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Asymmetric Synthesis of Novel Thioiso Dideoxynucleosides with Exocyclic Methylene as Potential Antiviral Agents

Title
Asymmetric Synthesis of Novel Thioiso Dideoxynucleosides with Exocyclic Methylene as Potential Antiviral Agents
Authors
金泫志
Issue Date
2004
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
鄭樂臣
Abstract
In an effort to find novel and effective anti hepatitis B virus and anti human immuno-deficiency virus, Novel thioiso pyrimidine and purine nucleosides substituted with exocyclic methylene have been synthesized, starting from D-xylose. The glycosyl donor 15 was synthesized from D-xylose, using cyclization of dimesylate 10 with sodium sulfide as a key step. Cyclization proceeded in pure S_(N)₂reaction without going through S_(N)₁reaction in the presence of an allylic functional group at low reaction temperature (0 ℃) in polar solvent (DMF), affording compound 12 as a major product. On the other hand, glycosylation of 15 with 6-chloropurine under Mitsunobu conditions afforded the desired S_(N)₂product 18. All synthesized final nucleosides were tested against several viruses, but only 6-chloropurine derivative 19 showed weak anti-hepatitis C virus (HCV) activity. Even though compounds which are highly active are not found, it is sure that the novel thiosugar 12 developed in this work has the potential to serve as a new template for the design of new antiviral nucleosides.;HIV-1과 HBV에 활성이 있고 효과적이고 새로운 항바이러스제의 구조를 디자인하기 위해, D-xylose에서 시작하여 exocyclic methylene이 첨가된 thioiso pyrimidine 과 purine nucleoside 를 합성하여 그 활성을 테스트하여 보고 이 새로운 구조와 기존의 구조의 활성을 비교하여 보았다. Sodium sulfide를 사용하여 dimesylate 10 의 cyclization을 하였는데 이는 전체적인 scheme중에서 key step이다. cyclization하는 과정에서, S_(N)₁을 거치지 않고 낮은 온도(0℃)와 polar solvet (DMF)의 환경에서 S_(N)₂의 과정으로 진행되어서 compound 12가 중요 결과물로 나왔다. 합성된 모든 nucleosides를 여러 바이러스에 대해 테스트를 해봤지만, 오직 6-chloropurine derivative 19만 약한 anti-hepatitis C Virus (HCV)효과를 나타내었다. 비록 강한 활성을 가진 nucleoside가 합성되진 못했지만, 활성이 있는 항바이러스제를 개발하기 위한 새로운 template를 개발하였고, 이를 토대로 새로운 항바이러스제의 효과적인 개발 연구에 사용되어질 것으로 생각된다.
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