Synthesis of a 2′-deoxyguanosine adduct of cis-2-butene-1,4-dial, a reactive metabolite of furan

Choua C. Vu, Lisa A. Peterson

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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 with 2′-deoxyguanosine generates 3-(2′-deoxy-β-D-erythropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy- 7-(ethane-2″-al)-9H-imidazo[1,2-α]purine-9-one as the major reaction product. A synthetic approach to this adduct is presented in this report. The key step in this synthesis is the preparation 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)-β-D-erythropentafuranosyl]-6-hydroxy-8-formyl-5,6,7, 8-tetrahydropyrimidino[1,2-α]-purin-10(3H)-one; and the 1,N 2-bicyclic adduct, 3-[2′-deoxy-3′,5′-O-bis(tert- butyldimethylsilyl)-β-D-erythropentafuranosyl]-3,5,6,7-tetrahydro-6- hydroxy-7-(ethane-2″-al)-9H-imidazo[1,2-α]purine-9-one. The one-substituted and 1,N2-cyclic reaction products were unstable and rearranged over time to yield the 1,N2-bicyclic 2′- deoxyguanosine adducts. The desired reaction product was obtained as a mixture of four diastereomers by removing the tert-butyldimethylsilyl groups with 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 is the thermodynamically stable isomer, supporting our previous observations that this adduct is the major product formed in vitro. Finally, these studies provide the necessary groundwork for the preparation of oligonucleotides with site specifically incorporated cis-2-butene-1,4-dial-derived adducts.

Original languageEnglish (US)
Pages (from-to)1012-1017
Number of pages6
JournalChemical research in toxicology
Issue number6
StatePublished - Jun 2005


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