S-Methylation

Methyl groups from SAM are also transferred to thiol-containing drugs and xeno-biotics. It appears that the only structural requirements are the presence of a free thiol and that the compound is not too hydrophilic in nature. S-Methylation has been demonstrated with mercaptoethanol, thioacetanilide, and 6-mercaptopurine, as well as with a variety of thiopurine and thiopyrimidine drugs. In general, aromatic thiols are the best substrates, while simple aliphatic thiols are less active. 

Thiol methyltransferase has been detected in erythrocytes, lymphocytes, lungs, cecal, and colonic mucosae. The nature and number of thiol methyltransferases is not clear at the present time. A cytosolic enzyme and a microsomal enzyme have been reported, with the microsomal enzyme being dissociated from membrane relatively easily. The microsomal enzyme in rat liver has been purified to homogeneity. The enzyme is a 28,000-dalton monomer with an isoelectric point of 6.2. A wide variety of xenobiotic thiols are methylated, but cysteine and glutathione are not substrates. S-Methylation is an important component in the thiomethyl shunt. Thiomethyl conjugates are metabolized to the methylsulfoxides by oxidation (see Chapter 10) and reenter the mercapturic acid pathway as substrates for glutathione S-transferase. 

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In 1896, Gabriel and Freiherr von Hirsch (96) condensed CSj with what they believed to be 1-aminopropylene (2-methylaziridine) and obtained isomeric 4- and S-methyl-Z-mercaptothiazoline (63 and 64). 

Why IS there such a marked difference between methyl and trifluoromethyl substituents m their influence on electrophilic aromatic substitution s Methyl is activating and ortho para directing trifluoromethyl is deactivating and meta directing The first point to remember is that the regioselectivity of substitution is set once the cyclohexadienyl cation intermediate is formed If we can explain why... 

Table 3. U.S. Methyl Chloride Production and Price Statistics...

Primary synthesis has limited application in making pyrimidine-carboxylic acids or even their esters. However, some pyrimidine-4(and 5)-carboxylic acids can be effectively so made. For example, bromomucic acid (785) reacts as an aidehydo ketone with S-methyl-thiourea to give 5-bromo-2-methylthiopyrimidine-4-carboxylic acid (786) directly (53JCS3129) while the Whitehead synthesis (Section 2.13.3.1.2<7) can give, for instance, 3-methylcytosine-5-carboxylic acid (787) (55MI21300). 

Halide ions may attack 5-substituted thiiranium ions at three sites the sulfur atom (Section 5.06.3.4.5), a ring carbon atom or an 5-alkyl carbon atom. In the highly sterically hindered salt (46) attack occurs only on sulfur (Scheme 62) or the S-methyl group (Scheme 89). The demethylation of (46) by bromide and chloride ion is the only example of attack on the carbon atom of the sulfur substituent in any thiiranium salt (78CC630). Iodide and fluoride ion (the latter in the presence of a crown ether) prefer to attack the sulfur atom of (46). cis-l-Methyl-2,3-di-t-butylthiiranium fluorosulfonate, despite being somewhat hindered, nevertheless is attacked at a ring carbon atom by chloride and bromide ions. The trans isomer could not be prepared its behavior to nucleophiles is therefore unknown (74JA3146). 

S-methyl dithiocarbonate (76S413). Stereoselective isomerization of 1,2-disubstituted alkenes may be achieved by a sequence such as the following fr<2n5-alkene bromo-hydrin -> /3-hydroxythiocyanate -> cw-thiirane -> cw-alkene (75TL2709). 

Dibenzothiophene, 8-ethoxy-4-iodo-2-nitro-synthesis, 4, 881 Dibenzothiophene, ethyl-occurrence, 4, 910 Dibenzothiophene, methyl-occurrence, 4, 910 Dibenzothiophene, S-methyl-theoretical methods, 4, 3... 

Naphthothiazole-2-carboxylic acid decarboxylation, 6, 279 Naphthothiene nomenclature, 1, 21 Naphthothiete, S-methyl-reactions... 

FREUDENBERG - SCHdNBERG Xanthate Rearrangement Rearrangement of S-methyl xanthates to S-methyIdithiocarbonatas (conversion of alcohols lo thiols via xanthates, also phenols to thiophenols via thiocarbamates). 

COOH), pK 8. 73 (NHj, 8.97). Likely impurities are cysteine and S-methyl- f/-cysteine. Crystd from water by adding 4 volumes of EtOH. 

S-Methyl-L-methionine chloride (Vitamin U) [1115-84-0] M 199.5, [a]p +33 (0.2M pK[ 1.9, pKj 7.9. Likely impurities are methionine, methionine sulfoxide and methionine sulfone. from water by adding a large excess of EtOH. Stored in a cool, dry place, protected from light. 

Other functional groups that are easily differentiated are cyanide (5c =110-120) from isocyanide (5c = 135- 150), thiocyanate (5c =110-120) from isothiocyanate (5c = 125 - 140), cyanate (5c = 105- 120) from isocyanate (5c = 120- 135) and aliphatic C atoms which are bonded to different heteroatoms or substituents (Table 2.2). Thus ether-methoxy generally appears between 5c = 55 and 62, ester-methoxy at 5c = 52 N-methyl generally lies between 5c = 30 and 45 and. S-methyl at about 5c = 25. However, methyl signals at 5c = 20 may also arise from methyl groups attached to C=X or C=C double bonds, e.g. as in acetyl, C//j-CO-. 

Similarly, androstane-5a,6a,17)S-triol 6-tosylate 17-benzoate (115b) is converted to 17)S-hydroxy-6)S-methyl-10(5 6)SH)flZ)en-androstan-5-one benzoate (116b) on treatment with calcium carbonate in dimethylformamide. Similar treatment of 10-methyldecalin-l,9-diol 1-tosylate (121) gives 10-methylbicyclo[5.3.0]decan-l-one (122). 

Alkylation of these mercapto compounds in alkaline solution gives only the S-methyl derivatives. Of the four isomeric A-methyl derivatives, the 4-thioquinazolines, (28) and (29), have been obtained from the corresponding oxo compounds with phosphorus pentasulfide but the corresponding 2-thio derivatives (30) and (31) are not known. However, derivatives of substance (31) with methyl replaced by... 

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