Synthesis and biological evaluation of 2- and 7-substituted 9-deazaadenosine analogues

Article abstract of DOI:10.1081/NCN-200046784

A series of 2-halogen and 7-alkyl substituted analogues of 9-deazaadenosine and 2′-deoxy-9-deazaadenosine was synthesized by new efficient methodology involving transformation of corresponding 9-deazaguanosine and 2′-deoxyguanosine, which in turn were synthesized by direct C-glycosylation of 1-benzyl-9-deazaguanine with 1-O-acetyl-2,3,5-tri-O-benzoyl- D-ribofuranose and methyl 2-deoxy-3,5-di-O-(p-toluoyl)-D-ribofuranoside, respectively. Deoxychlorination of C6 and diazotization/chloro-or fluoro-dediazoniation of the sugar-protected 9-deazaguanosine, followed by selective ammonolysis at C6 and deprotection of the sugar moiety, gave 2-chloro- and 2-fluoro-9-deazaadenosine (6 and 9). Substitution of the 7-position of the dihalogen-intermediate with alkyl groups, followed by ammonolysis and deprotection, provided 2-chloro-7-alkyl-9-deazaadenosines (13a-e) and 2-fluoro-7-benzyl-9-deazaadenosine (13f). Catalytic hydrogenation of 13a-e gave 7-alkyl-9-deazaadenosines 14a-e. Similarly, 2-chloro-2′-deoxy-9- deazaadenosine (21), 2-chloro-2′-deoxy-7-methyl-9-deazaadenosine (25), 2′-deoxy-9-deazaadenosine (22), and 2′-deoxy-7-methyl-9- deazaadenosine (26) were prepared from sugar-protected 2′-deoxy-9- deazaguanosine. Among these compounds, 7-benzyl-9-deazaadenosine (14b) showed the most potent cytotoxic activity, with IC₅₀ values of 0.07, 0.1, 0.2 and 1.5 μM, while both 7-methyl-9-deazaadenosine (14a) and 2-fluoro-9-deazaadenosine (9) also demonstrated significant cytotoxic activity with IC₅₀ values of 0.4, 0.7, 0.3, and 1.5 μM, and 1.5, 0.9, 0.3, and 5 μM against L1210 leukemia, P388 leukemia, CCRF-CEM lymphoblastic leukemia, and B₁₆F₁₀ melanoma cells, respectively.