Side-chain hydroxylations

A side chain hydroxyl group in 5//-pyrido[l,2,3-de]-l,4-benzoxazin-5-one was changed for chloro atom by treatment with SOCE at room temperature for 16h (98M1P13). 

Omission of the side chain hydroxyl group from molecules based on epinephrine or ephedrine does not abolish the sympathomimetic activity of the resulting compounds. Many of these agents exert a considerable stimulant action on the central nervous system. As such, drugs in this class have been widely used—and... 

The conversion of tyrosine to epinephrine requires four sequential steps (1) ring hydroxylation (2) decarboxylation (3) side chain hydroxylation to form norepinephrine and (4) N-methylation to form epinephrine. The biosynthetic pathway and the enzymes involved are illustrated in Figure 42-10. 

Although UGTs catalyze only glucuronic acid conjugation, CYPs catalyze a variety of oxidative reactions. Oxidative biotransformations include aromatic and side chain hydroxylation, N-, O-, S-dealkylation, N-oxidation, sulfoxidation, N-hydroxylation, deamination, dehalogenation and desulfation. The majority of these reactions require the formation of radical species this is usually the rate-determining step for the reactivity process [28]. Hence, reactivity contributions are computed for CYPs, but a different computation is performed with the UGT enzyme (as described in Section 12.4.2). 

ACID-INDUCED O-ACYLATION OF SIDE-CHAIN HYDROXYLS AND THE O-TO-N ACYL SHIFT... 

The in vivo metabolism of a homologous series of alkyl carbamates (7.2, Fig. 7.3) has yielded some informative results [13]. The hydrolysis of these esters liberates carbamic acid (7.3, Fig. 7.3), which breaks down spontaneously to C02 and NH3, allowing the extent of hydrolysis to be determined conveniently and specifically by monitoring C02 production. When such substrates were administered to rats, there was an inverse relationship between side-chain hydroxylation and ester-bond hydrolysis. Thus, for compounds 12 the contribution of hydrolysis to total metabolism (90 - 95% of dose) decreased in the series R=Et (ca. 85-90%), Bu (ca. 60-65%), hexyl (ca. 45 - 50%), and octyl (ca. 30%). Ethyl carbamate (urethane) is of particular toxicological interest, being a well-established carcinogen in experimental animals. In vitro studies of adduct formation have confirmed the competition between oxidative toxification mediated by CYP2E1 and hydrolytic detoxification mediated by carboxylesterases [14]. 

HETE (138) is known to inhibit 5-LO [334]. A group at Revlon created a series of combined 5-LO inhibitors/LT antagonists derived conceptually from the structure of 15-HETE. REV 5901A (139) [335], the best of the series, inhibited 5-HETE release from rat ISN (0.12 //M) and was fairly selective with respect to CO and 12-LO inhibition. The quinoline could be replaced by another lipophilic aromatic group, but potency decreased (naphthalene was 40-fold less potent, and substituted phenyl was 5- to 20-fold less active). Pyridines were active but also less potent 2-pyridyl was only 4-fold less active, while 3- and 4-pyridyl were 20-fold weaker. Ortho-and pnra-substituted phenylene groups were less active. Elimination of the side-chain hydroxyl to the olefin caused a loss of activity, as did the use of shorter alkyl chains. 

False neurotransmitters are amines which are similar enough in structure to normal amine neurotransmitters that they bind to receptors but are much less active or totally inactive (i.e. they are antagonists). One such false neurotransmitter is octopamine, which is formed from tyrosine by decarboxylation followed by side-chain hydroxylation. 

The mechanism of catalysis by these enzymes has been extensively investigated (for review see ref. 10). Essentially, the active site serine via its side chain hydroxyl group performs a nucleophilic attack on the carbonyl carbon of the scissile peptide bond thus forming a tetrahedral intermediate. A histidine residue in the active site serves as a general base accepting the proton from the serine residue. The acyl enzyme thus formed is broken down via a nucleophilic attack of a water molecule to complete the hydrolysis of the peptide bond. 

Last year s Report numbered some hydroxylated cannabinoid metabolites inconsistently. The numbering system used in these Reports (see Vol. 2, p. 61) requires that the pentyl side-chain be numbered C-1" — C-5" references to microbiological hydroxylation last year (Vol. 7,pp. 50,51) designated as occurring at C-1, C-2, C-3, C-4, and C-5 referred to side-chain-hydroxylated metabolites which should have been numbered C-T, C-2", C-3", C-4", and C-5" respectively. 

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