Stereoselective Synthesis and Anti-HCV Activity of 2΄-C-Substituted Cyclopropyl-Fused Carbanucleosides

Abstract

2'-C-substituted cyclopropyl-fused carbanucleosides의 입체선택적 합성과 C형 간염 바이러스에 대한 활성C형 간염치료제로서 식약청의 승인을 받은 물질은 뉴클레오사이드 유도체인 ribavirin 에 불과하므로 새로운 C형 간염치료제를 개발하기 위해 많은 뉴클레오사이드와 비 뉴클레오사이드 유도체가 합성되었다. 그 중에 2′-C-methyladenosine (3)과 2′-C-methylguanosine (4) 이 cell-based replicon assay에서 좋은 anti-HCV 활성을 보였다 (EC_(50) = 0.26 μM and 3.5 μM). 이를 바탕으로 β-2′-C-hydroxymethyl 유도체 (5)가 합성이 되었고 그 중에 아데노신 유도체가 cell-based replicon assay에서 좋은 anti-HCV 활성을 보였다. 이 물질들은 Northern C3′-endo 입체배치를 보이는 것으로 판명되었다. 이러한 발견들을 바탕으로, β-2′-C-hydroxymethyladenosine 의 유도체이면서 Northern C3′-endo 입체배치로 제한되어있는 뉴클레오사이드 6-10 이 합성되었다. 타겟 물질은 D-ribose에서부터 입체선택적인 epoxidation과 cyclic sulfate chemistry를 key step으로 하여 합성되었다. 입체선택적인 epoxidation은 ketone을 trimethylsulfoxonium anion으로 처리하여 얻어졌다. Tetra-n-butylammonium acetate (n-Bu₄NOAc) 또는 sodium azide로 epoxide ring을 개환하여 2′-C-hydroxymethyl 유도체들이 합성되었고, 모든 합성된 물질들은 C형 간염 바이러스에 대해 활성연구가 진행되었다. 안타깝게도 모든 최종 물질들은 C형 간염 바이러스에 활성을 보이지 않았다.;The only approved treatment option by the Food and Drug Administration for HCV-infected patients is the nucleoside analogue ribavirin. To discover new anti-RNA viral agent, a number of nucleoside and non-nucleoside derivatives have been synthesized. Among these, 2'-C-methyladenosine (3) and 2'-C-methylguanosine (4) showed potent anti-HCV activity (EC50 = 0.26 μM and 3.5 μM, respectively) in a cell-based replicon assay. On the basis of potent anti-HCV activity of 2'-C-methyladenosine (3), the corresponding β-2'-C-hydroxymethyl analogues (5) were designed and synthesized. Among these, the adenosine derivative exhibited potent anti-HCV activity in a cell-based replicon assay. These compounds were reported to display a strong preference for Northern C3′-endo conformation. Based on these findings, conformationally restricted analogues 6-10 of β-2'-C-hydroxymethyladenosine, adopting the Northern C3′-endo conformation were designed, synthesized, and evaluated for anti-HCV activity. The target nucleosides were synthesized from D-ribose via stereoselective epoxidation and cyclic sulfate chemistry as key steps. Stereoselective epoxidation was achieved by treating ketone with trimethylsulfoxonium anion. Cleavage of the epoxide with tetra-n-butylammonium acetate (n-Bu4NOAc) and sodium azide, respectively, afforded the 2'-C-hydroxymethyl derivative, and all synthesized nucleosides were tested against HCV. Unfortunately, all compounds did not show a significant anti-HCV activity.