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

• Published in: Journal of heterocyclic chemistry 2001-11, Vol.38 (6), p.1297-1306
• Main Authors: Robins, Morris J., Lindmark, R. J., Wnukt, Stanislaw F., Wilson, John S., Madej, Danuta, Tyrrell, D. Lorne J., Gati, Wendy P.
• Format: Article
• Language: English
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.5570380609

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‐thiono‐carbonates that underwent Corey‐Winter elimination. Treatment of unprotected ribonucleosides with α‐ace‐toxyisobutyryl 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‐fluoro‐purine 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‐(sub‐stituted)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.