Stereospecific synthesis of oligonucleotides containing crotonaldehyde adducts of deoxyguanosine
Stereospecific synthesis of oligonucleotides containing crotonaldehyde adducts of deoxyguanosine
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DOI：
10.1021/tx0100690
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发表时间：
2001-11-01
影响因子：
4.1
通讯作者：
Harris, TM
中科院分区：
文献类型：
--
作者：
Nechev, LV;Kozekov, I;Harris, TM
巴豆醛与DNA反应形成两个非对映体的脱氧鸟苷的1，N-2环状加合物。通过4-氨基-1，2-戊二醇的混合非对映体与2-氟-O-6-（三甲基硅乙基）-脱氧肌苷反应，合成了两种非对映体脱氧核苷。用NaIO 4处理所得的N-2-（1-甲基-3，4-二羟基丁基）-脱氧鸟苷，将邻位二醇裂解成醛。自发环化得到巴豆内酯去加合物核苷的两种非对映异构体，其易于通过HPLC分离。通过由（S）-3-氨基丁酸合成一种非对映异构体来指定绝对构型。该合成策略已扩展到通过4-氨基-1，2-戊二醇的混合非对映异构体与含有2-氟-O-6-（三甲基甲硅烷基乙基）-脱氧肌苷的8-mer寡核苷酸的反应制备位点特异性加合的寡核苷酸。通过HPLC分离非对映体寡核苷酸，并通过酶消化加合的核苷建立加合物的绝对构型。
Crotonaldehyde reacts with DNA to form two diastereomeric 1,N-2 cyclic adducts of deoxyguanosine. A synthesis of the two diastereomeric deoxynucleosides has been achieved by reaction of mixed diastereomers of 4-amino-1,2-pentanediol with 2-fluoro-O-6-(trimethylsilylethyl)-deoxyinosine. The resulting N-2-(1-methyl-3,4-dihydroxybutyl)-deoxyguanosine was treated with NaIO4, cleaving the vicinal diol to the aldehyde. Spontaneous cyclization gave the two diastereomers of the crotonaldehyde-adducted nucleoside that were readily separated by HPLC. The absolute configurations were assigned by an enantiospecific synthesis of one diastereomer from (S)-3-aminobutanoic acid. The synthetic strategy has been extended to preparation of a site-specifically adducted oligonucleotide by reaction of the mixed diastereomers of 4-amino-1,2-pentanediol with an 8-mer oligonucleotide containing 2-fluoro-O-6-(trimethylsilylethyl)-deoxyinosine. The diastereomeric oligonucleotides were separated by HPLC and absolute configurations of the adducts were established by enzymatic digestion to the adducted nucleosides.