Synthesis and anti-HIV activity of novel phenyl branched cyclopropyl nucleosides and Neplanocin A derivatives

Abstract

본 논문에서는 페닐측쇄를 가진 뉴크레오사이드 유도체와 네프라노신 A 유도체를 합성하고 이들의 항HIV-1 약효를 검색하고자 하였다. Zn(Et)2, CH2I2 시약으로 Simmons-Smith 반응을 수행하여 높은 수율로 우니가 얻자고 하는 물질을 합성하였으며 11 와 12에 K2CO3, 18-Crown-6, DMF를 사용하여 natural bases을 붙여서 페닐측쇄를 가진 최종 뉴크레오사이드 (21-28)를 합성하였다. 그리고 NBS, PPh3, CH2Cl2 시약으로 SN2반응을 수행하여 allylic bromide 34 합성하였다. 여기에 base (T, U, 5-FU, 5-IU, C, A)을 붙여서 네프라노신 A derivatives를 합성하였다. 이어서 이 화합물들의 HIV-1, HSV-1, HSV-2, 및 HCMV 등 여러 가지 바이러스에 대한약효를 검색하였다. 그 결과 (22, 25, 42 와 43) 화합물이 HIV-1에 현저한 항바이러스효과를 나타내었다.|Nucleoside analogues play a major role in antiviral chemotherapy. Al- though interest in the design of these analogues has relatively decreased during the past few years, the emergence of resistance to drugs has generated new interest for search of new active nucleoside analogues. In view of these results, the novel phenyl branched cyclopropyl nucl- eoside analogues and acyclic Neplanocin A analogues were designed and synthesized as potential antiviral agents. Firstly, cyclopropanation was performed via classical Simmons-Smith reaction using Zn(Et)2 and CH2I2. Condensation of the mesylate 11 and 12 with natural base (A. C. T. U) under nucleophilic substitution reaction condition (K2CO3, 18-Crown-6, DMF) afforded a series of novel cyclop- ropyl nucleosides (21-28). Secondly, the coupling of the alkyl bromide 34 with nucleoside base (T. U. 5-FU. 5-IU. C. A) and desilylation afforded a series of novel acyclic nucleosides. The synthesized compounds were evaluated for their antiviral and antitumor activity against various viruses such as HIV, HSV-1, HSV-2 and HCMV.