Nucleic Acid Related Compounds. 114. Synthesis of 2,6-(Disubstituted)purine 2',3'-Dideoxynucleosides and Selected Cytotoxic, Anti-Hepatitis B, and Adenosine Deaminase Substrate Activities

Selected 2,6-(disubstituted)purine 2',3'-didehydro-2',3'-dideoxynucleosides and 2',3'-dideoxynucleosides were prepared and evaluated. Treatment of 5'-protected ribonucleosides with phenoxythiocarbonyl chloride and 4-(dimethylamino)pyridine, or under Schotten-Baumann conditions, gave high yields of 2',3'-O-thionocarbonates that underwent Corey-Winter elimination. Treatment of unprotected ribonucleosides with α-acetoxyisobutyryl bromide in "moist" acetonitrile gave trans 2',3'-bromohydrin acetate mixtures that underwent reductive elimination with zinc-copper couple or zinc/acetic acid. Catalytic hydrogenation of the resulting 2',3'-enes gave 2',3'-dideoxynucleosides. Treatment of the 2-amino-6-chloropurine and 6-amino-2-fluoropurine derivatives with nucleophiles gave 2,6-(disubstituted)purine 2',3'-dideoxynucleosides. 2',3'Dideoxyguanosine and the 2-amino-6-[amino (16d), methoxy (16b), ethoxy (16c), and methylamino (16j)]purine 2',3'-dideoxynucleosides showed good anti-hepatitis B activity with infected primary duck hepatocytes. Cytotoxic effects with selected analogues were evaluated in human T-lymphoblastic and promyelocytic leukemia cell lines. The 2-amino-6-fluoro derivative 16m was the most cytotoxic of the 2-amino-6-(substituted)purine 2',3'-dideoxynucleosides, and 2-fluoro-2',3'-dideoxyadenosine (21a) was the most cytotoxic compound. The order of efficiency of hydrolysis of the 6-substituent from 2-amino-6-(substituted)purine 2',3'-dideoxynucleosides (Vmax/Km) with adenosine deaminase from calf intestine was: 2-amino-6-[amino (16d) > methoxy (16b) > ethoxy (16c)], all of which were <3% of the efficiency with adenosine. The 6-methylamino derivative 16j, as well as 16b, 16c, and 16d were readily converted into 2',3'-dideoxyguanosine by duck cell supernatants.