616239-76-0Relevant articles and documents
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
Nomura, Makoto,Shuto, Satoshi,Matsuda, Akira
, p. 2453 - 2461 (2007/10/03)
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.
