Design and Synthesis of Base Modified Carbanucleosides as Potential Adenosine Receptor Ligands

Abstract

On the basis of the potent binding affinities at the A2A adenosine receptor (AR) and A3AR activity of truncated C2-substituted 4'-thioadenosine derivatives 2, truncated C2-substituted cyclopropyl-fused carbanucleosides 4a and 4b were designed and synthesized from D-ribose via Mitsunobu condensation and palladium-catalyzed cross-coupling reactions as key steps. Since the introduction of a small substituent at C8 position increases the binding affinity at the A2AAR, the furan ring was introduced at C8 position in the presence of C2-hexynyl moiety to give 4c and 4d. The synthesized compounds 4a and 4b were tested for the binding affinity at the A3 adenosine receptors. These compounds showed high binding affinity at the A3AR as in the case of compound 2. Binding affinities at other subtypes were in progress.;C2-substituted-4'-thioadenosine 화합물 2가 A2AAR와 A3AR에 강한 binding affinity를 가지고 있다는 문헌을 근거로 하여, truncated-C2-substituted cyclopropyl fused carbanucleosides 4a 와 4d을 설계하고 합성하였다. 기질로서 D-ribose을 이용하였고, 핵심 반응으로는 Mitsunobu reaction과 유기 금속 촉매를 이용한 다양한 C-C bond 결합 반응을 적용하였다. C8 위치에 보다 작은 치환기가 도입된 화합물들이 A2A adenosine receptor 에 보다 강한 binding affinity을 가지게 될 것이라 추측하였다. 따라서, C2-hexynyl 기를 가지면서 동시에 C8 위치에 furanyl로 치환된 화합물들을 설계 합성하였다. 합성된 화합물들은 화합물 2처럼 A3 adenosine receptor에 대한 강한 binding affinitiy가 나타났다. 다른 adenosine receptors 에 대한 실험은 자세한 연구는 현재 진행중이다.