Li K M, George M, Gross M L, Seidel A, Luch A, Rogan E G, Cavalieri E L
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Chem Res Toxicol. 1999 Sep;12(9):758-67. doi: 10.1021/tx980197x.
Model adducts to be used in the identification of biologically formed adducts were synthesized by reaction of fjord-region dibenzo[a,l]pyrene 11,12-dihydrodiol 13,14-epoxides (DB[a,l]PDE) and deoxyadenosine (dA). The (+/-)-anti-DB[a,l]PDE was reacted with dA in dimethylformamide at 100 degrees C for 30 min to give four DB[a, l]PDE-14-N(6)dA adducts: (-)-anti-trans (26%), (+)-anti-trans (26%), (-)-anti-cis (17%), and (+)-anti-cis (17%). The (+/-)-syn-DB[a,l]PDE was reacted with dA under the same conditions to yield four DB[a, l]PDE-14-N(6)dA adducts and one N7Ade adduct: (+)-syn-cis (19%), (+)-syn-trans (13%), (-)-syn-cis (19%), (-)-syn-trans (13%), and (+/-)-syn-DB[a,l]PDE-14-N7Ade (22%). The structures of the eight stereoisomers of DB[a,l]PDE-14-N(6)dA were unequivocally assigned by reacting optically pure (-)-anti-DB[a,l]PDE and (+)-syn-DB[a,l]PDE with dA and by a combination of NMR, circular dichroism, and fast atom bombardment mass spectrometry. Reactions at 100 degrees C yielded mainly the trans-opened adducts at the benzylic C-14 position for both (+/-)-anti-DB[a,l]PDE and (-)-anti-DB[a,l]PDE, whereas (+/-)-syn-DB[a,l]PDE and (+)-syn-DB[a,l]PDE afforded mainly cis-opened adducts. At room temperature, however, only trans-opened adducts were obtained from (+/-)-anti-DB[a,l]PDE and only cis-opened adducts from (+/-)-syn-DB[a,l]PDE. Steric hindrance created by the fjord region may be an important factor for the stereoselectivity observed at room temperature.
用于鉴定生物形成加合物的模型加合物是通过峡湾区二苯并[a,l]芘11,12 - 二氢二醇13,14 - 环氧化物（DB[a,l]PDE）与脱氧腺苷（dA）反应合成的。（±）-反式-DB[a,l]PDE在100℃的二甲基甲酰胺中与dA反应30分钟，得到四种DB[a,l]PDE - 14 - N(6)dA加合物：（-）-反式-反式（26%），（+）-反式-反式（26%），（-）-反式-顺式（17%）和（+）-反式-顺式（17%）。（±）-顺式-DB[a,l]PDE在相同条件下与dA反应，生成四种DB[a,l]PDE - 14 - N(6)dA加合物和一种N7Ade加合物：（+）-顺式-顺式（19%），（+）-顺式-反式（13%），（-）-顺式-顺式（19%），（-）-顺式-反式（13%）和（±）-顺式-DB[a,l]PDE - 14 - N7Ade（22%）。通过使光学纯的（-）-反式-DB[a,l]PDE和（+）-顺式-DB[a,l]PDE与dA反应，并结合核磁共振、圆二色性和快原子轰击质谱，明确确定了DB[a,l]PDE - 14 - N(6)dA的八种立体异构体的结构。对于（±）-反式-DB[a,l]PDE和（-）-反式-DB[a,l]PDE，在100℃下的反应主要在苄基C - 14位置产生反式开环加合物，而（±）-顺式-DB[a,l]PDE和（+）-顺式-DB[a,l]PDE主要提供顺式开环加合物。然而，在室温下，（±）-反式-DB[a,l]PDE仅得到反式开环加合物，（±）-顺式-DB[a,l]PDE仅得到顺式开环加合物。峡湾区产生的空间位阻可能是室温下观察到的立体选择性的一个重要因素。
