The concept of regioselectivity in drug metabolism

Testa, Bernard; Jenner, Peter

doi:10.1111/j.2042-7158.1976.tb04038.x

Cited by 26 publications

(4 citation statements)

References 62 publications

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“…Unlike glafenic acid, however, floctafenic acid does not yield an N-oxide either in vivo in the rat or in man or in vitro on treatment by m-chloroperbenzoic acid. This difference could be explained by electronic or steric factors (25). On the contrary although N-oxidation of hydroxyglafenic acid IV is not observed in vivo, it occurs readily in vitro, suggesting that the factors controlling N-oxidation in vivo are in this case less of a chemical than of a biochemical nature, e.g.…”

Section: Discussionmentioning

confidence: 87%

Biotransformations of glafenine in the rat and in man

Pottier¹,

Busigny²,

Raynaud³

1979

European Journal of Drug Metabolism and Pharmacokinetics

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The biotransformations of a therapeutic dose of the non-narcotic analgesic, glafenine, have been studied in the rat and in man. In the rat, the ester bond is extensively hydrolysed to give glafenic acid which is the major metabolite excreted in bile and in urine. Two minor pathways have been identified one leading by hydroxylation of the benzene ring of glafenine or glafenic acid in para of the amino-substituent to the corresponding phenols, the other, by oxidation of the quinoline nitrogen of glafenic acid, to its N-oxide. In vivo this N-oxide is partly reduced into the parent compound. Hydroxyglafenic acid is the product of both direct oxidation of glafenic acid and hydrolysis of hydroxyglafenine. The glyceric esters are conjugated as glucuro-ethers and/or sulfo-esters and the carboxylic metabolites as acyl glucuronides. The conjugation rate, high for glafenine, its phenol homologue and glafenic acid, is low for hydroxyglafenic acid and the N-oxide. The analogous urinary excretion patterns in man and in the rat suggest a similarity in the biotransformation of glafenine in these two species.

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Section: Discussionmentioning

confidence: 87%

Biotransformations of glafenine in the rat and in man

Pottier¹,

Busigny²,

Raynaud³

1979

European Journal of Drug Metabolism and Pharmacokinetics

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“…The topic of regioselective biotransformation has been extensively reviewed. 23 Recent studies of interest include the first report of enzymic hydroxylation a to an acetylenic 0022-2623/78/1821-0683$01.00/0 group24 and a careful investigation of the metabolism of 1-methylcyclohexene and related terpinoids in mammals showing high regioselectivities for allylic positions. 25 The biotransformation of /V-n-propylamphetamine by rat liver homogenates yielded ten times more N-dealkylated metabolites (resulting from C0-hydroxylation) than C3hydroxylated metabolites.…”

mentioning

confidence: 99%

An ab initio study of electronic factors in metabolic hydroxylation of aliphatic carbon atoms

Testa¹,

Mihailova²

1978

J. Med. Chem.

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The monooxygenase-mediated hydroxylations of aliphatic carbon atoms are known to be regioselective for positions alpha to heteroatoms or to pi systems (aromatic rings, carbon-carbon double bonds, carbonyl groups). Ab initio calculations (STO-3G and in some cases 4-31G) were performed on model molecules, indicating that the Mulliken overlap populations (taken as indices of electron bond densities) of Calpha-H bonds being regioselectively hydroxylated are larger than Cbeta-H and Cgamma-H overlap populations. These results support the hypothesis that metabolic C-hydroxylations occur by insertion of an activated oxygen species of electrophilic nature, probably oxene.

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“…38,[56][57][58] Although the rapid kinetics of these reactions has attracted considerable attention, 59 two major drawbacks including the low chemoselectivity (see the Supporting Information for detailed chemoselectivity experiments on peptide models with maleimide and iodoacetamide, Figure S63-S73) and poor stability of the conjugated products in the presence of external thiols (like glutathione) plagued their applications in chemical biology (Figure 1a) 8,[60][61] . Even recent progresses employing innovative Michael acceptors with electron-deficient alkynes, including phosphonamidate 62 and diethynyl phosphinates 63 have been explored, challenges in the stereo-and regioselectivities, and the stability of the conjugated products, which are important for drug discovery [64][65] , still remain (Figure 1b) 38,60,66 . Ynamides are strongly polarized alkyne derivatives due to the direct attachment of the electron-donating nitrogen atom to the triple bond and the electron-withdrawing group (EWG) on the nitrogen atom, which provides an optimal balance between the stability and reactivity.…”

Section: Introductionmentioning

confidence: 99%

Highly Chemo-, Regio- and Stereoselective Cysteine Modification of Peptides and Proteins with Ynamides

Wang

Zhao

Ghadir

et al. 2021

Preprint

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Chemoselective modification of peptides and proteins has wide applications in chemical biology and pharmaceutical development. An efficient cysteine (Cys) precise modification protocol via rationally designed β-addition of ynamides is reported. The strong electron-withdrawing triflyl group on the nitrogen atom of ynamides plays a crucial role for controlling the chemo-, stereo- and regioselectivities of this protocol. Another substituent of the terminal ynamides offers a handle for functionality diversification. This Cys modification with ynamides proceeds efficiently in a slightly basic aqueous media (pH 8) to provide a series of Z-isomer of the corresponding conjugated products with excellent stereoselectivity (> 99%) and superior stability. All the reactive peptide side chain functional groups such as amino, carboxyl, primary amide, and hydroxyl groups, as well as the unprotected imidazole and indole rings are compatible. This method displays a broad substrates scope including linear and cyclic peptides and proteins. The potential application of this method in peptide and protein chemical biology was exemplified by Cys-bioconjugation with ynamides containing different functional molecules, including drug, fluorescent and affinity tags. In addition, this strategy is also compatible with click chemistry (performed in one pot), which remarkably extends the toolbox for further applications. The chemoselective biotinylation of ubiquitin(G47C) variant with a biotinylated ynamide, as well as the regioselective modification of Cys14 and Cys38 in bovine pancreatic trypsin inhibitor (BPTI) were accomplished under the optimized conditions and in high yield, without perturbation of disulfide bonds.

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The concept of regioselectivity in drug metabolism

Cited by 26 publications

References 62 publications

Biotransformations of glafenine in the rat and in man

Biotransformations of glafenine in the rat and in man

An ab initio study of electronic factors in metabolic hydroxylation of aliphatic carbon atoms

Highly Chemo-, Regio- and Stereoselective Cysteine Modification of Peptides and Proteins with Ynamides

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