在脱氧核糖核苷或腺嘌呤存在的情况下，1,2,3,4-四氢-7,12-二甲基苯并[a]蒽电化学氧化形成的加合物的合成与结构测定。

Synthesis and structure determination of the adducts formed by electrochemical oxidation of 1,2,3,4-Tetrahydro-7,12-dimethylbenz[a]anthracene in the presence of deoxyribonucleosides or adenine.

作者信息

Mulder P P, Chen L, Sekhar B C, George M, Gross M L, Rogan E G, Cavalieri E L

机构信息

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805, USA.

出版信息

Chem Res Toxicol. 1996 Dec;9(8):1264-77. doi: 10.1021/tx960099g.

DOI:10.1021/tx960099g

PMID:8951228

Abstract

Study of DNA adducts formed with aromatic hydrocarbons is part of the strategy to elucidate the mechanisms of tumor initiation by these compounds. 1,2,3,4-Tetrahydro-7,12-dimethylbenz[a]anthracene (THDMBA) is of special interest because it allows discrimination between the pathways of bioactivation by one-electron oxidation and monooxygenation. To study and identify adducts formed biologically, synthetic adducts are needed as reference standards. THDMBA was electrochemically oxidized in the presence of deoxyadenosine (dA), adenine (Ade), deoxyguanosine (dG), or deoxycytidine (dC). In the presence of dA, four adducts were isolated: 7-methyl-1,2,3,4-tetrahydrobenz[a]anthracene-12-CH2-N7Ade (7-MTHBA-12-CH2-N7Ade, 3.6%), 12-MTHBA-7-CH2-N7Ade (4.2%), 7-MTHBA-12-CH2-N6dA (5.8%), and 12-exo-methylene-7-MTHBA-7-N6dA (22.8%); a dehydrogenated product, 7,12-di-exo-methylene-THBA (44.2%), was also obtained. In the presence of Ade, nine adducts were synthesized: 7-MTHBA-12-CH2-N7Ade (1.1%), 12-MTHBA-7-CH2-N7Ade (2.4%), 7-MTHBA-12-CH2-N1Ade (10.2%), 12-MTHBA-7-CH2-N1Ade (13.2%), 7-MTHBA-12CH2-N3Ade (1.7%), 12-MTHBA-7-CH2-N3Ade (1.7%), 7-exo-methylene-12-MTHBA-12-N3Ade (11.2%), 12-exo-methylene-7-MTHBA-7-N3Ade (27.9%), and 12-exo-methylene-7-MTHBA-7-N6Ade (12.1%), as well as the dehydrogenated product 7,12-di-exo-methylene-THBA (16.7%). In the presence of dG, three adducts were produced: 7-MTHBA-12-CH2-N7Gua (24.2%), 12-MTHBA-7-CH2-N7Gua (12.2%), and 7-MTHBA-12-CH2-N2dG (3.7%), as well as the dehydrogenated product 7,12-di-exo-methylene-THBA (38.9%). Anodic oxidation in the presence of dC yielded a large amount of 7,12-di-exo-methylene-THBA (80.4%), but no adducts. The structure of the adducts was elucidated by using UV, NMR, and MS. The N-7 positions in dG, dA, and Ade, the 2-NH2 in dG, and the N-1 position in Ade form exclusively methyl-linked adducts. In contrast, the 6-NH2 group of dA and Ade and the N-3 of Ade prefer to attack the meso-anthracenic positions rather than the methyl groups. The order of reactivity of dG and dA in the formation of methyl-linked THDMBA adducts agrees well with that previously found for 7,12-dimethylbenz[a]anthracene [RamaKrishna et al. (1992) J. Am. Chem. Soc. 114, 1863-1874.

摘要

研究由芳香烃形成的DNA加合物是阐明这些化合物引发肿瘤机制策略的一部分。1,2,3,4-四氢-7,12-二甲基苯并[a]蒽（THDMBA）特别受关注，因为它能区分单电子氧化和单加氧生物活化途径。为了研究和鉴定生物形成的加合物，需要合成加合物作为参考标准。THDMBA在脱氧腺苷（dA）、腺嘌呤（Ade）、脱氧鸟苷（dG）或脱氧胞苷（dC）存在下进行电化学氧化。在dA存在下，分离出四种加合物：7-甲基-1,2,3,4-四氢苯并[a]蒽-12-CH2-N7Ade（7-MTHBA-12-CH2-N7Ade，3.6%）、12-MTHBA-7-CH2-N7Ade（4.2%）、7-MTHBA-12-CH2-N6dA（5.8%）和12-外向亚甲基-7-MTHBA-7-N6dA（22.8%）；还得到一种脱氢产物，7,12-二外向亚甲基-THBA（44.2%）。在Ade存在下，合成了九种加合物：7-MTHBA-12-CH2-N7Ade（1.1%）、12-MTHBA-7-CH2-N7Ade（2.4%）、7-MTHBA-12-CH2-N1Ade（10.2%）、12-MTHBA-7-CH2-N1Ade（13.2%）、7-MTHBA-12CH2-N3Ade（1.7%）、12-MTHBA-7-CH2-N3Ade（1.7%）、7-外向亚甲基-12-MTHBA-12-N3Ade（11.2%）、12-外向亚甲基-7-MTHBA-7-N3Ade（27.9%）和12-外向亚甲基-7-MTHBA-7-N6Ade（12.1%），以及脱氢产物7,12-二外向亚甲基-THBA（16.7%）。在dG存在下，产生了三种加合物：7-MTHBA-12-CH2-N7Gua（24.2%）、12-MTHBA-7-CH2-N7Gua（12.2%）和7-MTHBA-12-CH2-N2dG（3.7%），以及脱氢产物7,12-二外向亚甲基-THBA（38.9%）。在dC存在下进行阳极氧化产生大量7,12-二外向亚甲基-THBA（80.4%），但未产生加合物。通过紫外、核磁共振和质谱对加合物结构进行了阐明。dG、dA和Ade中的N-7位、dG中的2-NH2以及Ade中的N-1位仅形成甲基连接的加合物。相比之下，dA和Ade的6-NH2基团以及Ade的N-3位更倾向于进攻中位蒽位置而非甲基。dG和dA在形成甲基连接的THDMBA加合物中的反应活性顺序与先前在7,12-二甲基苯并[a]蒽中发现的顺序非常一致[拉马克里希纳等人（1992年）《美国化学会志》114, 1863 - 1874]。