| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
During our continuing studies on the synthesis of branched-sugar nucleosides, ring opening of epoxy-sugar nucleosides with organoaluminum reagents was investigated. In one example, 4',5'-unsaturated thymine-nucleoside was oxidized with dimethyldioxirane (DMDO). Ring opening of the resulting epoxide with organoaluminum reagents disclosed a new access to the 4'-branched analogues. As a result of this study, a various types of 4'-carbon-substituted 2',3'-didehydro-3'-deoxy-thymidines were synthesized. Among these compounds, the 4'-ethynyl analogue (4'-Ed4T) was found to have a higher inhibitory activity against HIV than does stavudine (d4T), which is clinically used for chemotherapy of AIDS.
This compound (4'-Ed4T) is much less toxic to various cells than d4T and has several promising features as anti-HIV agent : 1) not inhibitory to mitochondrial DNA synthesis, 2) better substrate for human thymidine kinase than d4T, 3) very much resistant to catabolism by thymidine phosphorylase, and 4)
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its activity improves in the presence of a major mutation, K103N, known for nonnucleoside reverse transcriptase inhibitor resistant HIV.
To further evaluate 4'-Ed4T in preclinical studies, we were in need of an alternative synthetic method suitable for its large scale preparation, since the use of DMDO is frustrated by inaccessibility of its highly concentrated solution. It was found that the reaction of Pb(OBz)_4 with the previously employed 4',5'-unsaturated thymine-nucleoside allowed to introduce a benzoyloxy leaving group into the 4'-position. Upon reacting this substrate with Me_3SiC≡CAl(Et)Cl, the ethynyl group was introduced stereoselectively to the 4'-position. These reactions were performed in several 10 g-scale, and we assume this approach would be successful even in industrial scale. It is planed that the preclinical studies of 4'-Ed4T will complete in 2007, and its clinical studies will start in 2008.
We have also investigated the structure-activity relationship studies of 4'-Ed4T. The presence of sp-hybridized carbon-substituent seems to be essential for the anti-HIV activity. However, introduction of a cyano group instead of the ethynyl group decreased the inhibitory activity. Replacement of the furanose oxygen in 4'-Ed4T with methylene was totally ineffective. On the other hand, such replacement with a sulfur atom allowed to retain the activity to some extent. Less
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