Synthesis of N-(purin-8-yl)arylamines

Abstract

Methods for direct synthesis of N-(purin-8-yl)arylamines were investigated. N-(Purin-8-yl)arylamines are adducts from reaction of electrophilic metabolites of arylamines with DNA and have not been readily available by direct synthesis. Ability to generate significant quantities of this class of DNA adduct by synthetic means would facilitate basic research in molecular toxicology. Two routes with common thiourea intermediates were developed for this purpose. In the first route, 6-hydroxy-2,4,5-triaminopyrimidine was caused to react in aqueous medium with dithiocarbamate derivatives of o-, m-, or p-toluidine to form corresponding 2,4-diamino-5-(tolylthioureido)aminopyrimidin-6-ones in 60-70% yields. The thiourea intermediates were converted to carbodiimides and isolated in 20-25% yields after treatment with HgO in dimethylformamide. The carbodiimides were cyclized at 125 degrees C in dimethylformamide under N2 for 45 h to yield N-(guanin-8-yl)(o-, m-, or p-)toluidines in 65-75% yields. In the second route, direct reaction of p-tolyl isothiocyanate with 6-hydroxy-2,4,5-triaminopyrimidine or with 4,5,6-triaminopyrimidine in dimethylformamide and triethylamine led to the formation of 2,4-diamino-5-(p-tolylthioureido)aminopyrimidin-6-one and 4,6-diamino-5-(tolylthioureido)aminopyrimidine, respectively, in 77-79% yields. Methylation of the two thiourea derivatives by methyl iodide in dimethylformamide gave the corresponding methylisothiuronium derivatives, which were isolated in 71% and 84% yields (as HI salts), respectively. Conversion of the methylisothiuronium derivatives to N-(guanin-8-yl)-p-toluidine or N-(adenin-8-yl)-p-toluidine was accomplished by heating in dimethylformamide for 5-7 h at 80-90 degrees C, in 70% and 62% yields, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis, Characterization, and Conformational Analysis of DNA Adducts from Methylated Anilines Present in Tobacco Smoke

“…The use of more stable electrophilic synthons, such as N-acetoxy-N-(trifluoroacetyl)arylamines and N-acetyl-N-(acyloxy)arylamines, which is quite successful for the synthesis of dG-C8-Ar adducts from carcinogenic polyarylamines (55)(56)(57), failed to produce more than trace quantities of adducts from the monoarylamines under investigation, 2 possibly due to insufficient stabilization of the presumed nitrenium/carbenium ion intermediates by a single aromatic ring. On the other hand, although an alternate method, based upon the synthesis of N-(purin-8-yl)tolylamines from thiourea derivatives (35), should have general applicability, the problem of building the β-glycosyl bond to generate the corresponding nucleosides/nucleotides is not straightforward. For example, the chemical coupling of adducted bases to activated deoxyribose derivatives would require multiple protecting steps (58), and previous attempts to achieve enzymatic coupling have failed for guanine C8arylamine adducts (59).…”

“…The preparation of well characterized monoarylamine−DNA adduct standards would be of obvious importance to test this hypothesis by allowing the unambiguous identification and quantification of trace amounts of potential adducts formed in vivo through comparison with the synthetic standards ( e.g ., by 32 P-postlabeling). However, the difficulty in producing substantial quantities of DNA adducts from single-ring arylamines is reflected in the limited number of successful syntheses that have been reported ( − ).…”

New Syntheses of DNA Adducts from Methylated Anilines Present in Tobacco Smoke

“…Monoarylamines are present in considerable quantities in tobacco smoke, but their contribution to the putative arylamine−DNA adducts detected in bladder biopsies from smokers () remains to be established. DNA adducts from monoarylamines have been difficult to characterize, due to the poor efficiency of synthetic procedures, and this is reflected in the scarce number of syntheses described in the literature ( − ). With few exceptions ( , ), these procedures have been based on the reaction between 2‘-deoxyguanosine and N -acyloxyarylamines (ArNHOCOR) .…”

“…DNA adducts from monoarylamines have been difficult to characterize, due to the poor efficiency of synthetic procedures, and this is reflected in the scarce number of syntheses described in the literature ( − ). With few exceptions ( , ), these procedures have been based on the reaction between 2‘-deoxyguanosine and N -acyloxyarylamines (ArNHOCOR) . Minor adducts, such as (2‘-deoxyguanosin- N 2 -yl)arylamine (dG- N 2 -Ar), (2‘-deoxyguanosin- O 6 - yl)arylamine (dG- O 6 -Ar), and N -(2‘-deoxyadenosin-8-yl)arylamine, have not been isolated by this methodology.…”

A Novel Practical Synthesis of C‐2‐Arylpurines

“…Orthoformate was reacted with 8 in toluene and DMF at 90 8C to afford the corresponding 2-phenylpurine (9a) in high yield (entry 1). 8-Phenyl-(9b), [29] 8-methyl-(9c), [19e] 8-phenylamino-(9d), [30] 8-hydroxy-(9e), [31] and 8-mercapto-(9f) [30] derivatives were easily prepared in good yields by the reported methods listed in Table 4 (entries 2 -6).…”