Synthesis of para-benzoquinone and 1,3-bis(2-chloroethyl)nitrosourea adducts and their incorporation into oligonucleotides.
Benzene is a widely known carcinogen and a cause of bone-marrow toxicity and leukaemia in humans. para-Benzoquinone is a stable metabolite of benzene. Its reaction with deoxycytidine, deoxyadenosine and deoxyguanosine produces the major stable exocyclic compounds (3-hydroxy)-1,N4-benzetheno-2'-deoxycytidine, (9-hydroxy)-1,N6-benzetheno-2'-deoxyadenosine and (7-hydroxy)-1,N2-benzetheno-2'-deoxyguanosine, respectively, on a large scale and at high yield. The desired products were identified by fast atom bombardment-mass spectrometry, proton nuclear magnetic resonance and UV spectroscopy. These adducts were converted to the fully protected phosphoramidites and incorporated site-specifically into a series of oligonucleotides. 1,N6-Ethano-2'-deoxyadenosine is one of the exocyclic adducts formed during DNA reaction with the antitumour agent, 1,3-bis(2-chloroethyl)nitrosourea. This compound was synthesized on a large scale with a high yield (62%) and then was converted to the phosphoramidite and incorporated site-specifically into oligonucleotides. The coupling efficiency of the incorporation of all these adducts was high (> or = 93%). After de-protection and purification of these oligomers, enzymatic hydrolysis and analysis by high-performance liquid chromatography confirmed the presence of the adduct in the oligomers. These oligomers are being used to investigate the biochemical and physical properties of these adducts.
Chenna
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Donner Laboratory, Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA.
Maruenda
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H
Singer
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B
D001483:Base Sequence; D016227:Benzoquinones / Q000138:chemical synthesis*; D002330:Carmustine / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000138:chemical synthesis*; D003839:Deoxyadenosines / Q000378:metabolism; D003841:Deoxycytidine / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000138:chemical synthesis
D016227:Benzoquinones; D018736:DNA Adducts; D003839:Deoxyadenosines; D009841:Oligonucleotides; D003841:Deoxycytidine; C004532:quinone; D003849:Deoxyguanosine; D002330:Carmustine