Regioselective synthesis of deuterated analogs of the neurotoxin MPTP

Mabic, Stéphane; Castagnoli, Neal

doi:10.1002/(sici)1099-1344(199603)38:3<255::aid-jlcr835>3.0.co;2-0

Cited by 3 publications

(1 citation statement)

References 9 publications

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“…Deuterated analogs of the neurotoxin MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine), which is oxidized to more toxic species, were prepared to study the pathway that leads to these changes (Mabic and Castagnoli 1996). Dideuterated analogs of nordiazepam and diazepam were prepared to study isotope effects in oxidative reactions catalyzed by drug-metabolizing enzyme systems (Yang et al 1996).…”

Section: Properties and Uses Of Deuterated Drugsmentioning

confidence: 99%

Pharmacological uses and perspectives of heavy water and deuterated compounds

Kushner¹,

Baker²,

Dunstall³

1999

Can. J. Physiol. Pharmacol.

259

177

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Since the discovery of D20 (heavy water) and its use as a moderator in nuclear reactors, its biological effects have been extensively, although seldom deeply, studied. This article reviews these effects on whole animals, animal cells, and microorganisms. Both "solvent isotope effects," those due to the special properties of D20 as a solvent, and "deuterium isotope effects" (DIE), which result when D replaces H in many biological molecules, are considered. The low toxicity of D20 toward mammals is reflected in its widespread use for measuring water spaces in humans and other animals. Higher concentrations (usually >20% of body weight) can be toxic to animals and animal cells. Effects on the nervous system and the liver and on formation of different blood cells have been noted. At the cellular level, D20 may affect mitosis and membrane function. Protozoa are able to withstand up to 70% D20. Algae and bacteria can adapt to grow in 100% D2O and can serve as sources of a large number of deuterated molecules. D2O increases heat stability of macromolecules but may decrease cellular heat stability, possibly as a result of inhibition of chaperonin formation. High D2O concentrations can reduce salt- and ethanol-induced hypertension in rats and protect mice from gamma irradation. Such concentrations are also used in boron neutron capture therapy to increase neutron penetration to boron compounds bound to malignant cells. D2O is more toxic to malignant than normal animal cells, but at concentrations too high for regular therapeutic use. D2O and deuterated drugs are widely used in studies of metabolism of drugs and toxic substances in humans and other animals. The deuterated forms of drugs often have different actions than the protonated forms. Some deuterated drugs show different transport processes. Most are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity. It may also lead to lower activity, if the drug is normally changed to the active form in vivo. Deuteration can also lower the genotoxicity of the anticancer drug tamoxifen and other compounds. Deuteration increases effectiveness of long-chain fatty acids and fluoro-D-phenylalanine by preventing their breakdown by target microorganisms. A few deuterated antibiotics have been prepared, and their antimicrobial activity was found to be little changed. Their action on resistant bacteria has not been studied, but there is no reason to believe that they would be more effective against such bacteria. Insect resistance to insecticides is very often due to insecticide destruction through the cytochrome P450 system. Deuterated insecticides might well be more effective against resistant insects, but this potentially valuable possibility has not yet been studied.

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Section: Properties and Uses Of Deuterated Drugsmentioning

confidence: 99%

Pharmacological uses and perspectives of heavy water and deuterated compounds

Kushner¹,

Baker²,

Dunstall³

1999

Can. J. Physiol. Pharmacol.

259

177

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Regioselective deuterium labeling of 1,4-disubstituted-1,2,3,6-tetrahydropyridines

Mabic

Rimoldi

Castagnoli

1997

J Label Compd Radiopharm

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Reactions leading to the regioselective deuterium labeling of the 1,4‐disubstituted‐1,2,3,6‐tetrahydropyridine system are presented. Three synthetic approaches were explored: Base catalyzed proton‐deuteron exchange, reductive deuteration, and ring synthesis using deuterated agents. The methods were applied to various pyridinium salts, pyridones, and piperidones. The syntheses of several new labeled compounds are described and a brief review of the relevant literature is included. © 1997 John Wiley & Sons, Ltd.

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