Synthesis sulfate conjugates

Conjugation of 0-, N- and S-contalnlng functional groups with sulfate Is very common In animal systems. Sulfate Is transferred from adenosine 3 -phosphate-5 -sulfatophosphate (PAPS) by a variety of transfer enzymes. The mechanisms for sulfation of xenobiotics (74,75) and the chemistry of sulfate esters and related compounds and the synthesis of these have been reviewed (75-77). Syntheses of 0-, N- and S-sulfate conjugates of xenobiotics may be carried out by the methods described below. 

Reactions with sulfur trloxlde. Sulfur trloxlde (SO3) may react violently with nucleophiles unless the conditions are well controlled and this route Is not commmonly used for syntheses of xenobiotic sulfate conjugates. However a method suitable for both macro and micro scale synthesis of ascorbic acid 2-P sj sulfate (Figure 6A) was recently reported where the SO3 was Introduced to the substrate dissolved In DMF at -180"C (7 ). The reaction was completed at -15 C In 30 min and gave a 74Z yield of the 2-0-sulfate. 

Reactions with persulfate and pyrosulfate. The persulfate (peroxy-dlsulfate Ion, S2O8 ) reaction, also known as the Elba persulfate oxidation, has been Important In synthesis of hydroxylated phenols. The method has occasionally been used for synthesis of 0-sulfate conjugates. For example, 4-hydroxy-2-nltrophenyl sulfate was obtained when 3-nltrophenolate was stirred with potassium peroxydlsulfate at room temperature for 2 days (91,). The persulfate reaction has been used for the sulfation of various phenols and aromatic amines however the yields are usually low to moderate (77 ). The sulfate group Is preferentially Introduced In the 4-posltlon of phenols and In the 2-posltlon of aromatic amines but If these positions are blocked substitution at the 2- and... 

Miscellaneous methods. Sulfamic acid (NH2SO3H) has been used mainly In synthesis of sulfate conjugates of steroids (94.95). However the reaction, catalysed by pyridine and performed at 80-100 C for an hour, has also been used for phenolic subtrates (.77). Pyrldlnlum sulfate and acetic anhydride has been used for synthesis of estrone sulfate (9 ). 

A study of the urinary metabolites of the hypnotic, flurazepam hydrochloride, Ro 5-6901 (III), in the dog reveals non-conjugated (IV) and (V), conjugated (IV), (V), (VI) and (VIII) and a phenolic derivative of (VII). Human urine contained only the glucosuronic acid or sulfate conjugate of (VI). The synthesis and a comparison of the pharmacology of flurazepam hydrochloride with that of other 1,4-benzodiazepines has been reported , as well as the clinical use of this compound as a hypnotic. ... 

There have been very few examples of PTV derivatives substituted at the vinylene position. One example poly(2,5-thienylene-1,2-dimethoxy-ethenylene) 102 has been documented by Geise and co-workers and its synthesis is outlined in Scheme 1-32 [133]. Thiophene-2,5-dicarboxaldehyde 99 is polymerized using a benzoin condensation the polyacyloin precursor 100 was treated with base to obtain polydianion 101. Subsequent treatment with dimethyl sulfate affords 102, which is soluble in solvents such as chloroform, methanol, and DMF. The molar mass of the polymer obtained is rather low (M = 1010) and its band gap ( ,.=2.13 eV) is substantially blue-shifted relative to PTV itself. Despite the low effective conjugation, the material is reasonably conductive when doped with l2 (cr=0.4 S cm 1). 

Microbial oxidation of drug substrates occurs in a similar fashion to mammalian oxidative biotransformation. In contrast, microbial cultures rarely catalyze conjugations comparable to those in mammalian system (glucuronidation, sulfation and GSH conjugation). It is thus not surprising that microbial bioreactors are mainly used in the synthesis of oxidative metabolites. 

Acetylenic alcohols, usually of propargylic type, are frequently intermediates in the synthesis, and selective reduction of the triple bond to a double bond is desirable. This can be accomplished by carefully controlled catalytic hydrogenation over deactivated palladium [56, 364, 365, 366, 368, 370], by reduction with lithium aluminum hydride [555, 384], zinc [384] and chromous sulfate [795], Such partial reductions were carried out frequently in alcohols in which the triple bonds were conjugated with one or more double bonds [56, 368, 384] and even aromatic rings [795]. 

Dimethylaminonitroethylene is prepared from the anion of nitromethane and the salt prepaffed from dimethylformamide and dimethyl sulfate. The condensation step is general for other types of active methylene compounds, indicating further potential for pyrrole synthesis. A related process involves the condensation of ketones with the moao-N,N-dimethylhydrazone of glyoxal base-catalyzed condensation affords the hydrazones of a conjugated 1,4-dicarbonyl system, and sodium thiosulfate reduction then affords 2,3-disubstituted pyrroles (equation 85) (77CB491). 

It would seem that, at present, the data demand the interpretation that /3-D-glucuronidase is a purely hydrolytic enzyme that it does not catalyze glucosiduronic acid synthesis that it may, in some cases, be associated with rapid, cell division, and that its apparent relationship to estrogen and to cancer is probably on this basis and, finally, that, although its adaptive characteristics have not been disproved, they are unlikely to exist. If they should exist, the basis is most probably the hydrolytic function. It would seem that /3-D-glucuronidase bears the same relationship to glucuronic conjugates that phenolsulfatase bears to ester sulfates. 

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