and their dependence on the initial preparation of the system have been investigated for pyrrole and deuterated pyrrole. It is shown that the excitation of the NH stretching mode strongly enhances the reaction rate, while the excitation of the coupling mode influences the branching ratio of different dissociation channels. The results suggest that laser control of the photodissociation of pyrrole via mode-specific vibrational excitation should be possible. The calculations provide insight into the microscopic details of ultrafast internal-conversion processes in pyrrole via hydrogen-detachment processes, which are aborted at the (1)pi sigma(*)-S(0) conical intersections. These mechanisms are of relevance for the photostability of the building blocks of life (e.g., the DNA bases).

Journal Article↗
PubMed2003

CloN2, a novel acyltransferase involved in the attachment of the pyrrole-2-carboxyl moiety to the deoxysugar of clorobiocin.

The aminocoumarin antibiotic clorobiocin contains a 5-methylpyrrole-2-carboxylic acid unit, attached via an ester bond to the 3-OH group of the deoxysugar moiety. To investigate candidate genes responsible for the formation of this ester bond, a gene inactivation experiment was carried out in the clorobiocin producer Streptomyces roseochromogenes var. oscitans DS 12.976. An in-frame deletion was created in the coding sequence of the gene cloN2. The production of secondary metabolites in the wild-type and in the cloN2 mutant was analysed. The wild-type showed clorobiocin as the main product, whereas the cloN2 mutant accumulated a new aminocoumarin derivative, novclobiocin 104, lacking the pyrrole moiety at the 3-OH of the deoxysugar. In addition, free pyrrole-2-carboxylic acid accumulated in the culture extract of the cloN2 mutant. The structures of the metabolites were confirmed by NMR and LC-MS analysis. Clorobiocin production was successfully restored in the cloN2 mutant by introducing a replicative plasmid containing the cloN2 sequence. These results prove an involvement of cloN2 in the formation of the ester bond between the pyrrole moiety and the deoxysugar in clorobiocin biosynthesis. Furthermore, they indicate that the C-methylation at position 5 of the pyrrole moiety occurs after the attachment of pyrrole-2-carboxylic acid unit to the deoxysugar moiety.

Acyltransferases↗
PubMed2002

Ethyl 3,5-dimethyl-4-phenyl-1H-pyrrole-2-carboxylate.

In the title compound, C(15)H(17)NO(2), the ethoxycarbonyl group is anti with respect to the pyrrole N atom. The angle between the planes of the phenyl and pyrrole rings is 48.26 (9) degrees. The molecules are joined into dimeric units by a strong hydrogen bonds between pyrrole N-H groups and carbonyl O atoms. The geometry of the isolated molecule was studied by ab initio quantum mechanical calculations, employing both molecular orbital Hartree-Fock (MO-HF) and density functional theory (DFT) methods. The minimum energy was achieved for a conformation where the angle between the planes of the phenyl and pyrrole rings is larger, and that between the ethoxycarbonyl and pyrrole planes is smaller than in the solid-state molecule.

Journal Article↗
PubMed2000

Formation of protein bound lysine-derived galactosyl and glucosyl pyrroles in heated model systems.

Residues of lysine-substituted AGEs (advanced glycosylation end-products) arising from the Maillard reaction and containing the carbon backbone of lactose or maltose, thus deriving from 1-desoxy-ketose degradation, were produced when casein was heated in the presence of the corresponding U14C labelled disaccharides. The enzymatic hydrolysates of the washed casein were purified by SPE and submitted to HPLC on a C18 column flushed with diluted acetic acid. A specific chromatographic peak (lambda max, 288.1 nm; MW, 416.2 Da) with a different retention time was obtained for each disaccharide reacted. On the basis of the value of the specific radioactivity, the two compounds appeared to contain the whole carbon backbone of the parent sugar. Analyses by MS/MS and NMR performed on the same two compounds extracted at preparative scale from lysine-lactose and lysine-maltose model systems allowed the structure assignment of 6-[2-acetyl-3-(beta-D-galactopyranosyloxy)-1-pyrrolyl] 2-amino hexanoic acid and 6-[2-acetyl-3-(alpha-D-glucopyranosyloxy)-1-pyrrolyl] 2-amino hexanoic acid, respectively. Both compounds submitted to enzymatic deglycosylation by specific alpha- or beta-glucosidases produced the lysine-derived acetyl pyrrole 6-(2-acetyl-3-hydroxy-1-pyrrolyl) 2-amino hexanoic acid (lambda max, 288.1 nm; MW, 254.1 Da). Galactosyl- and glucosyl-isomaltoles, extracted from the lysine-containing systems, identified with the reference molecules and heated in the presence of lysine under slightly alkaline conditions, gave the expected lysine-derived glycosyl pyrroles as identified above. The HPLC conditions were optimized by adjusting the composition of the eluting solvent and temperature of the column to achieve the best separation and identification of the AGEs in mixtures such as foods with possible interfering molecules like Trp and lysyl pyrrole aldehyde. Because of the reported presence of the two precursors isomaltol glycosydes in some foods, the corresponding lysine-derived glycosyl pyrroles can occur as both protein bound and in free form.

Caseins↗
PubMed1986

Structural basis of gamma-diketone neurotoxicity: non-neurotoxicity of 3,3-dimethyl-2,5-hexanedione, a gamma-diketone incapable of pyrrole formation.

The chronic exposure to gamma-diketones results in the formation of giant neurofilament (NF)-containing axonal enlargements, followed by axonal degeneration in peripheral axons. Based on the specific ability of gamma-diketones to react with primary amino groups to form pyrroles, and the observation of such reaction with NF protein in vitro and with other proteins in vivo, it has been proposed that pyrrole formation at primary amino groups of NF protein is responsible for the neurotoxicity of gamma-diketones. We have tested this hypothesis through an investigation of the neurotoxicity in rats of 3,3-dimethyl-2,5-hexanedione (3,3-DMHD), a gamma-diketone which is incapable of forming pyrroles. 3,3-DMHD was found to produce only a slight alteration of axonal caliber and no clinical neurotoxicity after up to 12 weeks of administration, at a dose over 20 times that for which its isomer 3,4-dimethyl-2,5-hexanedione (3,4-DMHD) produced massive focal NF-containing axonal enlargements and complete paralysis in 4 weeks. These results support the view that the pyrrole-forming capability of gamma-diketones is the initial molecular event in the pathogenesis of gamma-diketone neurotoxicity.

Animals↗
PubMed2004

Novel pyrrole-containing progesterone receptor modulators.

A series of 1,4-dihydro-2H-[d][3,1]-benzoxazin-2-one and 1,3-dihydro-[3H]-indol-2-one containing 6- or 5-, respectively, appended substituted pyrrole moieties were synthesized and evaluated for their ability to modulate the activity of the progesterone receptor (PR). Key structural changes to the pyrrole moieties of these molecules were shown to have a predictive influence as to whether the compounds behaved as PR agonists or antagonists. Compounds with the 5(')-cyano-2(')-pyrrole moiety (e.g., 32, 33, and 38) were shown to be potent PR agonists (EC(50)'s of 1.1, 1.8, and 2.8 nM, respectively). Compounds with the 5(')-nitro-2(')-pyrrole moiety (e.g., 34 and 36) were shown to be PR antagonists (IC(50)'s of 180 and 36 nM, respectively).

Benzoxazines↗
PubMed2006

1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: new high affinity ligands for the cannabinoid CB1 and CB2 receptors.

Two series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles were synthesized and their affinities for the cannabinoid CB(1) and CB(2) receptors were determined. In the 2-phenyl series (5) the N-alkyl group was varied from n-propyl to n-heptyl. A second series of 23 1-pentyl-2-aryl-4-(1-naphthoyl)-pyrroles (6) was also prepared. Several compounds in both series have CB(1) receptor affinities in the 6-30nM range. The high affinities of these pyrrole derivatives relative to JWH-030 (1, R=C(5)H(11)) support the hypothesis that these pyrroles interact with the CB(1) receptor primarily by aromatic stacking.

Binding, Competitive↗
PubMed1999

Anti-repression of RNA polymerase II transcription by pyrrole-imidazole polyamides.

Pyrrole-imidazole polyamides are ligands that bind in the minor groove of DNA with high affinity and sequence selectivity. Molecules of this class have been shown to disrupt specific transcription factor-DNA interactions and to inhibit basal and activated transcription from various RNA polymerase II and III promoters. A set of eight-ring hairpin-motif pyrrole-imidazole polyamides has been designed to bind within the binding site for the human cytomegalovirus (CMV) UL122 immediate early protein 2 (IE86). IE86 represses transcription of the CMV major immediate early promoter (MIEP) through its cognate cis recognition sequence (crs) located between the TATA box and the transcription initiation site. The designed polyamides bind to their target DNA sequence with nanomolar affinities and with a high degree of sequence selectivity. The polyamides effectively block binding of IE86 protein to the crs in DNase I footprinting experiments. A mismatch polyamide, containing a single imidazole to pyrrole substitution, and also a polyamide binding to a site located 14 base pairs upstream of the repressor binding site, do not prevent IE86 binding to the crs. IE86-mediated transcriptional repression in vitro is relieved by a match polyamide but not by a mismatch polyamide. Transcription from a DNA template harboring a mutation in the crs is not affected either by IE86 protein or by the match polyamides. These results demonstrate that this new class of small molecules, the pyrrole-imidazole polyamides, are not only effective inhibitors of basal and activated transcription, but also can be used to activate transcription by blocking the DNA-binding activity of a repressor protein.

Binding Sites↗
PubMedDate not supplied

Solution phase synthesis of a library of tetrasubstituted pyrrole amides.

An efficient strategy for the solution-phase parallel synthesis of a library of pyrrole-amides is described. Key reactions include functional homologation of beta-ketoesters with a set of aldehydes followed by oxidation to produce a series of differently substituted 1,4-dicarbonyl compounds. Rapid cyclization using a microwave-assisted Paal-Knorr reaction provided a set of 24 pyrrole esters that were further functionalized through a trimethylaluminum-mediated aminolysis to obtain a larger library of 288 diverse pyrrole-3-amides. The tetrasubstitution allows a good exploration of the chemical space around the central pyrrole core. The last step was entirely automated with a Bohdan Myriad personal synthesizer.

Amides↗
PubMed1995

Antifungal agents. 9. 3-Aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]pyrroles: a new class of potent anti-Candida agents.

A new class of potent antifungal agents, namely, 3-aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]-pyrroles, is described. These compounds are related to bifonazole and pyrrolnitrin, two compounds belonging to the class of antimycotic drugs. The synthesis of the title pyrroles has been performed starting from 1,3-diaryl-2-propen-1-ones, which were reacted with tosylmethyl isocyanide to give 3-aroyl-4-arylpyrroles. Reduction of the resulting compounds by lithium aluminum hydride furnished the related alcohols, which were treated with 1,1'-carbonyldimidazole to afford the required imidazole derivatives. Forty-four new pyrroles which incorporate an (arylmethyl)imidazole moiety in the 3-arylpyrrole structure were prepared by the above procedure and tested in vitro against Candida albicans and Candida spp. Among test compounds, 10 were found to be highly active against C. albicans. The most active derivative (27) was twice as potent (MIC90) as bifonazole, and its activity was 4 times greater than those of miconazole and ketoconazole. The other nine compounds showed antifungal activity of the same order of that of bifonazole and were ca. 2 times as active as miconazole and ketoconazole. Derivatives 21 and 27 tested in vivo against C. albicans A170 were shown to be highly effective in rabbit skin candidosis. Pharmacological studies on compounds 27 and other related pyrroles (19, 35, 36, 38, 39, and 49) are in progress to select one of them as a potential candidate for clinical experiments.

Adult↗