PHYSICAL AND CHEMICAL INTERACTIONS OF BPDE AND DNA

我们已经获得了抗BaP二醇环氧化物的证据，它是 前致癌物质苯并[a]芘(BaP)嵌入DNA。这 结论是基于以下证据：1)碳氢化合物 络合物的紫外光谱显示出红移2)荧光 碳氢化合物被淬灭3)镁和亚精胺导致解离 4)碳氢化合物将SV40 DNA展开18度。 初步的温度跳跃弛豫动力学呈现三个指数 用60,650和4200微秒的动力学常数，结果表明 插层是一个三步过程。对此有不同的解释 三个指数是不同的结合部位或立体选择性结合 抗BaP二醇环氧化物的两个对映体。这项建议是 研究了BaP二元醇的插层机理。 环氧化物。我们建议合成并分解代谢产生的 (+)和(-)抗AND(+)和(-)syn-bap二醇环氧化物。我们会 从烃类角度探讨插层机理 结构修饰(对映体和非对映异构体)和 多脱氧核苷酸组成(序列和左手螺旋)。我们 建议合成稳定的苯并苯二醇环氧化物的氮杂环丙烷类似物 (用氮气取代环氧氧)，将用于 插层络合物构象的光谱研究。我们 将研究t跳跃动力学的插层机制，并通过a 物理热力学和平衡参数的测定 反应。将通过测量复合体来研究序列特异性 与16种可能的脱氧二核苷磷酸盐形成。它将是 有兴趣比较多环芳烃的作用机理 与水溶性药物的插层作用，因为后者可以在 简单的静电相互作用和前者不能。生物学的 四种二元醇环氧化物的性质差别很大，例如 (+)抗BaP二醇环氧化物是最具诱变性和致癌性的 活性致癌物质。这些碳氢化合物的物理相互作用 与DNA进行实验将有助于在分子水平上解释这些差异。

We have obtained evidence the anti-BaP diol epoxide, the activated form of the pre-carcinogen benzo[a]pyrene (BaP), intercalates into DNA. This conclusion is based on the following evidence, 1) the hydrocarbon in the complex exhibits a red shift in its uv spectrum 2) fluorescence of the hydrocarbon is quenched 3) magnesium and spermidine result in dissociation of the complex and 4) the hydrocarbon unwinds SV40 DNA by 18 degrees. Preliminary temparture-jump relaxation kinetics exhibit three exponentials with kinetic constants 60, 650 and 4200 Mus, results which suggest that intercalation is a three step process. Alternative explanations for these three exponentials are different binding sites or stereoselective binding of the two enantiomers of the anti-BaP diol epoxide. This proposal is designed to investigate the mechanism of intercalation of BaP diol epoxides. We propose to synthesize and resolve the metabolically produced (+) and (-) anti- and (+) and (-) syn-BaP diol epoxides. We will investigate the mechanism of intercalation in terms of hydrocarbon structural modifications (enantiomers and diastereomers) and polydeoxynucleotide composition (sequences and left handed helix). We propose to synthesize a stable aziridine analog of the BaP diol epoxide (replacing the epoxy oxygen with nitrogen), which will be used in spectroscopic studies on the conformation of the intercalation complex. We will investigate the mechanism of intercalation of t-jump kinetics and by a determination of thermodynamic and equioibrium parameters of the physical reactions. Sequence specificity will be investigated by measuring complex formation with the 16 possible deoxydinucleoside phosphates. It will be of interest to compare the mechanism of polycyclic aromatic hydrocarbon intercalation with that of water soluble drugs since the latter can under simple electrostatic interactions and the former cannot. The biological properties of the four diol epoxides differ considerably, e.g., the (+)anti-BaP diol epoxide is the most mutagenic and carcinogenic form of the activated carcinogen. The physical interactions that these hydrocarbons undergo with DNA will help explain these differences at the molecular level.