Design, Synthesis, Anti-Hepatitis C Virus (HCV) Activity of 3΄-C-Substituted Purine and Pyrimidine Nucleosides

Abstract

2'-C-Hydroxymethyl adenosine (2)의 항 c형 간염 바이러스 효과에 근거하여, D-xylose을 stereoselective Grignard reaction을 함으로써 vinyl group에서 hyroxymethyl group 전환하는 중요 반응 단계를 거쳐 3'-C-hydroxymethyl-substituted purine 과 pyrimidine nucleoside를 디자인하고 합성하였다. 중요한 중간체 (12)로부터 Bioisosteric 3'-C-Fluoromethyl-substituted 과 3'-C-azidomethyl-substituted purine and pyrimidine nucleosides을 합성하였다. 그리고 합성된 모든 뉴클레오시드들은 항 C형 간염 바이러스 (HCV)에 대해 테스트하였고 그 중에서 3'-C-hydroxymethyl adenosine 유도체가 항 C형 간염 바이러스 효과가 가장 높았다 (EC50 = 14.1μM). 일반적으로 3'-C-hydroxymethyl 유도체들이 3'-C-fluoro- 과 3'-C-azidomethyl 유도체보다 더욱 효과적이었다.;On the basis of the potent anti-hepatitis C virus (HCV) activity of 2'-C-hydroxymethyl adenosine (2), 3'-C-hydroxymethyl-substituted purine and pyrimidine nucleosides were designed and synthesized from D-xylose via stereoselective Grignard reaction and conversion of the vinyl into hydroxymethyl group as key steps. Bioisosteric 3'-C-fluoromethyl-substituted and 3'-C-azidomethyl-substituted purine and pyrimidine nucleosides were also synthesized from the key intermediate (12). All synthesized compounds were tested for anti-hepatitis c virus (HCV) activity, among which 3'-C-hydroxymethyl adenosine derivative showed the most potent anti-HCV activity (EC50 = 14.1 μM). 3'-C-Hydroxymethyl derivatives were in general more potent than 3'-C-fluoro- or 3'-C-azidomethyl derivatives.