PHYSICAL AND CHEMICAL INTERACTIONS OF BPDE AND DNA

苯并（a）芘被转化为一种强有力的化学致癌物， 细胞代谢 这个中间体是7 β，8 α- 二羟基-9 α，10 α-环氧-7，8，9，10-四氢苯并（a）芘 （抗BPDE）。 活性代谢产物以四种非对映体形式存在 （+）-和（-）-抗-和（+）-和（-）-顺式-BPDE。 最 诱变和致癌异构体是（+）-抗BPDE。 我们提出 继续我们在两方面的BPDE-DNA研究：（i）阐明 物理结合和共价结合机制的四个 天然和合成核酸聚合物的BPDE非对映异构体 和（ii）合成完全定义的、BPDE修饰的 寡核苷酸的化学和物理研究共价 配合物 我们将分析共价加合物之间的形成 syn-BPDE和DNA。 我们将确定反应机制， 将BPDE结合到合成的和合成的化合物中的dAdo和dCyd结合位点， 天然存在的多核苷酸。 我们将合成BPDE- 修饰的寡核苷酸，利用所有四种异构体的寡核苷酸， 致癌物质 碳氢化合物会专门附着在 dGuo、dAdo或dCyd站点。 这些合成分子将被 通过光谱和测序技术表征。 这些 位点特异性、致癌物修饰的寡核苷酸将 用于构象研究。 构象的变化 将评估位于不同碱基的加合物， 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，NMR， 质谱和X射线晶体学技术。 将确定病变的物理和化学性质， 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.