Stereoselective Synthesis of 2′-Deoxy-2′-fluoro-4′-selenoarabinofuranosyl Pyrimidines as Potent Anticancer Agents

Abstract

The recent discovery of 4′-selenonucleosides, with unusual southern conformation has prompted us to focus our attentions to develop new analogue in the 4′-selenonucleosides. Towards this goal, the modification at 2′-position of selenosugar was attempted. A series of 2′-deoxy-2′-fluoro-4′-seleno arabinofuranosyl pyrimidines was accomplished, using DAST fluorination on a key step. The selenium atom participated in the DAST fluorinaton of 4′-selenonucleosides and conformational bias induced by bulky selenium proved to be a decisive factor. In a same time, the 2,2′-anhydro nucleosides, which was formed from the abstraction of the amide hydrogen by fluoride anion was produced as the major product. Among the synthesized fluoro compounds, 2′-F-4′-seleno ara-C was tested and this was found to be more potent than ara-C itself. This project discusses with a successful synthetic strategy of the 2′-fluoro-4′-seleno pyrimidine nucleosides, with for biological result. ;1-β-D-arabinofuranosyl cytidine (ara-C)(1)의 항암 효과에 근거하여, 4′-selenosugar을 염기와 축합함으로써 셀레노핵산을 합성하였고, 합성된 셀레노핵산을 이용하여 DAST 플루오르화 반응을 수행해 2′-deoxy-4′-selenopyrimidine nucleosides를 합성하였다. 셀레노핵산은 핵산은 DAST 플루오르화 반응의 메커니즘이 설퍼뉴크레오사이드와 달라서 2, 2′-anhydro nucleoside가 주요 물질로 생성된다. 합성된 셀레노핵산 중 2′-deoxy-4′-fluoro-selenoarabinosyl uridine 2′-deoxy-4′-fluoro-selenoarabinosyl cytidine을 항암 효과에 관해 시험해 본 결과, 우수한 효과를 나타내었다.