SYNTHESIS AND STRUCTURE DETERMINATION OF THE ADDUCTS OF THE POTENT CARCINOGEN 7,12-DIMETHYLBENZ[A]ANTHRACENE AND DEOXYRIBONUCLEOSIDES FORMED BY ELECTROCHEMICAL OXIDATION - MODELS FOR METABOLIC-ACTIVATION BY ONE-ELECTRON OXIDATION

被引:46
作者
RAMAKRISHNA, NVS
CAVALIERI, EL
ROGAN, EG
DOLNIKOWSKI, G
CERNY, RL
GROSS, ML
JEONG, H
JANKOWIAK, R
SMALL, GJ
机构
[1] UNIV NEBRASKA,MED CTR,EPPLEY INST RES CANC,600 S 42ND ST,OMAHA,NE 68198
[2] UNIV NEBRASKA,DEPT CHEM,MIDWEST CTR MASS SPECT,LINCOLN,NE 68588
[3] IOWA STATE UNIV SCI & TECHNOL,US DOE,AMES LAB,AMES,IA 50011
[4] IOWA STATE UNIV SCI & TECHNOL,AMES,IA 50011
关键词
D O I
10.1021/ja00031a047
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative of 7,12-DMBA: 7-methylbenz[a]anthracene (MBA)-12-CH2-C8dG (13%), 7-MBA-12-CH2-N7Gua (55%),12-MBA-7-CH2-N7Gua(12%), 7-MBA-12-CH2-C8Gua(10%), and 7,12-(CH2OH)2-BA(10%). The first three are primary products of the electrochemical reaction, whereas the last two are secondary products. Binding occurs predominantly at the 12-CH3 group of 7,12-DMBA and specifically to the N-7 and C-8 of Gua. On the other hand, anodic oxidation of 7,12-DMBA in the presence of dA gives only two detectable adducts: 7-MBA-12-CH2-N7Ade (45%) and 12-MBA-7-CH2-N3Ade (55%). Binding at the 12-CH3 group is specific for the N-7 of Ade, whereas the 7-CH3 group of 7,12-DMBA is specific for the N-3 of Ade. Structures of the adducts were elucidated by NMR and fast atom bombardment tandem mass spectrometry (FAB MS/MS). The adducts were also investigated by fluorescence line narrowing spectroscopy (FLNS). Both the FAB MS/MS and FLNS techniques can be used to distinguish between the adducts formed at the 7-CH3 and 12-CH3 groups of 7,12-DMBA (i.e., between 7-MBA- 1 2-CH2-N7Gua and 12-MBA-7-CH2-N7Gua and between 7-MBA-12-CH2-N7Gua and 7-MBA-12-CH2-C8Gua). FLNS can distinguish 12-MBA-7-CH2-N3Ade from 7-MBA-12-CH2-N7Ade. On the other hand, the distinction between 7-MBA-12-CH2-C8Gua and 7-MBA-12-CH2-C8dG is straight forward by FAB MS but very difficult by FLNS. The electrochemical synthesis not only provides a demonstration of the specific reactivity of nucleosides and 7,12-DMBA under oxidizing conditions but is also a source of the necessary reference materials for studying the 7,12-DMBA-DNA adducts formed in biological systems. Furthermore, the analytical methodology is now appropriate for supporting in vivo studies of 7,12-DMBA-DNA adducts. A mechanism is proposed, although there are not sufficient data to prove it.
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页码:1863 / 1874
页数:12
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