Demethyl homologs

The three possible demethyl homologs of the natural retinoids retinol (1), retinaldehyde (2), and retinoic acid (3) were synthesized for use in biological studies by combining the aldehydes (526) with the phosphonates (527) (Van den Tempel and Huisman, 1966 Lee et aL, 1976). 

Reflux 6.9 g triphenylphosphine and 6.6 g lauryl bromide (or equimolar amount of homolog) in 40 ml xylene for 60 hours. Remove solvent and wash residue with 5X20 ml ether (by decanting) to get 11 g lauryl triphenylphosphonium bromide (I). To a stirred suspension of 5.6 g (0.011M)(I) in 50 ml ether add 0.01M butyllithium solution (see Organic Reactions 8,258(1954) for preparation). Stir Vz hour at room temperature and slowly add 1.66 g 3,5-dimethoxybenzaldehyde (preparation given elsewhere here) in 10 ml ether over Vi hour. After 15 hours, filter, wash filtrate with water and dry, evaporate in vacuum. Dilute residue with pentane, filter and remove solvent. Dissolve the residual oil in 25 ml ethyl acetate and hydrogenate over O.lg Adams catalyst at one atmosphere and room temperature for 2 hours. Filter and evaporate in vacuum to get the 5-alkylresorcinol dimethyl ether which can be reciystallized from pentane and demethylated as described elsewhere here. 

Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSDl. Cell 119 941-953 Sims RJ 3rd, Reinberg D (2006) Histone H3 Lys 4 methylation Caught in a bind Genes Dev. 20 2779-2786... 

As already mentioned, with time the mid-molecule cleavage typical of a bifunctional catalyst decreases over the molybdenum based catalyst and the demethylation reaction becomes dominant. Demethylation also increases with increasing pressure. Amir-Ebrahimi and Rooney proposed that the metallacyclobutane isomerization mechanism should have a significant methanation and homologation contribution.34 Homologation products were not analysed in this study but have been observed in studies of the C4 and C5 reactions 35 however, methane was an important component of the cracking products over the molybdenum catalysts. 

It shares homology with the JmjC domains found in the histone lysine demethylases. JMJD6 can demethylate H3 R2 and H4 R3 in biochemical and cell-based assays (42). The recent data that are emerging place histone arginine methylation as a key player of cell growth and cell proliferation processes. 

Shi Y, et al. Histone demethylation mediated by the nuclear 110. amine oxidase Homolog ESDI. Cell 2004 119 941-953. 

Percentage Cross Reactions of Methylated and Demethylated Drugs Compared to Inhibition Observed with the Homologous Antigen at Im... 

With the advent of tritiated nicotine (and other radioligands) to label neuronal nACh receptors came fairly simple questions such as (a) which is the higher affinity optical isomer of nicotine, ( — )nicotine or (-I- )nicotine, (b) what is the effect of N-demethylation, to afford nomico-tine, and what is the effect of A-methyl homologation, (c) is the pyridine ring of nicotine necessary for high affinity,... 

It is often found that the first member of many thermochemical series is an outlier, e.g. Slayden and Liebman, op. cit., ref. 34. However, since most of the preceding demethylated species so qualify as first members of their respective homologous series, this does not seem to be an adequate reason. 

Amphetamine possesses an a-methyl group. As already mentioned at the beginning of this chapter, a-demethylation (to afford phenylethylamine or 2-phenyl-1-aminoethane in the case of amphetamine) results in agents with decreased lipophilicity and increased susceptibility to metabolism. Phenylethylamine lacks central stimulant activity. Homologation of the a-methyl group to, for example, an a-ethyl or a-n-propyl group results in a decrease or loss of central stimulant activity. The presence of the a-methyl group in amphetamine creates a chiral center hence, amphetamine exists as a pair of optical isomers. With respect to central stimulant actions, the S-(+)-isomer (i.e., dextroamphetamine) is several-fold more potent than its R-(-)- enantiomer (i.e., levamphetamine) this is not necessarily the case with other actions produced by amphetamine, particularly those produced in the periphery, such as its cardiovascular actions. 

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