Synthesis and Biological Evaluation of Novel 4’-Thio- and 4’-Selenonucleosides

Abstract

Part I. Design, Synthesis, and Anticancer Activity of C8-Substituted-4'-Thionucleosides as Potential HSP90 Inhibitors A series of C8-substituted-4'-thioadenosine analogs 3a-3g, 16, and 18 and their truncated derivatives 4a-4j, 28-30, and 32 have been successfully synthesized from D-ribose and D-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100 µM. However, the 8-iodo derivatives 16, 18, and 32 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity. Part II. Synthesis and Anti-HIV Activity of 5'-Homo-2',3'-dideoxy-2',3'-didehydro-4'-selenonucleosides On the hypothesis that one carbon homologation of 4'-selenonucleosides might relieve the steric repulsion between cellular kinases and bulky selenium, 5'-Homo-4'-Se-d4Ns, 3a-e, as anti-HIV agents were designed and synthesized stereoselectively from D-gulonic γ-lactone, with the conversion of 2',3'-diol into the olefin as the key step. The anti-HIV activity of all synthesized compounds, 5'-homo-4'-Se-d4Ns, was toxicity-dependent, unlike normal 4'-Se-d4Ns, which were inactive against HIV-1. This result indicates that 5'-homo-4'-Se-d4Ns might be phosphorylated by cellular kinases as per the hypothesis.;Part I. Design, Synthesis, and Anticancer Activity of C8-Substituted-4'-Thionucleosides as Potential HSP90 Inhibitors C8-Substituted-4'-thioadenosine 유도체의 시리즈 3a-3g, 16, 18. 그리고 그들의 truncated 유도체 4a-4j, 28-30 과 32 는 Pummerer type 이나 Vorbrüggen 축합반응. 그리고 still coupling 이나 nucleophilic aromatic substitution 반응을 핵심으로 한 누클리오베이스의 C8 포지션의 기능화를 적용하여 각각 D-ribose 와 D-mannose로 부터 성공적으로 합성되었다. 모든 합성된 화합물들은 HSP90 저해제로써의 효과가 분석되어졌지만, 100 µM 이하로는 효과가 나타나지 않았다. 하지만 8-iodo 유도체 16, 18, 그리고, 32 는biological activity에 다는mechanism 이 연류되어있음을 나타내여 항함제로써 강력한 효력을 보였다. Part II. Synthesis and Anti-HIV Activity of 5'-Homo-2', 3'-dideoxy-2',3'-didehydro-4'-selenonucleosides (5'-Homo-4'-Se-d4Ns) 4'-selenonucleosides 의 one carbon homologation이 세포의 kinases와 부피가 큰 selenium 과의 원자의 공간배치에 의한 repulsion을 완화한다는 가설에 따라, 5'-Homo-4'-Se-d4Ns, 3a-e 가 2',3'-diol을 olefin으로 변화시키는 것을 핵심으로 하여 D-gulonic γ-lactone 으로부터 항HIV agent 로 선택적으로 합성되었다. 합성되어진 모든 5'-Homo-4'-Se-d4Ns 화합물들은 항HIV 호력은, 기존의 HIV-1에는 호력없던 4'-Se-d4Ns 들과는 달리, 독성에 의존적이다. 이결과는 5'-Homo-4'-Se-d4Ns가 가설에 따라 세포의 kinase에 의해 인산화 될수도 있다는것을 의미한다.