Construction of an isonucleoside on a 2,6-dioxobicyclo[3.2.0]-heptane skeleton.

Yuichi Yoshimura,Satoshi Kobayashi,Hitomi Kaneko,Takeshi Suzuki,Tomozumi Imamichi

doi:10.3390/molecules20034623

Abstract

We have built a new isonucleoside derivative on a 2,6-dioxobicyclo[3.2.0]heptane skeleton as a potential anti-HIV agent. To synthesize the target compound, an acetal-protected dihydroxyacetone was first converted to a 2,3-epoxy-tetrahydrofuran derivative. Introduction of an azide group, followed by the formation of an oxetane ring, gave a pseudosugar derivative with a 2,6-dioxobicyclo[3.2.0]heptane skeleton. The desired isonucleoside was obtained by constructing a purine base moiety on the scaffold, followed by amination.

Highlights

Since the discovery of 3'-azidothymidine (AZT), much attention has been paid to the development of effective chemotherapeutic agents against the human immunodeficiency virus (HIV), a causative agent for AIDS [1,2]
We have been focusing on the design and synthesis of nucleoside derivatives attached to a pseudosugar scaffold [10,11,12,13,14,15,16,17]
Since our initial attempt to synthesize 6 by directly introducing the adenine moiety was not successful, we synthesized it by the de novo synthesis of an adenine ring on a pseudosugar moiety

Summary

Introduction

Since the discovery of 3'-azidothymidine (AZT), much attention has been paid to the development of effective chemotherapeutic agents against the human immunodeficiency virus (HIV), a causative agent for AIDS [1,2]. From the viewpoint of designing new anti-HIV agents, nucleosides constructed on a novel scaffold are expected to have antiviral activity against the resistant virus strains and may avoid cross-resistance to the known NRTIs. we have been focusing on the design and synthesis of nucleoside derivatives attached to a pseudosugar scaffold [10,11,12,13,14,15,16,17]. We planned to build isonucleoside 6 on a 2,6-dioxobicyclo[3.2.0]heptane skeleton, an analogue of dioxolane nucleoside 5 which exhibited potent anti-HIV activity [18,19,20]. The similar conformationally-restricted analogue of d4T was known: cyclopropane-fused carbocyclic d4T (N-MCd4T), fixed in north conformation, was originally reported by Marquez and his colleagues and had significant anti-HIV activity with lesser cytotoxicity [21]. Isonucleoside 6 should be promising the thietane-fused derivative 4 was inactive (Figure 3)

Results and Discussion

Experimental Section

Conclusions