| Abstrakt: |
Selected 2,6disubstitutedpurine 2′,3′didehydro2′,3′dideoxynucleosides and 2′,3′dideoxynucleosides were prepared and evaluated. Treatment of 5′protected ribonucleosides with phenoxythiocarbonyl chloride and 4dimethylaminopyridine, or under SchottenBaumann conditions, gave high yields of 2′,3′Othionocarbonates that underwent CoreyWinter elimination. Treatment of unprotected ribonucleosides with αacetoxyisobutyryl bromide in “moist” acetonitrile gave trans2′,3′bromohydrin acetate mixtures that underwent reductive elimination with zinccopper couple or zincacetic acid. Catalytic hydrogenation of the resulting 2′,3′enes gave 2′,3′dideoxynucleosides. Treatment of the 2amino6chloropurine and 6amino2fluoropurine derivatives with nucleophiles gave 2,6disubstitutedpurine 2′,3′dideoxynucleosides. 2′,3′Dideoxyguanosine and the 2amino6amino 16d, methoxy 16b, ethoxy 16c, and methylamino 16jpurine 2′,3′dideoxynucleosides showed good antihepatitis B activity with infected primary duck hepatocytes. Cytotoxic effects with selected analogues were evaluated in human Tlymphoblastic and promyelocytic leukemia cell lines. The 2amino6fluoro derivative 16mwas the most cytotoxic of the 2amino6substitutedpurine 2′,3′dideoxynucleosides, and 2fluoro2′,3′dideoxyadenosine 21a was the most cytotoxic compound. The order of efficiency of hydrolysis of the 6substituent from 2amino6substitutedpurine 2′,3′dideoxynucleosides VmaxKm with adenosine deaminase from calf intestine was: 2amino6amino 16d > methoxy 16b > ethoxy 16c, all of which were ≤3 of the efficiency with adenosine. The 6methylamino derivative 16j, as well as 16b, 16c, and 16dwere readily converted into 2′,3′dideoxyguanosine by duck cell supernatants. |
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