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The metabolism of the isomeric tert.-butylcyclohexanones.

ABSTRACT: 1. (+/-)-2-, (+/-)-3- and 4-tert.-Butylcyclohexanone are reduced in the rabbit to secondary alcohols, which are excreted extensively conjugated with glucuronic acid. 2. The major metabolite of (+/-)-2-tert.-butylcyclohexanone is (+)-cis-2-tert.-butylcyclohexanol, which has been isolated from the urine as [(+)-cis-2-tert.-butylcyclohexyl beta-d-glucosid]uronic acid. The minor metabolite is (+)-trans-2-tert.-butylcyclohexanol. 3. (+/-)-3-tert.-Butylcyclohexanone is reduced mainly to (+/-)-cis-3-tert.-butylcyclohexanol, and to a smaller extent to (+/-)-trans-3-tert.-butylcyclohexanol. 4. 4-tert.-Butylcyclohexanone yields mainly the trans-alcohol, which is excreted in conjugated form and has been recovered from the urine as (trans-4-tert.-butylcyclohexyl beta-d-glucosid)uronic acid. The cis-alcohol is formed to a minor extent and excreted in conjugated form. 5. The ratios of the amounts of cis- to trans-alcohols produced by the three ketones differed from the relative amounts of cis- and trans-alcohols produced by the corresponding methylcyclohexanones. 6. From these findings the suggestion is made that two orientations of ketone relative to coenzyme occur: alcohols with an equatorially orientated hydroxyl group are thought to be produced as a result of a ;face-to-face' interaction with NADH, and alcohols with axially orientated hydroxyl groups as a result of a ;perpendicular' interaction. Which will predominate is thought to depend on steric factors, particularly the size and position of alkyl substituents in the substrate.

SUBMITTER: Cheo KL

PROVIDER: S-EPMC1270561 | biostudies-other | 1967 Jul

REPOSITORIES: biostudies-other

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Project description:1. The metabolism of (+/-)-cis-1-, (+/-)-trans-1-, (+/-)-cis-2- and (+/-)-trans-2-decalone in the rabbit has been investigated. 2. (+/-)-cis-2- and (+/-)-trans-2-Decalone were both reduced to racemic secondary alcohols, conformationally related to the ketones administered, and possessing an equatorial hydroxyl group. These alcohols were excreted in the urine as glucuronides in amounts equal to about half the dose administered. The glucuronides were isolated both as triacetyl methyl esters and as sodium salts. The ester obtained after feeding with (+/-)-cis-2-decalone proved to be methyl (cis-cis-2-decalyl tri-O-acetyl-beta-d-glucosid)uronate, whereas (+/-)-trans-2-decalone yielded methyl (trans-cis-2-decalyl tri-O-acetyl-beta-d-glucosid)uronate. The sodium salts were shown to be sodium (cis-cis-2-decalyl glucosid)uronate and sodium (trans-cis-2-decalyl glucosid)uronate. 3. Enzyme hydrolysis of the sodium salts and acid hydrolysis of the esters derived from (+/-)-cis-2-decalone yielded (+/-)-cis-cis-2-decalol, and of those from (+/-)-trans-2-decalone yielded (+/-)-trans-cis-2-decalol. 4. (+/-)-cis-1-Decalone was reduced mainly to (-)-cis-cis-1-decalol and excreted as [(-)-cis-cis-1-decalyl glucosid]-uronic acid. A small amount of the corresponding (+)-isomer was produced, yielding [(+)-cis-cis-1-decalyl glucosid]uronic acid on isolation. Enzyme hydrolysis of these compounds gave the corresponding aglycones; both alcohols possessed an equatorial hydroxyl group. 5. (+/-)-trans-1-Decalone was reduced to (+)-trans-trans-1-decalol, with an equatorial hydroxyl group, and in smaller amount to (+)-trans-cis-1-decalol possessing an axial group. The former alcohol was excreted as [(+)-trans-cis-1-decalyl glucosid]uronic acid, and the latter as [(+)-trans-cis-1-decalyl glucosid]uronic acid. 6. From a knowledge of the conformations, and in some cases the absolute configurations, of the compounds administered and excreted, and by making the assumption that the coenzyme concerned in the reductions is NADH (or NADPH), an explanation of the above findings in terms of steric hindrance and thermodynamic stability is given.

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The metabolism of the isomeric tert.-butylcyclohexanones.

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