Stereospecificity of the chloride ion channel: the action of chiral clofibric acid analogs

Bettoni, Giancarlo; Loiodice, Fulvio; Tortorella, Vincenzo; Conte-Camerino, D; Mambrini, M.; Ferrannini, E.; Bryant, S. H.

doi:10.1021/jm00391a002

Cited by 64 publications

(41 citation statements)

References 6 publications

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“…The derivatives of classes 1, 2, and 4 (see Fig. 1) were synthesized as racemic mixtures by use of the procedures detailed elsewhere (Bettoni et al, 1987;Romstedt et al, 1996;Ferorelli et al, 1997;Carbonara et al, 2001). The derivative N8 of class 3 was synthesized starting from ␣,4-dichloroanisole and trimethylphosphite; compounds N9 and N10 were obtained by alkaline or acid hydrolysis of compound 8, respectively, according to the procedure described by Cornforth and Wilson (1994) and Bhattacharya and Thyagarajan (1981).…”

Section: Methodsmentioning

confidence: 99%

“…To date, the only substances available are derivatives of the 2-(p-chlorophenoxy)propionic acid (CPP), which are molecules that stereoselectively modulate the macroscopic resting Cl Ϫ conductance (gCl) of skeletal muscle as well as the activity of CLC-1, the muscle Cl Ϫ channel underlying gCl (Bettoni et al, 1987;Aromataris et al, 1999). As for native gCl, the S(Ϫ)-enantiomer is the most potent CPP-enantiomer able to block the currents of heterologously expressed human CLC (hCLC)-1 interfering with channel gating by acting from the intracellular side (Pusch et al, 2000).…”

Section: The Movement Of CLmentioning

confidence: 99%

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Molecular Requisites for Drug Binding to Muscle CLC-1 and Renal CLC-K Channel Revealed by the Use of Phenoxy-Alkyl Derivatives of 2-(p-Chlorophenoxy)Propionic Acid

et al. 2002

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CLC channels are a gene family of Cl Ϫ channels that serve a variety of functions, several of which are involved in genetic diseases. Few specific ligands of CLC channels are known that could be useful as pharmacological tools or potential drugs. We synthesized various derivatives of 2-(p-chlorophenoxy)propionic acid, the S(Ϫ)-enantiomer of which is a specific blocker of the muscle channel CLC-1. In particular, compounds with different alkyl or phenoxy-alkyl groups on the chiral center, isosteres of the oxygen in the aryloxy moiety, or bioisosteres of the carboxy function were prepared. We found that compounds containing a phenoxy and a phenoxy-alkyl group on the chiral center (bis-phenoxy derivatives) specifically inhibited renal CLC-K channels from the extracellular side with an affinity in the 150-M range and with almost no effect on other CLC channels when applied from the outside. Surprisingly, the same substances inhibited CLC-1 from the intracellular side in a voltage-dependent manner with an apparent K D of Ͻ5 M at Ϫ140 mV, thus being the most potent blockers of a CLC channel known so far. Although the chlorine atom in paraposition of the second phenoxy group was essential for inhibition of CLC-K channels from the outside, it could be substituted by a methoxy group without changing the potency of block for CLC-1 from the inside. These newly identified substances provide powerful tools for studying the structure-function relationship and the physiological role of CLC channels and may represent a starting point for the development of useful drugs targeting CLC-K channels.

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Section: Methodsmentioning

confidence: 99%

Section: The Movement Of CLmentioning

confidence: 99%

Molecular Requisites for Drug Binding to Muscle CLC-1 and Renal CLC-K Channel Revealed by the Use of Phenoxy-Alkyl Derivatives of 2-(p-Chlorophenoxy)Propionic Acid

et al. 2002

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“…After extraction, 1 (Table II). Such concentrations, if present in the chloroplasts, would be sufficient to fully inhibit ACCase from both ryegrass biotypes.…”

Section: Effect Of Diclofop Acid On Electrochemical Membrane Potentialsmentioning

confidence: 99%

“…The herbicide is a potent inhibitor of the enzyme ACCase (19) and can depolarize membranes (18,22,29). In animals and humans, similar compounds have been reported to inhibit ACCase (3), disrupt lipid metabolism (7), and interfere with membrane transport (1).…”

mentioning

confidence: 99%

Cross-Resistance to Herbicides in Annual Ryegrass (Lolium rigidum)

Holtum

Matthews²,

Häusler³

et al. 1991

Plant Physiol.

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Annual ryegrass (Lollum rigidum) biotype SLR 31 is resistant to the postemergent graminicide methyl-2-[4-(2,4-dichlorophenoxy)phenoxy]-propanoate (diclofop-methyl). Uptake of [14C](Uphenyl)diclofop-methyl and root/shoot distribution of radioactivity in susceptible and resistant plants were similar. In both biotypes, diclofop-methyl was rapidly demethylated to the biocidal metabolite diclofop acid which, in tum, was metabolized to ester and aryl-O-sugar conjugates. Susceptible plants accumulated 5 to 15% more radioactivity in dicloflop acid than did resistant plants. Resistant plants had a slightly greater capacity to form nonbiocidal sugar conjugates. Despite these differences, resistant plants retained 20% of 14C in the biocidal metabolite diclofop acid 192 hours after treatment, whereas susceptible plants, which were close to death, retained 30% in diclofop acid. The small differences in the pool sizes of the active and inactive metabolites are by themselves unlikely to account for a 30-fold difference in sensitivity to the herbicide at the whole plant level. Similar highpressure liquid chromatography elution patterns of conjugates from both susceptible and resistant biotypes indicated that the mechanisms and the products of catabolism in the biotypes are similar. It is suggested that metabolism of diclofop-methyl by the resistant biotype does not alone explain resistance observed at the whole-plant level. Diclofop acid reduced the electrochemical potential of membranes in etiolated coleoptiles of both biotypes; 50% depolarization required I to 4 Mm diclofop acid. After removal of diclofop acid, membranes from the resistant biotype recovered polarity, whereas membranes from the susceptible biotype did not. Intemal concentrations of diclofop acid 4 h after exposing plants to herbicide were estimated to be 36 to 39 micromolar in a membrane fraction and 16 to 17 micromolar in a soluble fraction. Such concentrations should be sufficient to fully depolarize membranes. It is postulated that differences in the ability of membranes to recover from depolarization are correlated with the resistance response of biotype SLR 31.

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“…This (R)-acid is a chiral analogue of clofibrate and exhibits higher anti-aggregatory activity, 11 lower miotonic effects 12 and hepatocarcinogenicity 13 compared to the corresponding (S)-enantiomer. The specific rotation of (R)-4, compared with the literature values, showed it to be essentially pure.…”

Section: Methodsmentioning

confidence: 99%

Dynamic kinetic resolution of alpha-bromoesters containing lactamides as chiral auxiliaries

Ammazzalorso¹,

Amoroso²,

Bettoni³

et al. 2004

Arkivoc

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The conversion of racemic α-bromobutanoic acid into the corresponding esters with amides of (S)-lactic acid as chiral auxiliaries was examinated. Displacement of the bromine with 4-chlorophenoxide, under suitable reaction conditions, was found to proceed with good to high diastereoselectivity to give 4-(chlorophenoxy)butanoyl esters. After hydrolysis, the (R)-enantiomer of antilipidemic 2-(4-chlorophenoxy)butanoic acid was obtained.

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Stereospecificity of the chloride ion channel: the action of chiral clofibric acid analogs

Cited by 64 publications

References 6 publications

Molecular Requisites for Drug Binding to Muscle CLC-1 and Renal CLC-K Channel Revealed by the Use of Phenoxy-Alkyl Derivatives of 2-(p-Chlorophenoxy)Propionic Acid

Molecular Requisites for Drug Binding to Muscle CLC-1 and Renal CLC-K Channel Revealed by the Use of Phenoxy-Alkyl Derivatives of 2-(p-Chlorophenoxy)Propionic Acid

Cross-Resistance to Herbicides in Annual Ryegrass (Lolium rigidum)

Dynamic kinetic resolution of alpha-bromoesters containing lactamides as chiral auxiliaries

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