Synthesis of L-2' -deoxy- 4' -thiopurine nucleosides as potential antiviral agents

Abstract

D-2 -deoxy-4 -thiopurine과 pyrimidine nucleosides는 항암, 항바이러스 작용을 나타내는 것으로 알려져 있으나, 높은 세포 독성을 나타내어 임상에서 치료제로 개발될 수 없었다. 일반적으로 D-nucleosides의 enantiomers인 L-nucleosides는 D-nucleosides보다 독성이 적은 것으로 알려져 있으므로 항바이러스 활성을 나타내면서 독성이 경감된 항바이러스제와 항암제의 개발을 위해 L-2 -deoxy-4 -thiopurine nucleosides를 합성하였다. 최종 물질은 D-xylose를 출발 물질로 하여 중요 중간체인 L-4-thioarabinose 유도체 8을 합성했고, 2 -benzoyl group의 neighboring group effect로 base축합시 β-anomer를 주로 얻을 수 있었고, ^1H NOE 실험을 통해 base축합 후의 α,β-anomer의 구조와 배열을 증명할 수 있었다. 합성된 최종 물질 1은 세포독성에서 유래된 약한 항바이러스 작용을 나타내었으며 현재 항암 작용을 검색 중에 있다.

Key words: L-nucleosides L-2 -deoxy-4 -thiopurine nucleosides L-4-thioarabitol derivative ^1H NOE 실험 ; D-2 -Deoxy-4 -thiopurine and pyrimidine nucleosides have been reported to show potent biological activities against cancer and viruses such as herpes simplex virus (HSV) and hepatitis B virus (HBV), but they were found to be too cytotoxic to be developed as clinically useful agents. Since L-nucleosides were in general found to be less toxic than their corresponding enantiomers, D-nucleosides, L-2 -deoxy-4 -thiopurine nucleosides were synthesized for the development of less toxic antiviral and anticancer agents while maintaining their antiviral and antitumor activity. The target L-2 -deoxy-4 -thiopurine nucleosides were synthesized in 18 steps, starting from D-xylose via the key intermediate, L-4-thioarabitol derivative 8. In order to obtain more β-anomer, neighboring group effect by 2 -benzoyl group was utilized during the condensation, which resulted in the formation of β-anomer as major product. Anomeric configuration of the target nucleosides was determined by ^1H NOE experiments on 15a (β-anomer) and 15b (α-anomer).

Key words: L-nucleosides L-2 -deoxy-4 -thiopurine nucleosides L-4-thioarabitol derivative ^1H NOE experiments