Kinetics of hydrolysis of 8-(arylamino)-2'-deoxyguanosines.
The 8-(arylamino)-2'-deoxyguanosines, or C-8 adducts, are the major adducts formed by reaction of N-arylnitrenium ions derived from carcinogenic and mutagenic amines with 2'-deoxyguanosine (d-G) and guanosine residues of DNA. The hydrolysis kinetics of three C-8 adducts 1a-c were determined by UV and HPLC methods at 20 degrees C under acidic, neutral, and mildly alkaline conditions. At pH < 2 the dominant hydrolysis process is spontaneous cleavage of the C-N bond of the doubly protonated substrate, 1H(2)(+2) (Scheme 2). The C-8 adducts are 2- to 5-fold more reactive than d-G under these conditions. At 3 < pH < 6 the hydrolysis kinetics are dominated by cleavage of the C-N bond of the monoprotonated nucleoside 1H(+). Under these conditions the hydrolysis kinetics are accelerated by 40- to 1300-fold over that of d-G. The rate increase appears to be caused by a combination of steric acceleration of C-N bond cleavage and a decrease in the ionization constant of 1H(+), K(a1), due to the electron-donating properties of the arylamino C-8 substituent. Under neutral pH conditions a slow (k(obs) approximately 10(-8) s(-1) to 5 x 10(-7) s(-1)) spontaneous cleavage of the C-N bond of the neutral nucleoside, 1, occurs that has not been previously reported for simple purine nucleosides. Finally, under mildly alkaline conditions a process consistent with spontaneous decomposition of the anion 1(-) or OH(-)-induced decomposition of 1 is observed. The latter process has been observed for other purine nucleosides, including the closely related 1d, and involves nucleophilic attack of OH(-) on C-8 to cleave the imidazole ring of the purine.
Novak
Michael
M
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, USA. novakm@muohio.edu
Ruenz
Megan
M
Kazerani
Shahrokh
S
Toth
Krisztina
K
Nguyen
Thach-Mien
TM
Heinrich
Brian
B
D000465:Algorithms; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D006868:Hydrolysis; D007093:Imidazoles / Q000737:chemistry; D007700:Kinetics; D015394:Molecular Structure; D011687:Purines / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D014867:Water
D018736:DNA Adducts; D007093:Imidazoles; D011687:Purines; D014867:Water; D004247:DNA; D003849:Deoxyguanosine