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PubMed2007

Syntheses, structures, and anion-binding properties of two novel calix[2]benzo[4]pyrroles.

Calix[2]benzo[4]pyrrole m-6 and p-6, each containing two dipyrromethane moieties and two m-phenylene or p-phenylene units, respectively, were readily synthesised from pyrrole, 1,3- and 1,4-bis(1,1'-dimethylhydroxymethyl)benzene, (m-4 and p-4, respectively) and acetone. Macrocycles m-6 and p-6 were tested as receptors for a selection of anions, such as acetate, dihydrogenphosphate and fluoride. The X-ray structures of m-6 and p-6 and those of the complexes m-6F(-), m-6Cl(-) and m-6CH(3)COO(-) (with an nBu(4)N(+) counterion) were also determined.

Journal Article↗
PubMed2000

Synthesis and antibacterial activity of new cephalosporines containing a pyrrole ring in the N-acyl chain.

Nine new cephalosporines containing a pyrrole ring in the N-acyl chain have been synthesized by the N-acylation of 7-ACA or of its 3-analogues via the acid chlorides of substituted 2-pyrrole-carboxylic, -acetic or -propionic acids. H1 NMR and IR data confirming the structure are presented. Preliminary microbiological tests in vitro show significant antibacterial activity, compared with that of cefalexin. Some common structure-activity relationships have been observed.

Acylation↗
PubMed2005

Monocrotaline pyrrole targets proteins with and without cysteine residues in the cytosol and membranes of human pulmonary artery endothelial cells.

A single injection of monocrotaline produces a pulmonary insult in rats with a phenotype similar to human primary pulmonary hypertension. Although extensively used as a model, the mechanism(s) by which this chemical insult mimics a condition with genetic and environmental links remains an enigma, although formation of protein adducts has been implicated. Monocrotaline (MCT) is non-toxic and must undergo hepatic dehydrogenation to the soft electrophile monocrotaline pyrrole as prerequisite to damaging endothelial cells lining arterioles at remote pulmonary sites. In this report we extend our earlier investigation (J. Biol. Chem. 2000, 275, 29091-29099) by examining protein adducts to lower abundance adducts, a pI range not covered before, and subcellular localization of adduct-forming proteins associated with plasma membranes. Human pulmonary artery endothelial cells were exposed to [(14)C]MCT pyrrole (MCTP) and protein targets were identified using 2-DE with IPG 4-11. Adducted proteins were identified by pI, apparent molecular weight, and PMF using MALDI-TOF MS. Results of this study show that the majority of adducts form on proteins that contain reactive thiols in a CXXC motif, such as protein disulfide isomerase A(3) (ERp57), protein disulfide isomerase (PDI), and endothelial PDI. These same proteins were the major adduct-forming proteins associated with the plasma membrane. Other proteins found to be targets were thioredoxin, galectin-1, reticulocalbin 1 and 3, cytoskeletal tropomyosin, mitochondrial ATP synthase beta-chain, annexin A2 and cofilin-1. For the first time, MCTP adducts were observed on proteins not known to contain cysteine residues. However, known reactive proteins including nucleophosmin did not form detectable adducts, potentially indicating that MCTP did not reach the interior of nucleus to the same extent as other cellular sites. These findings suggest that molecular events underlying MCTP toxicity are initiated at the plasma membrane or readily accessible subcellular regions including the cytosol and membranes of the endoplasmic reticulum and mitochondria.

Amino Acid Sequence↗
PubMed1991

Lung vascular injury from monocrotaline pyrrole, a putative hepatic metabolite.

The pyrrolizidine alkaloid, monocrotaline (MCT), is a plant toxin that causes injury to the vasculature of the lungs and pulmonary hypertension in animals. To produce lung injury, MCT is bioactivated in the liver by cytochrome P450 monooxygenases to pyrrolic metabolites which travel via the circulation to the lungs, where they cause injury by unknown mechanisms. One putative metabolite of MCT is monocrotaline pyrrole (dehydromonocrotaline, MCTP), a moderately reactive, bifunctional alkylating agent. A single, iv injection of chemically synthesized MCTP into rats causes delayed and progressive lung vascular injury and pulmonary hypertension similar to that caused by MCT itself. Since pulmonary vascular endothelium is likely an important target of MCTP in vivo, the effects of MCTP on cultured endothelium were studied. A single application of MCTP to confluent monolayers of cultured endothelium from bovine pulmonary artery results in release of lactate dehydrogenase, some cell detachment from the growth surface and markedly altered morphology of remaining viable cells. These effects are dose-dependent and, as in vivo, are delayed in onset (1-2 days) and progressive. In endothelial cells of porcine origin, these particular responses to MCTP are also apparent but much less pronounced. Inhibition of proliferation of cells plated at low density occurred in both cell types at nominal MCTP concentrations (0.5 micrograms/ml) that were not overtly cytotoxic. These results indicate that MCTP causes a direct, dose-dependent injury to pulmonary vascular endothelium in culture that is delayed and progressive and suggest a mechanism by which MCT may act in vivo to cause lung injury and pulmonary hypertension.

Animals↗
PubMed1996

Development of chiral high performance liquid chromatographic assays for the enantiomers of 8-hydroxy-(di-n-propylamino)tetralin and three 8-keto-pyrrole-substituted analogues.

Two chiral HPLC methods using protein-based stationary phases for the analysis of 8-hydroxy-(di-n-propylamino)tetralin and three 8-keto-pyrrole analogues are presented. Efficient solid-phase extraction enabled quantification of 0.02 microgram ml-1 of the 8-keto-pyrrole analogues from 500 microliters rat hepatocyte suspensions, and 0.2 microgram ml-1 to be measured from 50 microliters of rat plasma using UV detection at 315 nm.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2006

4,5-Diaryl-1H-pyrrole-2-carboxylates as combretastatin A-4/lamellarin T hybrids: synthesis and evaluation as anti-mitotic and cytotoxic agents.

The 4,5-diarylated-1H-pyrrole-2-carboxylates 3-8 have each been prepared as hybrids of the potent anti-mitotic agent combretastatin A-4 (1) and the similarly active marine alkaloid lamellarin T (2). The key steps involved selective lithium-for-halogen exchange at C5 within the N-PMB protected 4,5-dibromopyrrole 22 and Negishi cross-coupling of the derived zincated species with the relevant aryl iodide. The ensuing 5-aryl-4-bromopyrrole then engaged in Suzuki-Miyaura cross-coupling with the appropriate arylboronic acid to give the 4,5-diarylated pyrroles 4, 6 and 8. TFA-promoted removal of the N-PMB group within these last compounds then gave the N-unsubstituted congeners 3, 5 and 7. Compounds 3-8 have all been evaluated for their anti-mitotic and cytotoxic properties and two of them, 3 and 5, display useful activities although they are less potent than combretastatin A-4.

Animals↗
PubMed1998

Organotin complexes with pyrrole-2,5-dicarboxaldehyde bis(acylhydrazones). Synthesis, structure, antimicrobial activity and genotoxicity.

Mono- and bimetallic organotin complexes with pyrrole-2,5-dicarboxaldehyde bis(2-hydroxybenzoylhydrazone) (H5dfps) and pyrrole-2,5-dicarboxaldehyde bis(2-picolinoylhydrazone) (H3dfpp) were synthesized and characterized by IR, 1H and 119Sn NMR spectroscopy. X-ray analysis of the complex [Sn(H3dfps)(C6H5)2].(CH3)2SO revealed a pentacoordination around tin through a N,N,O terdentate ligand behaviour of the hydrazone. This complex is the most active compound, exhibiting MIC values of 3 and 12 micrograms/ml against Gram positive and Gram negative bacteria, respectively. None of the ligands or complexes produced DNA-damage in the Bacillus subtilis rec-assay or showed mutagenic activity in the Salmonella-microsome test.

Anti-Bacterial Agents↗
PubMed2000

Carbonic anhydrase inhibitors: sulfonamides incorporating furan-, thiophene- and pyrrole-carboxamido groups possess strong topical intraocular pressure lowering properties as aqueous suspensions.

Important physiological and physio-pathological functions are played by several carbonic anhydrase (CA, EC 4.2.1.1) isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. Here we report several new types of such sulfonamides, incorporating furan-, thiophene- and pyrrole-carboxamide moieties in their molecules. Some of these compounds showed very good CA II and CA IV inhibitory properties. with affinities for the enzymes in the low nanomolar range. Due to their relatively low water solubility, some of the most active CA II inhibitors reported here have been formulated as aqueous suspension for topical administration as antiglaucoma agents. in normotensive and glaucomatous rabbits. The derivatives incorporating furan- and pyrrole-carboxamide moieties (but not the corresponding thiophene-substituted derivatives), showed effective and long-lasting intraocular pressure (IOP) lowering both in normotensive as well as glaucomatous animals, with potencies superior to dorzolamide and brinzolamide, the two available topically acting sulfonamide drugs. This is the first example of non-water soluble sulfonamides that significantly lower IOP, being thus similar with the recently introduced drug brinzolamide, which belongs to a completely different chemical family of antiglaucoma sulfonamides.

Animals↗
PubMed2000

Laser-activated voltammetry: measurement of the diffusion coefficients of electropassivating species. Application to pyrrole and phenol in aqueous solution

Clean electrode surfaces can be achieved during the electrolysis of otherwise passivating species in aqueous and other solutions by means of surface ablation using a 10-Hz pulsed Nd:YAG 532-nm laser. This ability to remove passivating electrolytically generated layers on glassy carbon and platinum electrodes is shown first by an investigation of the stripping peaks formed from the electrogeneration of the neutral forms of methyl viologen and heptyl viologen during reduction in aqueous solution of dications. Next, laser ablation was conducted under well-defined hydrodynamic conditions using a channel flow cell to identify laser power thresholds below which transport-limited currents could be seen, which were in quantitative agreement with those expected in the absence of irradiation. Levich plots recorded in the channel flow cell for K4Fe(CN)6 at glassy carbon and platinum electrodes showed such agreement for laser intensities lower than 0.17 and 0.65 W cm(-2), respectively. Working at intensities below these thresholds, steady-state voltammetry was observed for the oxidation of both phenol and pyrrole at glassy carbon and platinum electrodes, respectively, in aqueous solution. The diffusion coefficients of these two species were then measured under hydrodynamic conditions using laser ablation voltammetry to continuously clean the surface. Diffusion coefficients were inferred using the Levich equation. The result for phenol at a pH of 12 in aqueous solution was 0.9 (+/-0.1) x 10(-5) cm2 s(-1), which is in good agreement with an independent nonelectrochemical method. The diffusion coefficient of pyrrole in aqueous solution was similarly evaluated as 1.25 (+/-0.1) x 10(-5) cm2 s(-1).

Journal Article↗
PubMed1998

The Intra- and Intermolecular Oxidative Coupling of Ni(II)-meso-Octaethyl Mono(pyridine)-Tris(pyrrole) Complex Leading to C-C Bonds: Pathways to Oligomeric Porphyrinogens.

This paper reports the oxidative transformations of the unprecedented meso-octaalkyl mono(pyridine)-tris(pyrrole) macrocycle [Et(8)(C(5)H(3)N)(C(4)H(2)NH)(3)], 1, which was obtained by a homologation of the corresponding porphyrinogen, [Et(8)(C(4)H(2)NH)(4)], A. The metallation of 1 was obtained via its deprotonation with LiBu, followed by the reaction with MCl(2).thf(n)(), leading to the bimetallic complexes: [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)M{Li(thf)(2)}] [M = Fe, 3; M = Co, 4; M = Ni, 6; M = Cu, 7]. The cobalt derivative occurs also in the separated ion-pair form [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)Co](-)[{Li(thf)(4)}](+), 5. The reaction of 4 and 6 with an excess of Cp(2)FeBPh(4) led to the oxidation of the macrocycle with the formation of a cyclopropane functionality [Et(8)(C(5)H(3)N){(C(4)H(2)N)(3)(Delta)}Ni](+)BPh(4)(-), 8. The cyclopropane unit underwent reductive cleavage back to the initial macrocycle using lithium metal. The use of a Ni/Cp(2)Fe(+) 1:1 ratio allowed the identification of a dimer derived formally from the monoelectronic oxidation of the macrocycle 1, which formed a radical coupling to 9, [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)Ni](2). The same compound formed from a disproportionation redox reaction occurring between 6 and 8. The C-C bond across the two metallamacrocycles involved the beta position of the pyrrole. Deprotonation of 9 by LiBu led to a dianionic form 10 [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)Ni{Li(thf)(2)}]. The formation of the cyclopropane functionality was also achieved via the oxidation of [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)Li(3)(thf)(2)}], 2, forming [Et(8)(C(5)H(3)N){(C(4)H(2)N)(3)(Delta)}Li(thf)], 11, which was ready to be used in metallation reaction. The proposed structures were supported by X-ray analyses on 4, 7, 8, 9, and 11.

Journal Article↗
PubMed2003

Highly stable self-assembly in water: ion pair driven dimerization of a guanidiniocarbonyl pyrrole carboxylate zwitterion.

The synthesis of a novel water-soluble guanidiniocarbonyl pyrrole carboxylate zwitterion 2 is described, and its self-association in aqueous solutions is studied. Zwitterion 2 forms extremely stable 1:1 dimers which are held together by an extensive hydrogen bonding network in combination with two mutual interacting ion pairs as could be shown by ESI MS and X-ray structure determination. NMR dilution studies in different highly polar solvents showed that dimerization is fast on the NMR time scale with association constants ranging from an estimated 10(10) M(-1) in DMSO to a surprisingly high 170 M(-1) in water. Hence, zwitterion 2 belongs to the most efficient self-assembling systems solely on the basis of electrostatic interactions reported so far. Furthermore, an amidopyridine pyrrole carboxylic acid 10 was developed as a neutral analogue of zwitterion 2, which also dimerizes with an essentially identical hydrogen bonding pattern (according to ESI MS and X-ray structure determination) but lacking the ionic interactions. NMR binding studies demonstrated that the solely hydrogen-bonded neutral dimer of 10 is stable only in organic solvents of low polarity (K > 10(4) M(-1) in CDCl3 but <10 M(-1) in 5% DMSO in CDCl3). The comparison of both systems impressively underlines the importance of ion pair interactions for stable self-association of such H-bonded binding motifs in water.

Journal Article↗
PubMed2005

Sensing of antipyretic carboxylates by simple chromogenic calix[4]pyrroles.

We present a simple, two- or three-step method for the synthesis of chromogenic octamethylcalix[4]pyrrole-based (OMCP) sensors for anions. Electrophilic aromatic substitution allows for converting the pyrrole moieties of OMCP into a dye. The formation of a sensor-anion complex results in partial charge transfer and a dramatic change in color. The absorption (UV-vis) and NMR titration experiments show that the chromogenic OMCPs sense anions administered as aqueous solutions, even at high ionic strength ( approximately 0.1 M NaCl), while displaying selectivity for pyrophosphate and carboxylate anions. The experiments with polyurethane sensor films show a strong response for aqueous carboxylates, such as antipyretics naproxen approximately ibuprofen > salicylate, without being biased by bicarbonate or carboxy termini of blood plasma proteins.

Analgesics, Non-Narcotic↗
PubMed2006

Strategies for electrooptic film fabrication. Influence of pyrrole-pyridine-based dibranched chromophore architecture on covalent self-assembly, thin-film microstructure, and nonlinear optical response.

The new dibranched, heterocyclic "push-pull" chromophores bis{1-(pyridin-4-yl)-2-[2-(N-methylpyrrol-5-yl)]ethane}methane (1), 1-(pyrid-4-yl)-2-(N-methyl-5-formylpyrrol-2-yl)ethylene (2), {1-(N-methylpyridinium-4-yl)-2-[2-(N-methylpyrrol-5-yl)]ethane}{(1-(pyridin-4-yl)-2-[2-(N-methylpyrrol-5-yl)]ethane}methane (3), N-methyl-2-[1-(N-methylpyrid-4-yl)ethen-2-yl]-5-[pyrid-4-yl]ethen-2-yl]pyrrole iodide (4), bis{1-(N-methyl-4-pyridinio)-2-[2-(N-methylpyrrol-5-yl)]ethane}methane iodide (5), and N-methyl-2,5-[1-(N-methylpyrid-4-yl)ethen-2-yl]pyrrole iodide (6) have been synthesized and characterized. The neutral (1 and 2) and monomethyl salts (3 and 4) undergo chemisorptive reaction with iodobenzyl-functionalized surfaces to afford chromophore monolayers SA-1/SA-2 and SA-3/SA-4, respectively. Molecular structures and other physicochemical properties have been defined by (1)H NMR, optical spectroscopy, and XRD. Thin-film characterization by a variety of techniques (optical spectroscopy, specular X-ray reflectivity, atomic force microscopy, X-ray photoelectron spectroscopy, and angle-dependent polarized second harmonic generation) underscore the importance of the chromophore molecular architecture as well as film growth method on film microstructure and optical/electrooptic response.

Journal Article↗
PubMed1983

Inhibitors of glycolic acid oxidase. 4-Substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives.

An extensive series of novel 4-substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives has been prepared and studied as inhibitors of glycolic acid oxidase (GAO). Compounds possessing large lipophilic 4-substituents are, in general, potent, competitive inhibitors of porcine liver GAO in vitro. Methylation of the nitrogen or the 3-hydroxy substituent reduced potency dramatically, indicating the requirement for the two acidic functions on the 1H-pyrrole-2,5-dione nucleus. In rat liver perfusion studies, with three representative compounds, concentration-dependent inhibition of the conversion of [1-14C]glycolate to [14C]oxalate was observed. Chronic oral administration to ethylene glycol fed rats of the 4-(4'-bromo[1,1'-biphenyl]-4-yl) derivative (83) was shown to effect a significant reduction in urinary oxalate levels over a 58-day period.

Alcohol Oxidoreductases↗
PubMed1997

Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing cinnamoyl groups.

A series of N-cinnamates of the A-ring pyrrole compound of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. The 4'-methoxy- and 4'-BocNH-cinnamates exhibited strong in vitro anticellular activity among the synthesized compounds. The ortho substitution of the 4'-methoxycinnamate did not affect the anticellular activity and contributed to an enhancement of water solubility. Most of the 8-O-(N,N-dialkylcarbamoyl) derivatives of the 4'-methoxycinnamate displayed remarkably superior in vivo antitumor activity to duocarmycin A or B2. Moreover, it is noteworthy that these 8-O-(N,N-dialkylcarbamoyl) derivatives exhibited significant antitumor activity at wider range of doses as compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment B.

Animals↗
PubMed2001

Synthesis of 2,3-disubstituted pyrroles and pyridines from 3-halo-1-azaallylic anions.

A new synthesis of 2,3-disubstituted pyrroles and pyridines is described. The reaction of 3-halo-1-azaallylic carbanions, regiospecifically generated from alpha-halogenated ketimines, with omega-iodoazides led to the regiospecific formation of omega-azido-alpha-haloketimines. Treatment of these functionalized imines with tin(II) chloride afforded halogenated five- and six-membered cyclic imines, which were transformed under mild conditions into 2,3-disubstituted pyrroles and pyridines. The stereoselective reduction of 2,3-dialkyl-3-chloro-1-pyrrolines to afford cis-2,3-dialkyl-3-chloropyrrolidines is also reported.

Journal Article↗
PubMed2003

Synthesis and reactivity of (C6F5)3B-N-heterocycle complexes. 1. Generation of highly acidic sp3 carbons in pyrroles and indoles.

The reaction of pyrroles and indoles with B(C(6)F(5))(3) and BCl(3) produces 1:1 B-N complexes containing highly acidic sp(3) carbons, for example, N-[tris(pentafluorophenyl)borane]-5H-pyrrole (1) and N-[tris(pentafluorophenyl)borane]-3H-indole (2), that are formed by a new formal N-to-C hydrogen shift, the mechanism of which is discussed. With some derivatives, restricted rotation around the B-N bond and/or the B-C bonds was observed by NMR techniques, and some rotational barriers were calculated from experimental data. The acidity of the sp(3) carbons in these complexes is shown by their ability to protonate NEt(3), with formation of pyrrolyl- and indolyl-borate ammonium salts. The driving force for this reaction is given by the restoration of the aromaticity of the heterocycle.

Journal Article↗
PubMed2002

One-pot synthesis of 3,4-disubstituted 1H-pyrroles from 2-tropanones.

3,4-Disubstituted pyrroles (2, 3) were prepared from 6/7-carboxyethyl-3-phenyl-3-tropen-2-ones (1) regioselectively and with high yields by using tosylmethyl isocyanide (TosMIC). This procedure enables the synthesis of pyrroles substituted with two distinct groups: a phenyl group and a substituted pyrrolidine analogue. The crystal structure of product 2a was determined, and the analogous derivatives were identified by (1)H and (13)C NMR spectroscopy.

Journal Article↗