STRUCTURES OF COVALENT NUCLEOSIDE ADDUCTS FORMED FROM ADENINE, GUANINE, AND CYTOSINE BASES OF DNA AND THE OPTICALLY-ACTIVE BAY-REGION 3,4-DIOL 1,2-EPOXIDES OF BENZ[A]ANTHRACENE
STRUCTURES OF COVALENT NUCLEOSIDE ADDUCTS FORMED FROM ADENINE, GUANINE, AND CYTOSINE BASES OF DNA AND THE OPTICALLY-ACTIVE BAY-REGION 3,4-DIOL 1,2-EPOXIDES OF BENZ[A]ANTHRACENE
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DOI：
10.1021/jo00067a039
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发表时间：
1993-07-16
影响因子：
3.6
通讯作者：
JERINA, DM
中科院分区：
文献类型：
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作者：
CHEH, AM;CHADHA, A;JERINA, DM
DNA 与苯并[a]蒽的四种光学活性 3,4-二醇 1,2-环氧化物在体外反应时形成的主要共价加合物的化学结构已在核苷水平上得到阐明。除了通过脱氧腺苷 (dA) 和脱氧鸟苷 (dG) 的环外氨基的顺式和反式加成以及反式脱氧胞苷 (dC) 加合物形成的加合物之外，还报道了通过反式打开 (4S,3R)-二醇 (2R,1S)-环氧化物异构体在 DNA 中形成的去糖基化 N-7 dG 加合物的化学表征。从乙酰化衍生物的四氢苯并环的次甲基质子的偶联常数推导出加合物的相对立体化学（环外氨基对环氧化物的顺式与反式打开）。在烃部分的附着位点处具有(S)-构型的加合物具有在250-260 nm处呈现正谱带和在较长波长处呈现负谱带的CD光谱，而在该中心处的(R)-构型产生具有近似相等强度和相反符号的谱带的CD谱。这允许将顺式与反式加成分配给手性环氧化物，以得到未产生足够数量以获得NMR谱的加合物。对苯并[a]蒽、苯并[c]菲和苯并[a]芘衍生的加合物模式的分析表明，每种烃的二醇环氧化物异构体的比较致瘤性与加合物形成的程度、环氧化物中顺式与反式加成的比例、在dC或dG的N-7位置形成加合物的倾向或加合物的比例没有很好的相关性尽管致瘤性可能与在 N-取代的苄基碳上形成具有 (S)-构型的 dG 加合物的能力相关，特别是那些由环氧化物反式加成产生的加合物，但 dA 与 dG 处的形成不同。
Chemical structures of the principal covalent adducts formed from DNA upon reaction in vitro with the four optically active 3,4-diol 1,2-epoxides of benz[a]anthracene have been elucidated at the nucleoside level. In addition to adducts formed by cis and trans addition of the exocyclic amino groups of deoxyadenosine (dA) and deoxyguanosine (dG) and a trans deoxycytidine (dC) adduct, chemical characterization of a deglycosylated N-7 dG adduct formed in DNA by trans opening of the (4S,3R)-diol (2R,1S)-epoxide isomer is reported. Relative stereochemistries of the adducts (cis versus trans opening of the epoxides by the exocyclic amino groups) were deduced from the coupling constants of the methine protons of the tetrahydro benzo rings of the acetylated derivatives. Adducts having (S)-configuration at the attachment site on the hydrocarbon moiety have CD spectra that exhibit a positive band at 250-260 nm and a negative band at longer wavelengths, whereas (R)-configuration at this center gives rise to CD spectra with bands of approximately equal intensity and opposite sign. This allowed assignment of cis versus trans addition to the chiral epoxides for adducts that were not generated in sufficient quantity to obtain NMR spectra. Analysis of the patterns of adducts derived from benz[a]anthracene, benzo[c]phenanthrene, and benzo[a]pyrene shows that the comparative tumorigenicities of the diol epoxide isomers of each hydrocarbon do not correlate well with the extent of adduct formation, the ratio of cis versus trans addition to the epoxide, the propensity for forming adducts at dC or the N-7 position of dG, or the ratio of adduct formation at dA versus dG, although tumorigenicity may correlate with the ability to form dG adducts with (S)-configuration at the N-substituted benzylic carbon, especially those arising from trans addition to the epoxide.