PHYSICAL & CHEMICAL INTERACTIONS OF BPDE & DNA

苯并(A)芘被转化为一种有效的化学致癌物 细胞新陈代谢。这个中间体是7β，8α- 二羟基-9α，LOα-环氧基-7，8，9，10-四氢苯并(A)芘 (抗BPDE)。活性代谢物以四种非对映异构体的形式出现 (+)-和(-)-抗和(+)-和(-)-syn-BPDE。最多的 致突变致癌异构体为(+)-抗BPDE。我们建议 在两个方面继续我们的BPDE-DNA研究：(I)澄清 四种化合物的物理结合和共价结合机制 BPDE非对映异构体合成天然和合成核酸聚合物 和(Ii)合成完全定义的、BPDE修饰的 用于共价化合物化学和物理研究的寡核苷酸 复合体。我们将分析共价加合物的形成 SYN-BPDES和DNA。我们将确定以下反应机理： BPDE与DADO和dCyd结合位点的结合 自然产生的多核苷酸。我们将合成BPDE- 修饰的寡核苷酸，利用所有四种异构体 致癌物质。碳氢化合物将专门附着在 DGuo、Dado或dCyd站点。这些合成分子将是 以光谱和测序技术为特征。这些 位点特异的致癌物修饰的寡核苷酸将是 用于构象研究的。构象的变化 将评估位于不同碱基的加合物和 不同的序列。这些物质的物理和化学性质 修饰的寡核苷酸将通过荧光、CD、核磁共振、 以及质谱学和X射线结晶学技术。 已定义损伤的物理和化学性质将是 与这些环境中的生物特性相关 重要的多环芳烃。

Benzo(a)pyrene is converted into a potent chemical carcinogen by cellular metabolism. This intermediate is the 7 beta, 8 alpha- dihydroxy-9 alpha,lO alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE). The active metabolite occurs as four diastereomers the (+)- and (-)-anti- and (+)- and (-)-syn-BPDEs. The most mutagenic and carcinogenic isomer is the (+)-anti-BPDE. We propose to continue our BPDE-DNA studies on two fronts: (i) elucidation of the physical binding and covalent binding mechanisms of the four BPDE diastereomers to natural and synthetic nucleic acid polymers and (ii) to synthesize completely-defined, BPDE-modified oligonucleotides for chemical and physical studies of covalent complexes. We will analyze covalent adduct formation between the syn-BPDEs and DNA. We will determine the reaction mechanisms for binding BPDEs to dAdo and dCyd binding sites in synthetic and naturally occurring polynucleotides. We will synthesize BPDE- modified oligonucleotides, utilizing all four isomers of the carcinogen. The hydrocarbons will be specifically attached to dGuo, dAdo or dCyd sites. These synthetic molecules will be characterized by spectroscopic and sequencing techniques. These site-specific, carcinogen-modified oligonucleotides will be employed in conformational studies. The change in conformation will be assessed for adducts located at different bases and in different sequences. The physical and chemical properties of these modified oligonucleotides will be defined by fluorescence, CD, NMR, and mass spectroscopies and X-ray crystallographic techniques. Physical and chemical properties of the defined lesions will be correlated with the biological properties of these environmentally important polycyclic aromatic hydrocarbons.