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Synthesis of Truncated C8-Modified-4'-thionucleosides as Potential HSP90 Inhibitors

Title
Synthesis of Truncated C8-Modified-4'-thionucleosides as Potential HSP90 Inhibitors
Authors
류승연
Issue Date
2014
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
최선
Abstract
On the basis of potent anticancer activity of Geldenamycin and PU3 (the first fully synthetic inhibitor of HSP90), the first series of truncated N6-substituted-C8-modified-4'-thioadenosine derivatives were designed and synthesized. The synthesis of truncated TBS protected glycosyl donor 10 was obtained starting from D-mannose. The large scale synthesis of 6-chloro-8-iodopurine was achieved by a sequence of lithiation, iodination, and the acid catalyzed deprotection. Modifications at the C8-position of 6-chloropurine derivatives were achieved using palladium-catalyzed cross coupling reactions (furanyl and thiophenyl) as key steps. A series of C8-substituted alkyl and benzylic amines were synthesized by aromatic nucleophilic substitution reactions. The synthesized C8 modified and N6-substituted 4'-thioadenosine derivatives, 17a, 17b, 19a, 19b, 21, and 24a-d are in biological assay as HSP90 inhibitors. ;Geldenamycin과 PU3 (최초로 합성된 HSP90 inhibitor)의 강한 항암효과에 근거하여, 최초의 truncated N6-substituted-C8-modified 4'-thio-adenosine 유도체들을 설계하고 합성하였다. D-Mannose로부터 TBS기로 protection된 truncated thio-glycosyl donor 10를 합성했고 lithiation과 Iodination reaction을 차례로 거쳐6-chloro-8-iodopurine의 대량합성 또한 성공하였다. 최종적으로, 산 촉매 조건 하의 THP치환기 제거반응으로 목표했던 6-chloro-8-iodopurine을 좋은 수율로 얻었다. 6-chloropurine의 C8 위치의 furanyl 혹은 thiophenyl 로의 변형은 Palladium 촉매의 cross coupling 을 주요반응으로 하여 일어나고, C8 위치의 alkyl기 혹은 benzylic amine 기로의 치환은 방향족 친핵성 치환반응으로 이루어졌다. 이렇게 합성된 C8-modified and N6-substituted 4'-thioadenosine 유도체들의 HSP90 억제제로서의 활성에 관한 생물학적 test가 진행 중에 있다.
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