Stereoselective Synthesis and Antiviral Activity of Selenonucleosides

Abstract

Part I. The modified nucleoside structure has proven to be an effective template for the development of therapeutically useful agents with antiviral and anticancer activity. In continuation to our interest in selenium containing nucleosides we have employed a novel seleno-Michael reaction to synthesize homo-selenosugars having promising anti-oxidant property. The homo-seleno sugars were elaborated to homo-seleno nucleosides, a potential antiviral agent. The homo-seleno sugar was synthesized by a tandem substitution and conjugate addition reaction to give undiastereoselective homo-selenosugar esters. The sugars were separated by using a protection-deprotection protocol, where the -selenoacetate was converted to corresponding lactone. The -epimer was transformed to appropriate glycosyl donor. The homo-seleno pyrimidine nucleosides were synthesized using Pummerer-type condensation, whereas the purine analogue was synthesized from corresponding acetate under classical Vorbrügen condensation conditions. Part II. A novelroute for the synthesis of seleno-adefovir and -tenofovir have been developed. The acyclic phosphonate nucleosides were synthesized by coupling the selenophosphonate and bromoethyladenine. The coupling of adenine with the bromoethyl partners was achieved by Mitsunobu reaction. ;Part I. 변형된 핵산 구조는 항암효과와 항바이러스 활성이 있는 치료학적으로 유용한 물질로서 알려져있다. 셀레늄이 포함된 핵산에 대한 지속적인 연구를 하는 과정에서 새로운 seleno-Michael 반응을 이용하여 homo-selenosugar을 합성하였다. Tandem 치환반응과 conjugation 반응을 거쳐 생성된 비입체 선택적인 4-homoselenosugar ester는 protection과 deprotection 프로토콜을 거쳐 -epimer가 분리 되었다. Voubrügen축합을통해Pyrimidin염기와, Pummerer반응을이용하여 Purine계열염기와축합되어, 4’-homoseleno 핵산을합성하였다. Part II. 새로운 합성법을 통해 seleno-adefovir 와 -tenofovir를 합성하였다. 비고리 인산화 핵산은 셀레노인산과 브롬에틸아데닌을 coupling 하여 합성하였다. 아데닌과 브롬에틸의coupling은 Mitsunobu 반응을 통해 얻어졌다.