Synthesis of the cyclic and acyclic acetal derivatives of 1-(3-C-Ethynyl-β-d-ribo-pentofuranosyl)cytosine, a potent antitumor nucleoside. Design of prodrugs to be selectively activated in tumor tissues via the bio-Reduction–Hydrolysis mechanism Original R

We have designed and synthesized the acetal derivatives of 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)cytosine (ECyd, 1), the 2′,3′-O-nitrobenzylidene derivatives 2 and 3 and the 5′-O-(alkoxy)(nitrophenyl)methyl derivatives 6–10 as potential prodrugs of ECyd. These prodrugs can be selectively activated in tumor tissues via a bio-reduction–hydrolysis mechanism owing to the characteristic properties of tumor tissues, such as hypoxia and lower pH. Although the 2′,3′-O-(4-nitrobenzylidene) derivatives 2 and 3 were converted bio-reductively into the corresponding 4-aminobenzylidene derivatives by rat S-9 mix, the reduction products, that is, the corresponding amino congeners 4 and 5, proved to be rather stable in an aqueous solution at pH 6.5 used as a pH model for acidic tumor tissues. In contrast, the 5′-O-(alkoxy)(4-nitropheny)methyl derivatives 6–8 were also reduced by rat S-9 mix to the corresponding amino congeners 11–13, which were hydrolyzed to release ECyd more effectively at pH 6.5 than at pH 7.4. Accordingly, the acyclic acetals 6–8 may be efficient prodrugs of ECyd, that are effectively reduced under physiological conditions releasing ECyd in acidic tumor tissues.