3'-H-phosphonate synthesis of chiral benzo[a]pyrene diol epoxide adducts at N(2) of deoxyguanosine in oligonucleotides.
3'-H-phosphonate synthesis of chiral benzo[a]pyrene diol epoxide adducts at N(2) of deoxyguanosine in oligonucleotides.
复制标题
寡核苷酸中脱氧鸟苷 N(2) 处手性苯并[a]芘二醇环氧化物加合物的 3-H-膦酸酯合成。
DOI：
10.1021/tx600282y
复制
发表时间：
2007
影响因子：
4.1
通讯作者：
Jerina,DonaldM
中科院分区：
文献类型：
--
作者：
Iyer,PremaC;Yagi,Haruhiko;Sayer,JaneM;Jerina,DonaldM
报道了7，8，9，10-四氢苯并[a]芘对映体7，8-二醇9，10-环氧化物的C-10位含N-脱氧鸟苷加合物的合成路线。这些加合物是脱氧鸟苷在C-10上反式加成到环氧化物上的结果。我们的合成是通过制备适当保护的脱氧鸟苷N_2-加合物的3‘-H-膦酸酯来进行的。封闭基团包括脱氧鸟苷上的O6-烯丙基，碳氢化合物部分的7-、8-和9-羟基上的乙酸酯，以及糖的5‘-羟基上的二甲氧基三苯基。这些封闭基团非常适合在固体载体上合成寡核苷酸。这种核苷加合物的3‘-羟基在吡啶中与亚磷酸二苯酯反应容易转化为3’-H-亚膦酸根，10R和10S异构体均能高产率地进行反应。为了合成寡核苷酸，使用标准的亚磷酰胺化学方法，利用自动合成器将最初的几个核苷酸结合到固体载体上。经过手动步骤(产率80%)将加成的脱氧鸟胺酸残基引入H-膦酸酯，然后在合成器上完成序列。虽然在手动偶联步骤中使用了超过10倍的3‘-H-膦酸盐，但可回收高达70%的反应物。受保护的10S核苷加合物的3‘-H-膦酸根被转化为不封闭的核苷酸加合物，不同的盐不能形成适合X射线分析的晶体。虽然脱氧鸟苷酸与外消旋二醇环氧化物直接反应形成了亚毫克量的混合非对映异构体，但本研究首次实际合成了哺乳动物中由苯并[a]芘形成的主要DNA加合物3‘-磷酸。
A synthetic route to oligonucleotides containingN2-deoxyguanosine adducts at C-10 of the enantiomeric 7,8-diol 9,10-epoxides of 7,8,9,10-tetrahydrobenzo[a]pyrene in which the epoxide oxygen and the 7-hydroxyl group are trans is described. The present adducts result from the trans addition ofN2of deoxyguanosine to the epoxide at C-10. Our synthesis proceeds via preparation of the 3‘-H-phosphonate of a suitably protected deoxyguanosineN2-adduct. The blocking groups consisted ofO6-allyl on the deoxyguanosine, acetates on the 7-, 8-, and 9-hydroxyl groups of the hydrocarbon moiety, and dimethoxytrityl on the 5‘-hydroxyl group of the sugar. These blocking groups are well suited to oligonucleotide synthesis on solid supports. The free 3‘-hydroxyl group of this nucleoside adduct was readily converted to its 3‘-H-phosphonate with diphenyl phosphite in pyridine in high yield for both the 10Rand 10Sisomers. For synthesis of oligonucleotides, the first several nucleotides were incorporated onto the solid support with an automated synthesizer using standard phosphoramidite chemistry. The adducted deoxyguanilic acid residue was introduced as theH-phosphonate in a manual step (80% yield), followed by completion of the sequence on the synthesizer. Although a 10-fold excess of the 3‘-H-phosphonate was used in the manual coupling step, as much as 70% of the reactant could be recovered. The 3‘-H-phosphonate of the protected 10Snucleoside adduct was converted to the unblocked nucleotide adduct, various salts of which failed to form crystals suitable for X-ray analysis. Although submilligram quantities of this compound have been formed as mixed diastereomers by direct reaction of deoxyguanylic acid with racemic diol epoxide, the present study represents the first actual synthesis of the major DNA adduct formed from benzo[a]pyrene in mammals as its 3‘-phosphate.