PHYSICAL AND CHEMICAL INTERACTIONS OF BPDE AND DNA

我们已经获得了证据，抗BaP二醇环氧化物， 前致癌物苯并[a]芘（BaP）嵌入DNA。 这 这一结论是基于以下证据：1） 复合物在其紫外光谱中表现出红移; 2） 烃被淬灭3）镁和亚精胺导致解离 4）碳氢化合物将SV 40 DNA解旋18度。 初步的温度跳跃弛豫动力学表现出三个指数 动力学常数为60、650和4200 Mus，结果表明， 插层是三步过程。 对这些问题的其他解释 三个指数是不同的结合位点或立体选择性结合 抗BaP二醇环氧化物的两种对映异构体。 这项建议是 旨在研究BaP二醇的插层机理 环氧化物。 我们建议合成并分解代谢产生的 （+）和（-）反式和（+）和（-）顺式BaP二醇环氧化物。 我们将 从烃类角度探讨插层机理 结构修饰（对映异构体和非对映异构体）和 多聚脱氧核苷酸组成（序列和左手螺旋）。 我们 建议合成BaP二醇环氧化物的稳定氮丙啶类似物 （用氮气代替环氧氧），将用于 光谱研究了插层复合物的构象。 我们 将研究插层的t-跳跃动力学机制，并通过一个 物理热力学和热力学参数的测定 反应. 将通过测量复合物来研究序列特异性。 与16种可能的脱氧二核苷磷酸形成。 将具有 多环芳烃的反应机理比较 由于水溶性药物可以在 简单的静电相互作用和前者不能。 生物 这四种二醇环氧化物的性质显著不同，例如，的 （+）抗BaP二醇环氧化物是最具致突变性和致癌性的 激活的致癌物质。 这些碳氢化合物 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.