Syntheses and antiviral activity of 2'-fluorohexopyranosyl nucleosides and L-4'-thionucleosides

Abstract

Since (-)-3TC and (-)-dioxolane-C were found to be a potent anti-HIV agent and antitumor agent, respectively and 2'-F-ddA was reported to have very promising anti-HIV activity, it was of interest to synthesize 2'-fluorohexopyranosyl nucleosides, where sulfur or oxygen of (-)-3TC and dioxolane-C was substituted by a bioisosteric double bond and 2'-position was fluorinated, were synthesized as potential anti-HIV agents. It was observed that the DAST fluorination to the 2'-position of hexopyranosyl nucleosides shows unusual participation of electron releasing group such as methoxy or chloro group at the 6-position of purine. The final nucleosides showed no biological activity. Prompted by the impressive antiviral activity displayed by L-nucleosides and D-4'-thionucleosides, L-4'-thiothymidine was synthesized in 18 steps starting from D-xylose via the key intermediate, L-4-thioarabinose derivative and its biological activity is being tested in our laboratory;(-)-3TC는 임상적으로 AIDS의 치료와 AIDS 관련 증상에 이용되고 있으며, (-)-dioxolane-C는 개발 중에 있다. 또한, 2'-위치에 불소가 도입된 2'-F-ddA 역시 우수한 항 HIV 활성을 가진 것으로 보고되고 있다. 여기에 기초하여 (-)-3TC와 (-)-dioxolane-C의 황과 산소 원소를 bioisostere인 이중결합으로 치환하고 2'-위치에 불소를 도입하여 항 HIV 작용이 기대되는 물질을 합성하였다. 합성과정 중 DAST를 이용한 불소화반응에서 이전에 보고되었던 바와는 달리 불소의 stereochemisoy가 보존(retention)되지 않았고, 최종목적화합물이 생물학적 활성을 나타내지는 않았다. 또, 최근에 보고된 L-nucleosides와 D-4'-thionucleosides의 활성에 기인하여 새로운 L-4'-thiothymidine을 합성하였다. 최종물질은 D-xylose로부터 시작하여 중요중간체인 L-4-thioarabinose 유도체를 거쳐 합성되었으며 최종물질의 생리 활성은 현재 검색 중에 있다.