Synthesis of Enzymatically Noncleavable Carbocyclic Nucleosides for DNA-N-Glycosylase Studies

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• 作者：Francis Johnson ; Gyorgy Dormá ; n ; Robert A. Rieger ; Ryuji Marumoto ; Charles R. Iden ; and Radha Bonala
• 刊名：Chemical Research in Toxicology
• 出版年：1998
• 出版时间：March 1998
• 年：1998
• 卷：11
• 期：3
• 页码：193 - 202
• 全文大小：315K
• 年卷期：v.11,no.3(March 1998)
• ISSN：1520-5010

文摘

Carbocyclic nucleosides have been of great interest asantiviral agents and in studies in thearea of antisense technology. The recent finding that thereplacement of a single 2'-deoxynucleoside in DNA by a carba analogue does not alter theWatson-Crick base pairing,yet at the same time provides a chemically and enzymatically stable"glycosidic" linkage, ledus to examine this class of compound as enzyme inhibitors of theDNA-repair enzymes involvedin oxidative damage. We now report the synthesis and incorporationinto oligomeric DNA viasuitable derivatives, the carbanucleosides8-oxo-7,8-dihydro-2'-deoxycarbainosine, 8-oxo-7,8-dihydro-2'-deoxycarbaguanosine, and 2'-deoxyaristeromycin.Aristeromycin (1) was deoxygenated at the 2'-position as follows. Treatment of 1with TPDSCl₂ gave the 3',5'-protectedderivative 3 (76%) which on phenylthiocarbonylation at the2'-position gave 4 in 51% yield.The latter compound on reduction with Bu₃SnH ledto the 2'-deoxy derivative 5 (90%).Benzoylation followed by deprotection with TBAF in THF then gavethe desired intermediate(6) in 65% yield.N²-Isobutyryl-8-oxo-7,8-dihydro-2'-deoxycarbaguanosine(16) was synthesizedfrom 3-chloro-2'-deoxycarbainosine (9). Treatment of9, either with hydrazine followed bycatalytic reduction of the 2-hydrazino derivative or with1-(2-nitrophenyl)ethylamine followedby photolysis of the resulting 2-substituted derivative, in bothinstances gave the desired 2'-deoxycarbaguanosine (12) in ~50% overall yield in eachcase. Bromination of 12 gave 13(90%)which, when treated with BnONa in DMSO at 65 mages/entities/deg.gif">C, led to the8-benzyloxy derivative 14(46%). Isobutyrylation of 14 followed by catalyticreduction then afforded 16. 8-Oxo-7,8-dihydro-2'-deoxycarbainosine (23) was prepared in four steps.Bromination of 2'-deoxyaristeromycin (19) at the 8-position gave 20 (>95%)which was converted to the 8-benzyloxy derivative21 (61%) using BnONa/DMSO at 80 mages/entities/deg.gif">C. Reductivedebenzylation of 21 then led to 8-oxo-7,8-dihydro-2'-deoxyaristeromycin (~100%) which, when treated withadenosine deaminase,provided the desired carbainosine derivative 23 inquantitative yield. Compounds 6, 16,and23 were converted to their respective 5'-O-DMT,3'-O-[(2-cyanoethoxy)-(N,N-diisopropylamino)phosphine] derivatives (8, 18, and 25)in excellent overall yields. The latter were then usedtosynthesize a series of DNA oligomers by automatedprocedures.