Kim S J, Jajoo H K, Kim H Y, Zhou L, Horton P, Harris C M, Harris T M
Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
Bioorg Med Chem. 1995 Jun;3(6):811-22. doi: 10.1016/0968-0896(95)00065-o.
Polycyclic aromatic hydrocarbons are metabolized to a wide variety of oxidized derivatives, including highly reactive diol epoxides which alkylate DNA. The reaction lacks regio- or stereospecificity but occurs primarily at the exocyclic amino groups of deoxyguanosine and deoxyadenosine. An efficient route to N6 adducts of deoxyadenosine is described using as examples those arising from trans opening of the anti-tetrahydrodiol epoxides of naphthalene, benzo[a]pyrene, and benzo[c]phenanthrene. The adducts were synthesized in 50-92% yields by reaction of 6-fluoropurine 2'-deoxyriboside with aminotriols formed by trans opening of racemic dihydrodiol epoxides using liquid NH3. The diastereomeric adducts were separated by HPLC and their absolute configurations were assigned by circular dichroism. 1H NMR studies revealed significant differences in conformation of the tetrahydroaromatic ring between the sterically unrestricted naphthalene derivative and the sterically congested derivatives of benzo[a]pyrene and benzo[c]phenanthrene. These differences may have a bearing on the higher carcinogenicity shown by the latter hydrocarbons. Undecadeoxyoligonucleotides bearing regio- and stereochemically defined adenine N6-anti-trans-benzo[a]pyrene adducts have been prepared.
多环芳烃可代谢为多种氧化衍生物，包括能使DNA烷基化的高活性二醇环氧化物。该反应缺乏区域或立体特异性，但主要发生在脱氧鸟苷和脱氧腺苷的环外氨基上。以萘、苯并[a]芘和苯并[c]菲的反式四氢二醇环氧化物的反式开环产生的那些产物为例，描述了一种合成脱氧腺苷N6加合物的有效途径。通过使6-氟嘌呤2'-脱氧核糖苷与使用液氨使外消旋二氢二醇环氧化物反式开环形成的氨基三醇反应，以50 - 92%的产率合成了加合物。通过高效液相色谱法分离了非对映体加合物，并通过圆二色性确定了它们的绝对构型。1H核磁共振研究表明，空间位阻不受限制的萘衍生物与空间位阻较大的苯并[a]芘和苯并[c]菲衍生物之间，四氢芳环的构象存在显著差异。这些差异可能与后两种烃类表现出的较高致癌性有关。已经制备了带有区域和立体化学定义的腺嘌呤N6 - 反式 - 苯并[a]芘加合物的十一脱氧寡核苷酸。
