Abstract |
We have designed and synthesized the acetal derivatives of 1-(3-C-ethynyl-beta-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.
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Authors | Makoto Nomura, Satoshi Shuto, Akira Matsuda |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 11
Issue 11
Pg. 2453-61
(May 29 2003)
ISSN: 0968-0896 [Print] England |
PMID | 12735992
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 1-(3-C-ethynylribopentofuranosyl)cytosine
- Acetals
- Antimetabolites, Antineoplastic
- Prodrugs
- Cytidine
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Topics |
- Acetals
(chemical synthesis, pharmacology)
- Animals
- Antimetabolites, Antineoplastic
(chemical synthesis, pharmacology)
- Cytidine
(analogs & derivatives, chemistry)
- Hydrogen-Ion Concentration
- Hydrolysis
- Oxidation-Reduction
- Prodrugs
(chemical synthesis, pharmacology)
- Rats
- Tumor Cells, Cultured
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