O 6-(Alkyl/aralkyl)guanosine and 2‘-Deoxyguanosine Derivatives:  Synthesis and Ability To Enhance Chloroethylnitrosourea Antitumor Action

A series of O 6-(alkyl/aralkyl)guanosines and 2‘-deoxyguanosine analogs extended to peracetyl and N 2-acetyl derivatives, potentially water soluble, was synthesized. Each was associated with N‘-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N‘-nitrosourea for in vitro evaluation on M4Beu melanoma cells of their ability to enhance the cytotoxic effect of this chloroethylnitrosourea, which is frequently reduced by repairs performed by O 6-alkylguanine-DNA-alkyltransferase. Structure−activity analysis revealed that (i) benzyl and 4-halobenzyl are the O 6-substituents required to afford a significant activity, (ii) 2‘-deoxyguanosine derivatives demonstrate greater potency than guanosine analogs, (iii) acetylation, especially at the N 2 position, generally results in compounds with moderate ability but may prevent incorporation of such nucleosides into DNA. Accordingly, O 6-(4-iodobenzyl)-N 2-acetylguanosine (3b) and O 6-benzylperacetyl-2‘-deoxyguanosine (2a), as well as O 6-benzyl-N 2-acetylguanosine (1b) and O 6-benzyl-N 2-acetyl-2‘-deoxyguanosine (2b), by far the most water soluble, exhibit a good profile for further in vivo trials by the intravenous route.