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This study compares the effect of three chemically unrelated cystic fibrosis transmembrane conductance regulator (CFTR) activators on epithelial cell monolayers expressing the G551D-CFTR mutant. We measured Cl− transport as the amplitude of short-circuit current in response to the membrane permeable cAMP analogue 8-(4-chlorophenylthio)adenosine-3′-5′-cyclic monophosphate (CPT-cAMP) alone or in combination with a CFTR opener. The correction of G551D-CFTR defect was quantified by comparison with maximal activity elicited in cells expressing wild type CFTR. To this end we used Fisher rat thyroid (FRT) cells transfected with wild type or G551D CFTR, and primary cultures of human nasal epithelial cells. In both types of epithelia, cAMP caused activation of Cl− transport that was inhibited by glibenclamide and not by 4,4′-diisothiocyanato-stilbene-2,2′-disulfonic acid. After normalising for CFTR expression, the response of FRT-G551D epithelia was 1% that of wild type monolayers. Addition of genistein (10–200 μM), but not of 8-cyclopentyl-1,3-dipropylxanthine (CPX, 1–100 μM) or of the benzo[c]quinolizinium MPB-07 (10–200 μM) to FRT-G551D epithelia pre-treated with cAMP, stimulated a sustained current that at maximal genistein concentration corresponded to 30% of the response of wild type epithelia. The genistein dose-response curve was bell-shaped due to inhibitory activity at the highest concentrations. The dose-dependence in G551D cells was shifted with respect to wild type CFTR so that higher genistein concentrations were required to observe activation and inhibition, respectively. On human nasal epithelia the correction of G551D-CFTR defective conductance obtained with genistein was 20% that of wild type. The impressive effect of genistein suggests that it might correct the Cl− transport defect on G551D patients. British Journal of Pharmacology (2002) 137, 504–512. doi:10.1038/sj.bjp.0704882

On the basis of their structure, we compared the ability of 35 xanthine derivatives to activate the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel stably expressed in chinese hamster ovary (CHO) cells using the cell-attached patch clamp and iodide efflux techniques. Activation of CFTR channels was obtained with 3-mono, 1,3-di or 1,3,7-tri-substituted alkyl xanthine derivatives (enprofylline, theophylline, aminophylline, IBMX, DPMX and pentoxifylline). By contrast, xanthine derivatives substituted at the C8- or N9-position failed to open CFTR channels. The CFTR chloride channel activity was blocked by glibenclamide (100 μM) but not by DIDS (100 μM). Activation of CFTR by xanthines was not mimicked by the calcium ionophore A23187, adenosine, UTP, ATP or the specific phosphodiesterase inhibitors rolipram, Ro 20-1724 and milrinone. In addition, we found no correlation between the effect of xanthines on CFTR and on the cellular cyclic AMP or ATP levels. We then synthesized a series of 3,7-dimethyl-1-alkyl xanthine derivatives; among them, 3,7-dimethyl-1-propyl xanthine and 3,7-dimethyl-1-isobutyl xanthine both activated CFTR channels without increasing the intracellular cyclic AMP level, while the structurally related 3,7-dimethyl-1-(2-propenyl) xanthine and 3,7-dimethyl-1-(oxiranyl methyl) xanthine were inactive. Our findings delineate a novel function for xanthine compounds and identify the molecular features that enable xanthine activation of CFTR. These results may be useful in the development of new molecules for studying the pharmacology of chloride channels. British Journal of Pharmacology (1998) 123, 683–693; doi:10.1038/sj.bjp.0701648

Heteroarylmethylation of halogenobenzonitriles in the presence of air (O 2 ) gives 1-hydroxy-3-oxo-1-aryl-1H,3H-isoindoles in liquid ammonia. A one-pot or two-step synthesis is described and a mechanism is proposed

The synthesis and in vitro pharmacology of a series of triaryl-1,4-dihydropyridines were investigated. Molecules containing a nitro group on the phenyl ring had a higher affinity for specific [ 3 H](+)-PN 200-110 binding sites. All the compounds possessed a radical scavenging effect and an antiperoxidant activity. These properties were more marked for molecules with 2-pyridinyl and 2-thienyl substituents. The synthesis of new triaryl-1,4-dihydropyridines with both a higher binding affinity and antioxidant activity might be effective in cerebral ischemic disease treatment.

The reaction of balogenobenzonitriles with 2-aminobenzenethiol is a new route, in a “one-pot” or two-step approach, to 11-aminodibenzo[b,f][1,4]thiazepine and fluoro derivatives.

A one-pot synthesis of 1, 3 and 4-cyanophenothiazines and a two-step approach to 2-cyanoisomer have been developed. The condensation of 2-aminobenzenethiol and 2,3 or 3,4-dihalogenobenzonitriles followed by Smiles rearrangement or by intramolecular aromatic substitution gave the desired ring systmes.

The synthesis and in vitro antioxidant activity of 17 new tetraarylpyrroles are investigated by 2 tests highly documented in the literature: capability to prevent Fe2+-induced lipid peroxidation on microsomes, which is a membrane preparation rich in polyunsaturated fatty acids, and direct scavenging effect on a stable free radical, 1,l-diphenyl-2-picryl-hydrazyl (DPPH). For the Fe2+-induced microsomal lipid peroxidation system, the results show that molecules which possess 2-pyrazinyl or 2-pyridyl in the 3- and 4-positions on the pyrrole ring are the most efficient. Introduction of methoxy groups on the phenyl ring in the 2- and 5-positions increases the effects but the higher activity is obtained with 2-furyl or 2-thienyl. The only compounds which possess a direct scavenger effect on trapping the stable free radical DPPH are those which have 2-pyridyl in the 3- and 4-positions and 2-furyl or 2-thienyl in the 2- and 5-positions.

A one-pot synthesis of 1, 3 and 4-cyanophenothiazines and a two-step approach to 2-cyanoisomer have been developed. The condensation of 2-aminobenzenethiol and 2,3 or 3,4-dihalogenobenzonitriles followed by Smiles rearrangement or by intramolecular aromatic substitution gave the desired ring systmes.

The reaction of balogenobenzonitriles with 2-aminobenzenethiol is a new route, in a “one-pot” or two-step approach, to 11-aminodibenzo[b,f][1,4]thiazepine and fluoro derivatives.

L'action du phenyllithium sur la pyrazine, la methyl pyrazine et l'acetonyl pyrazine conduit a des produits d'addition sur une ou sur deux liaisons iminiques du noyau pyrazine. L'addition de benzoate de methyle au milieu reactionnel entraine la formation de produits C ou N condenses a partir des intermediaires lithies formes. Nous n'avons pas isole de produits issus d'une metallation des chaines laterales (- CH3 ou -CH2COCH3). The action of phenyllithium on pyrazine, 2-methyl pyrazine and acetonyl pyrazine gave mono- or di-addition products with azomethines bonds of pyrazine. The adducts can be condensed with methyl benzoate to give C or N condensed derivatives. No product with initial metalation of methyl or acetonyl groups was observed.

L'action d'organolithiens comme le butyllithium et le phenyllithium sur la methyl-2 quinoxaline conduit soit a une metallation du methyle soit a l'addition de l'organolithien sur une (ou sur les deux) liaisons imini-ques du noyau pyrazinique suivie ou non de metallation du methyle. L'addition d'eau (reaction A) au melange reactionnel permet l'isolement de composes stables dihydro-ou tetrahydroquinoxalines. L'addition d'electrophiles comme l'o-chlorobenzonitrile (reaction B) ou le benzoate de methyle (reaction C) livre des produits C ou N condenses a partir des intermediates lithtes formes. Seul le benzoate de methyle donne des produits de condensation a l'azote. The action of organolithium reagents such as phenyllithium or n-bulyllithium on 2-methylquinoxaline gave lithiation of the methyl group which upon reaction with electtropholesphiles produce side chain alkenyl derivatives. On the other hand organolithium reagents react with the quinoxaline azomethine bond to give I-lithio-2-alkyl)or ary-1)-3 methylquinoxalines which can be further loithiated on the methyl group to give 2-alkyl(or aryl)-3-alkenylquinoxaline derivatives. The adducts can be condensed with clectrophiles such as benzonitrile or methlyl benzoate but only methyl benzoate leads to N condensed derivatives. Furthermore substituted 1,2,3,4-terahydroqinoxalines are available via the above lithio intermediates.

Pour introduire des centres polaires dans des systemes pluricycliques plans en vue d'etudier leur action intercalante, on a prepare des derives de benzo[c]quinolizinium fonctionnalises par un groupement OH ou NH2: les precurseurs cetoniques ou imines sont obtenus a partir du picolyl-2 ou du quinaldyllithium; ils subissent ensuite une cyclisation par quaternisation mettant vraisemblablement en jeu un processus concerte. La structure des composes obtenus et de certains de leurs derives est etudiee. The introduction of polar groups in planar polycyclic systems, for the purpose of studying their intercalating action, has been realized in the benzo[c]quinolizinium series. A functionalizing synthesis has been developed from 2-picolyl-and quinaldyllithium. Intermediate ketones or imines were cyclized by a quaternization reaction involving a concerted process. Structure and physico-chemical features of the compounds prepared were studied.

The structure of pyrrolo ([4,5-b]-1′,2′,3′,4′-tetrahydroquinoxaline) [1,2,3-Im]- 1 - methyl - 3 - propyl - 1, 3, 3a, 4, 9, 9a - hexahydrothieno[3,4-b]quinoxaline 2,2-dioxide, isolated in the course of a study on a series of thieno[3,4,-b]quinoxalines, was assigned on the basis of a spectral 1H-13C correlated inverse chemical shift experiment.