Benzo[a]pyrene diol epoxide forms covalent adducts with deoxycytidylic acid by alkylation at both exocyclic amino N(4) and ring imino N-3 positions.
Benzo[a]pyrene diol epoxide forms covalent adducts with deoxycytidylic acid by alkylation at both exocyclic amino N(4) and ring imino N-3 positions.
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苯并[a]芘二醇环氧化物通过在环外氨基N(4)和环亚氨基N-3位置上的烷基化与脱氧胞苷酸形成共价加合物。
DOI：
10.1021/tx0340201
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Meehan,Thomas
中科院分区：
文献类型：
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作者：
Wolfe,AlanR;Smith,TimothyJ;Meehan,Thomas
致癌物 7r,8t-二羟基-9t,10t-环氧-7,8,9,10-四氢苯并[a]芘（抗 BPDE）可在 dGuo、dAdo 和 dCyd 处烷基化 DNA。少量形成的 dCyd 加合物在更丰富的 dGuo 加合物附近洗脱。我们分离了用 dCMP 形成的 dCyd 加合物。每种 BPDE 对映体与 dCMP 形成三种主要加合物，两种顺式和一种反式。反式加合物和顺式加合物之一通过环外 N4 处的烷基化形成，而第二个顺式加合物是通过环 N-3 处烷基化然后脱氨基形成的双脲加合物。环氧化物开环几何形状是根据卤化物和温度对加合物产率的影响、主要CD带的符号和苯并环质子NMR耦合常数来指定的。每组顺式加合物中的一组是荧光的（FL），另一组是非荧光的（NF）。反式和 FL 顺式加合物的荧光量子产率为 BPDE 水解产物的 40−50%。 FL 和 NF 顺式加合物的长波长 UV 最大值相对于反式加合物红移 1 和 3 nm。 1 H NMR 氘交换实验表明，在反式和 FL 顺式加合物中，N4−H 与 C10−H 偶联。甲基保护的 Cyd 衍生物的加合物形成实验表明 NF 顺式加合物是由 N-3 处的烷基化产生的。 MS 结果、pKa 测量和 dUrd 烷基化实验表明 N-3 dCyd 加合物自发脱氨基为 dUrd 加合物。 NMR 耦合常数表明，与其他顺式 BPDE 加合物不同，在 NF 顺式加合物中，C7 和 C8 取代基是准平轴取代基，C9 取代基是准轴向取代基。 (−)-BPDE NF 顺式加合物的 1H NOESY 谱表明它存在两种构象异构体。分子模型表明，构象异构体是由两个能量非常相似的低能构象产生的，其中嘧啶方向相反，被尿嘧啶部分的旋转的显着障碍分开。
The carcinogen 7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) alkylates DNA at dGuo, dAdo, and dCyd. dCyd adducts, formed in small amounts, elute near the more abundant dGuo adducts. We isolated the dCyd adducts formed with dCMP. Each BPDE enantiomer forms three major adducts with dCMP, two cis and one trans. The trans adduct and one of the cis adducts form by alkylation at exocyclic N4, while the second cis adduct is a dUrd adduct formed by alkylation at ring N-3 followed by deamination. Epoxide ring-opening geometries were assigned on the basis of halide and temperature effects on adduct yield, the sign of the major CD band, and benzo ring proton NMR coupling constants. One of each set of cis adducts is fluorescent (FL), and the other is nonfluorescent (NF). The trans and FL cis adducts have fluorescence quantum yields 40−50% of that of the BPDE hydrolysis product. The long wavelength UV maxima of the FL and NF cis adducts are red-shifted 1 and 3 nm relative to the trans adduct.1H NMR deuterium exchange experiments indicate that in the trans and FL cis adducts N4−H is coupled to C10−H. Adduct formation experiments with methyl-protected Cyd derivatives show that NF cis adducts result from alkylation at N-3. MS results, pKameasurements, and dUrd alkylation experiments indicate that the N-3 dCyd adducts spontaneously deaminate to dUrd adducts. NMR coupling constants show that in the NF cis adduct the C7 and C8 substituents are quasi equatorial and the C9 substituent is quasi axial, unlike in other cis BPDE adducts.1H NOESY spectra of the (−)-BPDE NF cis adduct reveal that it exists in two conformers. Molecular modeling shows that the conformers result from two low-energy conformations of very similar energies with the pyrimidine in opposite orientations, separated by significant barriers to rotation of the uracil moiety.