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

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.