2004 Fiscal Year Final Research Report Summary
Synthesis and Biological Activities of 4'-Thionucleosides branched at the Sugar Portion
| Project/Area Number |
15590100
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Showa University |
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Principal Investigator |
HARAGUCHI Kazuhiro Showa University, Associate Professor, 薬学部, 助教授 (10218638)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Hiromichi Showa University, Professor, 薬学部, 教授 (50109477)
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| Project Period (FY) |
2003 – 2004
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| Keywords | nucleoside / glycal / thio-glycosidation / thymidine / lithiation / reduction / anti-viral |
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| Research Abstract |
When 3,5-O-(Tetraisopropyldisiloxane-1,3-diyl)-4-thiofuranoid glycal (1) was lithiated with lithium diisopropylamide (LDA) and the resultingl-lithio species (2) was treated with carbon electmphile, 1-carbon-substituted 4-thiofuranoid glycal (3) could be obtained in good yield. Electaophilic glyoosidation between the glycal 3 and silylated thymine was carried out in the presence of phenylselenenyl chloride (PhSeCI) or N-iodosuccinimide (NIS) to funish the β-anomer of 4'-thionudeoside (4), stereoselectively. The glycosylated product 4 was subjected to tin radical-mediated reduction to give the target 1'-carbon-substituted 4'-thiothymidine (5).
The reaction of 1-lithio derivative 2 with benzenesulfonyl chloride gave 1-chloro-glycal 6. When 6 was treated with lithium 2,2,6,6-tetramethylpiperidide (LTMP), C-2 lithiation proceeded to provide 1-chloro-2-lithioglycal 7. Reaction of 7 with carbon electrophile gave the corresponding 2-carbon-substituted 1-chloroglycal 8. The chloro-substituent of 8 could be removed by Birch reduction to furnish 2-carbon-substituted glycal 9. PbSeCl-mediated electrophilic glycosidation between 9 and silylated thymine gave β-anomer of the glycosidated product 10, stereoselectively. When 10 was treated with tributyltin hydride in the presence of triethylborane under 0_2 atmosphere at-30゜C, the target 2'-f3-carbon-substituted 4'-thiothymidine derivative 11.
Finally, 5 and 11 was desilylated with tetrabutylammonium fluoride to furnish 1'- and 2'-β-carbon-substituted 4'-thiothymidine 12 and 13. Among the novel nucleoside analogues synthesized in this study, 1'-methyl-4'-thiothymidine 14 was found to showed anti-HSV-1 activity and anti-angiogenic activity.
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Research Products
(6 results)
