Asymmetric Synthesis of 6′-Fluoroaristeromycin Analogues as Potential S-Adenosylhomocysteine Hydrolase Inhibitor

Abstract

Inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase have shown promise as antiviral agents. Aristeromycin and neplanocin A are naturally occurring carbocyclic nucleosides, which act as potent inhibitors of S-adenosylhomocysteine (SAH) hydrolase, resulting in the inhibition of viral mRNA capping. Although neplanocin A and aristeromycin act as good inhibitors of SAH hydrolase, they were too cytotoxic to be clinically useful agents. Thus, in the search of less toxic and more potent inhibitors of SAH hydrolase than these compounds, many D-carbocyclic analogues have been designed, synthesized and evaluated for their SAH hydrolase inhibitory activity. Our recent discovery of fluoroneplanocin A containing a fluorine atom in place of hydrogen at C6′ prompted us to focus our attention towards the development of 6′-fluoroaristeromycin derivatives as less toxic and more potent antiviral agents. This project is a modest attempt in developing a successful synthetic strategy for D-6′-β-fluoroaristeromycin. The key steps during the synthesis were the successful Michael reaction and electrophilic fluorination of the truncated cyclopentenone intermediate. ;S-adenosyl-L-homocysteine (AdoHcy) hydrolase 저해제들은 항바이러스제로서 전도유망하다. Aristeromycin과 neplanocin A는 자연적으로 존재하는 carbocyclic nucleosides로서 S-adenosylhomocysteine (SAH) hydrolase를 저해하여 mRNA capping을 억제한다. 이런 좋은 억제성에도 불구하고, neplanocin A과 aristeromycin은 임상적으로 쓰이기에는 세포 독성이 너무 강하다. 그리하여, 독성이 덜 하고 더 강력한 SAH hydrolase의 저해제를 개발하기 위해 많은 D-carbocyclic 유도체들이 설계, 합성 및 개발되어 왔다. 최근 우리 실험실에서 개발한 C6′위치에 수소 대신 플루오르 원소를 지닌 fluoro-neplanocin A는 좋은 활성을 보였으며, 이를 바탕으로 한 6′-fluoroaristeromycin 유도체 또한 효과적인 항바이러스제로서 설계하게 되었다. 이 연구는 Michael 반응과 친전자성 플루오르화 반응을 이용한 6′-β-fluoroaristeromycin의 성공적이고 assymetric한 합성법에 대한 것이다