Synthesis of a 2'-Deoxyguanosine Adduct of cis-2-Butene-1,4-dial, a Reactive Metabolite of Furan
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- 作者：Choua C. Vu and Lisa A. Peterson
- 刊名：Chemical Research in Toxicology
- 出版年：2005
- 出版时间：June 2005
- 年：2005
- 卷：18
- 期：6
- 页码：1012 - 1017
- 全文大小：122K
- 年卷期：v.18,no.6(June 2005)
- ISSN：1520-5010
文摘
Furan is a liver and kidney toxicant and a hepatocarcinogen in rodents. Its reactive metabolite, cis-2-butene-1,4-dial, reacts with nucleosides to form adducts in vitro. The reaction with2'-deoxyguanosine generates 3-(2'-deoxy-
-D-erythropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2' '-al)-9H-imidazo[1,2-
]purine-9-one as the major reaction product. A syntheticapproach to this adduct is presented in this report. The key step in this synthesis is thepreparation of 2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)-1-(1,2,5,6-tetrahydroxyhexan-3-yl)guanosine. Treatment of this intermediate with sodium periodate gave three reaction products: a one-substituted adduct, 2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)-1-(2,5-dihydroxy-tetrahydrofuran-3-yl)guanosine; a 1,N2-cyclic adduct, 3-[2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)--D-erythropentafuranosyl]-6-hydroxy-8-formyl-5,6,7,8-tetrahydropyrimidino[1,2-]purin-10(3H)-one; and the 1,N2-bicyclic adduct, 3-[2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)--D-erythropentafuranosyl]-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2' '-al)-9H-imidazo[1,2-]purine-9-one. The one-substituted and 1,N2-cyclic reaction products were unstable and rearrangedover time to yield the 1,N2-bicyclic 2'-deoxyguanosine adducts. The desired reaction product wasobtained as a mixture of four diastereomers by removing the tert-butyldimethylsilyl groupswith hydrogen fluoride. This synthetic approach to the cis-2-butene-1,4-dial-derived dGuo adducts confirms our previous structural characterization of the in vitro cis-2-butene-1,4-dial-dGuo reaction product. These studies demonstrate that the observed 1,N2 bicyclic structure isthe thermodynamically stable isomer, supporting our previous observations that this adductis the major product formed in vitro. Finally, these studies provide the necessary groundworkfor the preparation of oligonucleotides with site specifically incorporated cis-2-butene-1,4-dial-derived adducts.
-D-erythropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2' '-al)-9H-imidazo[1,2-]purine-9-one as the major reaction product. A syntheticapproach to this adduct is presented in this report. The key step in this synthesis is thepreparation of 2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)-1-(1,2,5,6-tetrahydroxyhexan-3-yl)guanosine. Treatment of this intermediate with sodium periodate gave three reaction products: a one-substituted adduct, 2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)-1-(2,5-dihydroxy-tetrahydrofuran-3-yl)guanosine; a 1,N2-cyclic adduct, 3-[2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)--D-erythropentafuranosyl]-6-hydroxy-8-formyl-5,6,7,8-tetrahydropyrimidino[1,2-]purin-10(3H)-one; and the 1,N2-bicyclic adduct, 3-[2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)--D-erythropentafuranosyl]-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2' '-al)-9H-imidazo[1,2-]purine-9-one. The one-substituted and 1,N2-cyclic reaction products were unstable and rearrangedover time to yield the 1,N2-bicyclic 2'-deoxyguanosine adducts. The desired reaction product wasobtained as a mixture of four diastereomers by removing the tert-butyldimethylsilyl groupswith hydrogen fluoride. This synthetic approach to the cis-2-butene-1,4-dial-derived dGuo adducts confirms our previous structural characterization of the in vitro cis-2-butene-1,4-dial-dGuo reaction product. These studies demonstrate that the observed 1,N2 bicyclic structure isthe thermodynamically stable isomer, supporting our previous observations that this adductis the major product formed in vitro. Finally, these studies provide the necessary groundworkfor the preparation of oligonucleotides with site specifically incorporated cis-2-butene-1,4-dial-derived adducts.