A Facile and Efficient Synthesis of Seleno-acyclic Nucleosides as Potential Antiviral Agents

Abstract

Acyclovir and ganciclovir are very potent antiviral agent in market for the treatment of herpes virus infection. However, these drugs are associated with low oral bioavailability and high cytotoxicity. To overcome these drawbacks, seleno-acyclic nucleosides were designed, based on bioisosteric relationship of selenium with oxygen and highly lipophilicity of selenium, making them penetrate cell membrane. In order to synthesize seleno-acyclovir 3a and its analogues 3b-3f, bromoethanol was converted to the corresponding diselenide 25 which was protected with TBDPS. The acyclic glycosyl donor 26 was synthesized by cleaving the diselenide 23 with NaBH_(4) and reacting with methylenebromide. Condensation of the glycosyl donor 26 with purine bases under basic condition afforded the desired N^(9)-nucleosides, which were further manipulated to furnish the seleno-acyclovir 3a and its analogues 3b-3f. A similar protocol was used to synthesize the seleno-ganciclovir 4a and its analogues 4b-4g. 1,3-Benzylidine protected glycerol 38 was mesylated and converted to the corresponding diselenide 40. The diselenide 40 was then converted to the glycosyl donor 41, which was condensed with purine bases to afford the desired N^(9)-nucleosides. These nucleosides were further manipulated to yield the final seleno-ganciclovir 4a and its analogues 4b-4g. Among the synthesized compounds, seleno-acyclovir 3a showed potent anti-HSV (EC_(50) = 1.47µg/mL) activity.;Acyclovir와 ganciclovir는 herpes virus 감염 치료에 사용되는 매우 효과적인 항바이러스제이다.그러나이 약물들은 낮은 생체이용률과 높은 세포 독성을 나타낸다.이러한 문제점을 극복하기 위해, oxygen과 bioisostere 관계에 있는 selenium을 도입한 seleno-acyclic nucleoside들을 고안하였고, selenium의 높은 친유성은 세포막을 잘 투과하게 해준다. Seleno-acyclovir 3a와 이것의 유도체인 3b-3f를 합성하기 위해,먼저 bromoethanol을 이에 해당하는 diselenide25로 변환시키고,이를 TBDPS로 보호하였다. Acyclic glycosyl donor인 26은 diselenide23을 NaBH_(4)로 자르고 이를 methylenebromide와 반응시켜 얻었다.염기성 조건에서 Glycosyl donor 26과 purine base의 축합 반응을 통해 원하는 N^(9)-nucleoside를 합성했고, 이것에 다양한 조작을 하여 selenoacyclovir 3a와 이것의 유도체인 3b-3f를 얻었다. Seleno-ganciclovir 4a와 이것의 유도체인 4b-4g를 합성하는 데에도 이와 유사한 프로토콜 을 적용하였다. 1,3-benzylidine으로 보호된 glycerol 38을 mesylation을 거쳐 해당하는 diselenide40로 변환하였다. Diselenide40을 glycosyldonor인 41로 변환했고, 이것을 purine base와 축합하여 원하는 N^(9)–nucleoside들을 얻었다.이후 조작을 거쳐이들 nucleoside로부터 final seleno-ganciclovir 4a와 이것의 유도체인 4b-4g를 합성하였다.이렇게 합성된 물질들 가운데 seleno-acyclovir 3a가 anti-HSV (EC_(50) = 1.47mg/mL)활성을 나타냈다.