Synthesis and conformation of a dinucleoside monophosphate modified by aniline

Abstract

The modified dinucleoside monophosphate, N-[deoxycytidylyl-(3'-5')-guanosin-8-yl]aniline (dCprG-An) has been prepared by the phosphotriester synthesis approach, using suitably blocked derivatives of dCp and N-guanosin-8-ylaniline (rG-An). The latter compound was synthesized by a route that featured nucleophilic displacement by antiline upon an 8-bromoguanosine derivative. A number of attempts to prepare N-(deoxyguanosin-8-yl)aniline (dG-An) by electrophilic substitution, using activated aniline derivatives, failed. Nucleophilic substitution reactions of aniline with 8-bromodeoxyguanosine derivatives afforded only the base, N-guanin-8-ylaniline. The conformation of dCprG-An has been studied by CD, proton magnetic resonance, and minimized potential energy calculations. A flexible molecule with a mixture of conformers is indicated. Base-base stacked states predominate, in contrast to the case of a dimer containing 4-aminobiphenyl bound to the 8-position of guanine, where carcinogen-base stacked states are dominant. The mutagenic and carcinogenic activities of aniline are much less than those of many polycyclic aromatic amines. The diminished stacking ability of the aniline ring, as well as the weak electrophilic reactivity of activated aniline derivatives, may be a cause of this weak biological activity.

Effect of Size and Shape of Nitrogen-Containing Aromatics on Conformational Preferences of DNA Containing Damaged Guanine

“…8,9 The resulting N-linked C 8 -dG adducts (addition products) contain a C−N−C linkage between the nucleobase and the aromatic moiety (Figure 1). 10 N-linked C 8 -dG adducts have been shown to originate from a variety of NCAs that exhibit a range in carcinogenic potential including, but not limited to, 2-aminofluorene (AF), 11 2-acetylaminofluorene (AAF), 12 aniline (AN), 13 4-aminobiphenyl (ABP), 14 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), 15 1-nitropyrene (1NP), 16 and 2-naphthylamine (2NP). 17 For example, AN dG (Figure 1A) is derived from AN, 18 which is used to manufacture dyes 13 and is considered to not be classifiable as a human carcinogen (group 3) by the International Agency for Research on Cancer (IARC).…”

Differentiation of isomeric C8-substituted alkylaniline adducts of guanine by electrospray ionization and tandem quadrupole ion trap mass spectrometry

“…The C8-substituted guanine adducts were synthesized as described [7,8], with minor modifications. The reaction mixture was evaporated and re-dissolved in a minimal amount of 2 M HCl.…”

“…The reaction mixture was evaporated and re-dissolved in a minimal amount of 2 M HCl. The C8-substituted guanine adducts were enriched by solid phase extraction and isolated by HPLC using a water:methanol gradient [7]. The concentrations of the guanine adducts were estimated from their UV absorbance using the max and values of the corresponding C8-substituted deoxyguanosine adducts [9,10].…”

“…As a control, we compared the product ion spectra of the BH 2 ϩ ions derived from N-(guan-8-yl)-2,6-dimethylaniline (7) and N-(deoxyguanosin-8-yl)-2,6-dimethylaniline (8). These experiments were conducted to investigate how sensitive fluctuations in product ion abundance might be to different ion generation mechanisms and/or adduct isolation procedures.…”

Synthetic and Oxidative Studies on 8-(Arylamino)-2 prime -Deoxyguanosine and -Guanosine Derivatives

“…In the more stable ribonucleoside series, it has been reported by Jacobson et al (25) that 8-bromo-2',3', 5'-tris-o-acetylguanosine (Structure 15) under controlled conditions reacts with aniline to give the 8-phenylamino derivative (Structure 16), which on base hydrolysis gives 8-phenylaminoguanosine. Taking this approach, we used 2-aminofluorene in place of aniline and the reaction afforded 8-(2-aminofluorenyl) -2',3', 5 '-tris-o-acetylguanosine (Structure 17) in better than 60% yield.…”