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PubMed2004

Brominated pyrrole alkaloids from marine Agelas sponges reduce depolarization-induced cellular calcium elevation.

Seven pyrrole alkaloids isolated from Agelas sponges were tested for interactions with the cellular calcium homeostasis. Brominated pyrrole alkaloids reduced voltage dependent calcium elevation in PC12 cells. Dibromosceptrin was the most potent alkaloid with a half maximal concentration of 2.8 microM followed by sceptrin (67.5 microM) and oroidin (75.8 microM). 4,5-Dibromopyrrole-2-carboxylic acid reduced calcium elevation at concentrations exceeding 30 microM but did not eliminate calcium elevation at concentrations up to 1 mM. 4-Bromopyrrole-2-carboxylic acid and pyrrole-2-carboxylic acid were not active in this respect. The aminoimidazole group appeared to have a significant effect on voltage dependent calcium elevation shown by the comparison of oroidin with 4,5-dibromopyrrole-2-carboxylic acid. The degree of bromination of the pyrrole moiety is another important factor, as was shown by the comparison of 4,5-dibromopyrrole-2-carboxylic acid with 4-bromopyrrole-2-carboxylic acid, as well as oroidin with hymenidin and dibromosceptrin with sceptrin. The previously reported feeding deterrent activity of brominated pyrrole alkaloids in Agelas sponges against predatory reef fish may partly be explained by a general interaction of these alkaloids with the cellular calcium homeostasis. The chemoreception of bromopyrrole alkaloids in sea water is shown using sensory neurons in the rhinophore of the sea slug Aplysia punctata.

Animals↗
PubMed2003

Synthesis and structure-activity relationships of a series of pyrrole cannabinoid receptor agonists.

We designed and synthesized a series of pyrrole derivatives with the aim of investigating the structure-activity relationship (SAR) for the binding of non-classical agonists to CB(1) and CB(2) cannabinoid receptors. Superposition of two pyrrole-containing cannabinoid agonists, JWH-007 and JWH-161, allowed us to identify positions 1, 3 and 4 of the pyrrole nucleus as amenable to additional investigation. We prepared the 1-alkyl-2,5-dimethyl-3,4-substituted pyrroles 10a-e, 11a-d, 17, 21, 25 and the tetrahydroindole 15, and evaluated their ability to bind to and activate cannabinoid receptors. Noteworthy in this set of compounds are the 4-bromopyrrole 11a, which has an affinity for CB(1) and CB(2) receptors comparable to that of well-characterized heterocyclic cannabimimetics such as Win-55,212-2; the amide 25, which, although possessing a moderate affinity for cannabinoid receptors, demonstrates that the 3-naphthoyl group, commonly present in indole and pyrrole cannabimimetics, can be substituted by alternative moieties; and compounds 10d, 11d, showing CB(1) partial agonist properties.

Animals↗
PubMed1997

N-conjugates of 2,5-disubstituted pyrrole and glutathione. Evaluation of their potency as antioxidants against photosensitization of NCTC 2544 keratinocytes by excess endogenous protoporphyrin IX.

A novel glutathione compound in which the amino group has been derivatized by a 2,5-dimethyl pyrrole is shown to be very effective against cell photosensitization in vitro. Protoporphyrin IX either added to the medium or produced endogenously by incubation of NCTC 2544 keratinocytes with 5-aminolevulinic acid has been chosen as the photosensitizer. The antioxidant effectiveness of glutathione-pyrrole derivatives against protoporphyrin photosensitization depends critically on the type of 2,5 substitution on the pyrrole ring. This structure-function relationship may be attributed to the difference in compartmentation and/or uptake of the various glutathione-pyrrole derivatives under study. The 2,5-dimethyl pyrrole derivative is much more effective than glutathione as a protective agent against phototoxic reactions induced by protoporphyrin IX.

Aminolevulinic Acid↗
PubMedDate not supplied

Synthesis and characterization of a pyrrole-alginate conjugate and its application in a biosensor construction.

N-(3-Aminopropyl)pyrrole was covalently coupled with alginate in an aqueous-phase reaction by means of carbodiimide-mediated activation chemistry to provide a pyrrole-alginate conjugate for subsequent use in biosensor applications. The pyrrole-alginate conjugate was quantified by UV spectroscopy at 230 nm, by an HPSEC-MALLS analytical method, as well as by FTIR and 13C NMR spectroscopies. The new pyrrole-alginate conjugate was used for the immobilization of polyphenol oxidase (PPO) onto an electrode surface by physical entrapment resulting from the gellification process and electrochemical polymerization of the pyrrole groups. The efficiency of this cross-linking approach (chemical and electrochemical) was investigated by comparing the amount of enzyme released from polypyrrole-alginate and regular alginate. In addition, biosensors were prepared by entrapment of the PPO in polypyrrole-alginate and regular alginate matrixes and their performance for the amperometric determination of catechol chosen as a model analyte was examined, yielding a sensitivity of 350 and 80 microA M(-1) cm(-2), respectively, for polypyrrole-alginate and alginate biosensors.

Alginates↗
PubMed2002

Theoretical study of anion binding to calix[4]pyrrole: the effects of solvent, fluorine substitution, cosolute, and water traces.

The binding of different anions to calix[4]pyrrole has been studied by means of molecular dynamics coupled to thermodynamic integration calculations. The effect of different apolar solvents, octafluoro substitution, and the change in binding free energy derived from the presence of cosolute and water traces (the hydrated salt used to introduce the anion in the solution) were examined. Calculations allow us to rationalize the differential binding of ions to calix[4]pyrrole and octafluorocalix[4]pyrrole as well as to predict the behavior in new solvents for which experimental data are not available yet. It is found that both calix[4]pyrrole and octafluorocalix[4]pyrrole have a dramatic preference for F- in the gas phase and pure aprotic solvents, but the situation can change dramatically in protic solvents or in the presence of the hydrated cation which is used as cosolute of the anion. Overall, our results provide interesting clues for a better understanding of the process detected experimentally as "binding".

Anions↗
PubMed2004

A likely biogenetic gateway linking 2-aminoimidazolinone metabolites of sponges to proline: spontaneous oxidative conversion of the pyrrole-proline-guanidine pseudo-peptide to dispacamide A.

A new spontaneous oxidative transformation of the associated pyrrole-proline-guanidine to the natural marine pyrrole 2-aminoimidazolinone derivative has been achieved. The sensitive reaction requires air oxygen and the N-acylation of proline by pyrrole-2-carboxylic acid. Proline metabolism and pyrrole 2-aminoimidazole secondary metabolites formation seem to be related and are utilized by sponges under stress conditions for their defense against predators. A plausible stress-induced oxidative chemical pathway that establishes dispacamide derivatives as the forerunners in the biogenetic synthesis of the key pyrrole 2-aminoimidazole oroidin is proposed. The mechanism of the reaction seems to be another development of the known luciferins' chemiluminescent reactions in bioluminescent marine organisms.

Amination↗
PubMed2004

Contribution of phospholipid pyrrolization to the color reversion produced during deodorization of poorly degummed vegetable oils.

The Ehrlich reaction was optimized to determine the formation of pyrrolized phospholipids in edible oils in an attempt to understand the color reversion produced during the deodorization of poorly degummed edible oils. The procedure consisted of the treatment of the oil with p-(dimethylamino)benzaldehyde in tetrahydrofuran/2-propanol at a controlled acidity and temperature and the spectrophotometric determination of adducts produced. The extinction coefficient of Ehrlich adducts was calculated by using 1-[1-(2-hydroxyethyl)-1H-pyrrol-2-yl]propan-1-ol (1) as a standard and was 15 300 M(-)(1) cm(-)(1). The response was linear and reproducible within the range of 0.334-48.6 microM of compound 1. When the assay was applied to a soybean oil treated with 100-1000 ppm of phosphatidylethanolamine and submitted to deodorization, the formation of pyrrolized phospholipids was observed at the same time that the disappearance of the phospholipid and the oil darkening were produced. The main changes were observed during the first steps of the deodorization process, when the oil was heated between 80 and 160 degrees C. During the initial heating of the oil until achieving 200 degrees C, oil darkening, phosphatidylethanolamine disappearance, and pyrrolized phospholipid formation were correlated, therefore suggesting a contribution of phospholipid pyrrolization to the oil darkening produced.

Benzaldehydes↗
PubMed2002

Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enterococci [corrected] and methicillin resistant Staphylococcus aureus.

A new series of short pyrrole tetraamides are described whose submicromolar DNA binding affinity is an essential component for their strong antibacterial activity. This class of compounds is related to the linked bis-netropsins and bis-distamycins, but here, only one amino-pyrrole-carboxamide unit and an amidine tail is connected to either side of a central dicarboxylic acid linker. The highest degree of DNA binding, measured by compound-induced changes in UV melting temperatures of an AT-rich DNA oligomer, was observed for flat, aromatic linkers with no inherent bent, i.e., terephthalic acid or 1,4-pyridine-dicarboxylic acid. However, the antibacterial activity is critically linked to the size of the N-alkyl substiutent of the pyrrole unit. None of the tetraamides with the commonly used methyl-pyrrole showed antibacterial activity. Isoamyl- or cyclopropylmethylene-substituted dipyrrole derivatives have the minimum inhibitory concentrations in the submicromolar range. In vitro toxicity against human T-cells was studied for all compounds. The degree to which compounds inhibited cell growth was neither directly correlated to DNA binding affinity nor directly correlated to antibacterial activity but seemed to depend strongly on the nature of the N-alkyl pyrrole substituents.

Amides↗
PubMed2003

Simple, potent, and selective pyrrole inhibitors of monoamine oxidase types A and B.

N-Benzyl- and N-propargyl-1H-pyrrole-2-carboxyamides and some related methylenamines were synthesized and tested for their monoamine oxidase types A and B inhibitory activity. 2-(N-Methyl-N-propargylaminomethyl)-1H-pyrrole (24) was the most potent MAO-A inhibitor of the series [K(i)(MAO-A) = 0.0054 microM], but it was not selective. Inhibitors N-4-fluorobenzyl-1H-pyrrole-2-carboxamide (12) and N-cyclohexylmethyl-1H-pyrrole-2-carboxamide (25) showed the highest MAO-A selectivity indexes (SI) corresponding to 2025 and >2500, respectively, while 2-(N-methyl-N-benzylaminomethyl)-1H-pyrrole (21) was the most selective MAO-B inhibitor, having an SI of 0.0057.

Alkynes↗
PubMed2004

3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides as a new class of synthetic histone deacetylase inhibitors. 2. Effect of pyrrole-C2 and/or -C4 substitutions on biological activity.

Previous SAR studies (Part 1: Mai, A.; et al. J. Med. Chem. 2003, 46, 512-524) performed on some portions (pyrrole-C4, pyrrole-N1, and hydroxamate group) of 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1a) highlighted its 4-phenylacetyl (1b) and 4-cynnamoyl (1c) analogues as more potent compounds in inhibiting maize HD2 activity in vitro. In the present paper, we investigated the effect on anti-HD2 activity of chemical substitutions performed on the pyrrole-C2 ethene chains of 1a-c, which were replaced with methylene, ethylene, substituted ethene, and 1,3-butadiene chains (compounds 2). Biological results clearly indicated the unsubstituted ethene chain as the best structural motif to get the highest HDAC inhibitory activity, the sole exception to this rule being the introduction of the 1,3-butadienyl moiety into the 1a chemical structure (IC50(2f) = 0.77 microM; IC50(1a) = 3.8 microM). IC50 values of compounds 3, prepared as 1b homologues, revealed that between benzene and carbonyl groups at the pyrrole-C(4) position a hydrocarbon spacer length ranging from two to five methylenes is well accepted by the APHA template, being that 3a (two methylenes) and 3d (five methylenes) are more potent (2.3- and 1.4-fold, respectively) than 1b, while the introduction of a higher number of methylene units (see 3e,f) decreased the inhibitory activities of the derivatives. Particularly, 3a (IC50 = 0.043 microM) showed the same potency as SAHA in inhibiting HD2 in vitro, and it was 3000- and 2.6-fold more potent than sodium valproate and HC-toxin and was 4.3- and 6-fold less potent than trapoxin and TSA, respectively. Finally, conformationally constrained forms of 1b,c (compounds 4), prepared with the aim to obtain some information potentially useful for a future 3D-QSAR study, showed the same (4a,b) or higher (4c,d) HD2 inhibiting activities in comparison with those of the reference drugs. Molecular modeling and docking calculations on the designed compounds performed in parallel with the chemistry work fully supported the synthetic effort and gave insights into the binding mode of the more flexible APHA derivatives (i.e., 3a). Despite the difference of potency between 1b and 3a in the enzyme assay, the two APHA derivatives showed similar antiproliferative and cytodifferentiating activities in vivo on Friends MEL cells, being that 3a is more potent than 1b in the differentiation assay only at the highest tested dose (48 microM).

Acrylamides↗
PubMed2000

Highly regioselective synthesis of 3,4-disubstituted 1H-pyrrole.

A highly regioselective method for the synthesis of 3, 4-disubstituted 1H-pyrroles has been developed employing the ipso-directing property of a trimethylsilyl group. As a key starting material in this study, the known 3,4-bis(trimethylsilyl)-1H-pyrrole (3), was protected with carefully chosen groups, namely tert-butoxycarbonyl, N,N-dimethylaminosulfonyl, p-toluenesulfonyl, and triisopropylsilyl. A highly regioselective monoiodination of these 1-protected pyrroles was achieved by reaction with iodine-silver trifluoroacetate at low temperatures. Subsequent palladium-catalyzed cross-coupling reactions afforded 1-protected-4-substituted 3-trimethylsilyl-1H-pyrroles, which again underwent further room-temperature ipso-iodination and palladium-catalyzed cross-coupling reactions to provide symmetrical and unsymmetrical 1-protected-3,4-disubstituted 1H-pyrroles. Deprotection of 1-(tert-butoxycarbonyl) and 1-(N, N-dimethylaminosulfonyl) groups was found to be nontrivial. The 1-(p-toluenesulfonyl) protecting group was eventually proved to be superior to other protection groups, because it was readily removed after stepwise ipso monoiodinations and palladium-catalyzed cross-coupling reactions.

Pyrroles↗
PubMedDate not supplied

Reactions of muconaldehyde isomers with nucleophiles including tri-O-acetylguanosine: formation of 1,2-disubstituted pyrroles from reactions of the (Z,Z)-isomer with primary amines.

(Z,Z)-Muconaldehyde reacts with primary amines, including valine and lysine (epsilon-amino), to afford N-substituted-2-(oxoethyl)pyrroles, which were reduced with sodium borohydride to the more stable N-substituted-2-(hydroxyethyl)pyrroles. The formation of the pyrrole aldehydes was performed in a variety of solvents including aqueous methanol. With tri-O-acetylguanosine, the putative pyrrole aldehyde derived from reaction at NH2 condenses with N-1 (guanine component) to afford a bicyclic adduct: 4,5-dihydro-5-hydroxy-10-beta-D-tri-O- acetylribosylpyrrolo[1',2':3,4]pyrimido[1,2-a]purin-7(10H)-one (5a). This was hydrolyzed to 4,5-dihydro-5-hydroxy-10-beta-D- ribosylpyrrolo[1',2':3,4]pyrimido[1,2-a]purin-7(10H)-one (5b). The structures of 5a and 5b were primarily based on NMR evidence and comparison with 4,5-dihydro-5-hydroxy-9-methylpyrrolo[1',2':3,4]pyrimido[2,1-b] pyrimidin-7-one (7), obtained from reacting (Z,Z)-muconaldehyde with 2-amino-4-hydroxy-6-methylpyrimidine. (E,Z)-Muconaldehyde also reacted with primary amines to give N-substituted-2-(oxoethyl)pyrroles, whereas (E,E)-muconaldehyde gave bis-imines. The results described are discussed in the context of the carcinogenicity of benzene.

Aldehydes↗
PubMed1995

Intermediates in the Paal-Knorr synthesis of pyrroles. 4-Oxoaldehydes.

The mechanism of pyrrole formation between a 4-ketoaldehyde, such as 4-oxohexanal (4), and a primary amine is examined. In organic solvents 4 readily formed the imine 6 that decomposed to pyrrole 9. In phosphate buffer (pH 7.4) the presence of deuteriums in the dideuterio (4-d2) and hexadeuterio (4-d6) analogs retarded the reaction rate by factors of 1.9 and 2.6, which are much less than the isotope effects exhibited by reactions involving cleavage of the carbon-hydrogen bond. Moreover, the deuterium labels from the uncyclized ketoaldehyde remained intact. These results suggest that the hemiaminal 5 rather than the enamine 8 is the intermediate undergoing cyclization. Due to the absence of a methyl substituent at one of the carbonyls the rate of pyrrole formation of 4-oxohexanal was 2 orders of magnitude larger than that of 2,5-hexanedione. The higher rate of pyrrole formation may account for the increased rate of pyrrole-mediated cross-linking of proteins caused by gamma-ketoaldehydes relative to gamma-diketones.

Aldehydes↗
PubMed1997

Characterization of polymer films of pyrrole derivatives for chemical sensing by cyclic voltammetry, X-ray photoelectron spectroscopy and vapour sorption studies.

Eight different conducting polymer films formed from pyrrole and N-substituted pyrrole derivatives were characterized by cyclic voltammetry, X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy. In particular, the XPS of poly[N-butylpyrrole], poly[N-(2-carboxyethyl)pyrrole], poly[N-(6-hydroxyhexyl)pyrrole] and poly[N-(6-tetrahydropyranylhexyl)pyrrole] is reported for the first time. The vapour sorption properties of these films were also examined by forming the films onto the electrodes of thickness-shear mode acoustic wave sensors. The influence of the pendant side chain is apparent in both the electrochemical behaviour, composition, doping level, morphology and the nature and extent of polymer-vapour interactions. The latter can be rationalized by consideration of vapour physical properties and solvatochromic parameters.

Chemical Phenomena↗
PubMed1992

The role of pyrrole formation in the alteration of neurofilament transport induced during exposure to 2,5-hexanedione.

Exposure to the gamma-diketone, 2,5-hexanedione (HD), results in the accumulation of neurofilaments within the distal axon and is associated with acceleration of neurofilament transport within the proximal axon. The epsilon-amino groups of lysyl residues react with HD forming pyrrole adducts, followed by pyrrole-mediated protein crosslinking. Both reaction steps have been proposed as mechanisms causing neurofilament accumulation and acceleration of transport. In order to assess the importance of these steps on neurofilament transport, we compared transport in the optic system of rats exposed to HD and 3-acetyl-2,5-hexanedione (AcHD), a non-toxic analog of HD which forms pyrroles but does not crosslink proteins. Control, HD-treated, and AcHD-treated rats received intraoptic injections of [35S]-methionine and were exposed to saline, HD, or AcHD by intraperitoneal injections before and during the period of neurofilament transport. Neurofilament triplet proteins in the optic nerve and tract were identified by polyacrylamide gel electrophoresis followed by fluorography. The rate of neurofilament transport was accelerated in HD-treated animals over that of controls. However, despite higher levels of protein-bound pyrroles in AcHD-treated animals, the rate of transport was indistinguishable from that of controls. These findings indicate that pyrrole formation alone is not sufficient to cause acceleration of neurofilament transport.

Animals↗
PubMed1981

Anti-inflammatory, antiproteolytic, and antihemolytic properties of pyrrole carboxylic acids.

Eight substituted pyrrole carboxylic acids were evaluated for their anti-inflammatory activity against carageenin-induced edema in rats. The protection afforded by seven of these compounds at a dose of 100 mg/kg i.p. ranged from 11 to 42%. Indomethacin (10 mg/kg i.p.), used as a reference drug, possessed 45% anti-inflammatory activity under similar experimental conditions. The ability of these compounds to exhibit in vitro antiproteolytic activity was reflected by their ability to inhibit trypsin-induced hydrolysis of bovine serum albumin. The inhibition of the activity of trypsin by these substituted pyrrole carboxylic acids (1 mM) ranged from 42 to 90% while such an inhibition with indomethacin (1 mM) was 95%. The in vitro membrane stabilizing property of these substituted pyrrole carboxylic acids was observed by their ability to provide protection against heat-induced dog erythrocyte hemolysis. The I50 value of these compounds, representing the concentration required to inhibit one-half of heat-induced erythrocyte hemolysis, ranged from 0.29 to 6.0 mM. Such an inhibition was concentration-dependent and biphasic in nature. The I50 value for indomethacin, showing greater antihemolytic activity was found to be 0.02 mM under similar experimental conditions. These results have provided some correlation of anti-inflammatory activity with antiproteolytic and membrane stabilizing properties for substituted pyrrole-3-carboxylic acids alone but not for pyrrole-2-carboxylic acids.

Animals↗
PubMed2007

Characterization of a glucose sensor prepared by electropolymerization of pyrroles containing a tris-bipyridine osmium complex.

A glucose sensor was developed by electrocopolymerization using pyrroles containing a tris-bipyridine (bpy) osmium complex (Os-py), pyrrole (py), pyrrole propanoic acid (PPA) and glucose oxidase (GOx) to improve the key performance characteristics, such as the sensitivity, selectivity, and long-term stability. Tris-bipyridine osmium pyrrole complexes with four different methylene moieties were utilized to correlate the methylene length with the glucose sensor performance. The electrocatalytic response of glucose was clearly observed at electrodes modified with Os-py, except for the electrode immobilized with the Os-py complex containing the shortest methylene moiety. The current response to glucose increased up to a concentration of 100 mmol dm(-3). The electrocatalytic response to glucose at the [Os(bpy)(2)(py(6)-bpy)](2+/3+)/py/PPA/GOx electrode was stable for more than 100 days. Dissolved oxygen and potential interference compounds (ascorbic acid, uric acid, and acetaminophen) minimally perturbed the current response to glucose at the [Os(DM-bpy)(2)(py(6)-bpy)](2+/3+)/py/PPA/GOx electrode. Based on these results, a longer methylene moiety appears to improve the performance characteristics of a glucose sensor fabricated via the electropolymerization of tris-bipyridine osmium pyrrole complexes.

2,2'-Dipyridyl↗
PubMed1988

[Monoamine oxidase inhibition by pyrrole quinoline derivatives].

The effect of 1-(beta-aminoethyl)-3H-pyrrole[2,3-h]quinoline (I), 3-(beta-aminoethyl)-1H-pyrrole[2,3-h]quinoline (I'), 8-amino-3H-pyrrole[2,3-h]quinoline (II), 6-amino-3H-pyrrole[2,3-h]quinoline (II') and 8-amino-1H-pyrrole[2,3-h]quinoline (III) on tyramine, serotonin and 2-phenylethylamine deaminase activities of mitochondrial monoamine oxidase from bovine brain were studied. All the compounds tested appeared to be reversibly inhibit MAO without preliminary incubation. Compounds II, II' and III specifically inhibited type A MAO; compound III exhibited the highest selectivity. The inhibition was of a mixed type. The effects of compounds I and I' were competitive and inconsistent with a classical concept on the dual activity of MAO, i. e., deamination of tyramine, a substrate common for MAO type A and MAO type B was inhibited in a greater degree than the deamination of specific substrates of MAO type A (serotonin) or type B (2-phenylethylamine). Possible reasons for the observed phenomenon are discussed.

Animals↗