Synthesis and biological evaluation of nucleosides containing 8‐amino‐imidazo[1,2‐α]pyrazine as an isosteric replacement for adenine

Abstract

AbstractA number of novel C‐nucleosides related to purine derivatives are described in which the purine moiety has been replaced by the isosteric heterocycle, 8‐aminoimidazo[1,2‐α]pyrazine. The nucleosides prepared include the ribo, 3′‐deoxy, 2′,3′‐dideoxy, and 2′,3′‐unsaturated derivatives. These C‐nucleosides represent derivatives containing acid stable glycosyl bonds and they can be considered as analogs of adenine‐ or 3‐deazaade‐nine‐containing nucleosides. Preparation of the parent ribonucleoside was accomplished by reaction of the C‐l functionalized sugar, (2ξ)‐1‐amino‐3,6‐anhydro‐l‐deoxy‐4,5‐O‐isopropylidene‐7‐O‐trityl‐D‐allo‐heptitol with 2,3‐dichloropyrazine, followed by ring closure to the 8‐chloroimidazo[1,2‐α]pyrazine nucleoside, conversion to the 8‐amino derivative and deblocking. A single crystal X‐ray structure of the parent 8‐amino‐3‐(β‐D‐ribofuranosyl)imidazo[1,2‐α]pyrazine is described and the conformation compared to that of formycin. The sugar‐modified analogs were prepared by subsequent functional group manipulations on the sugar moiety. Biological evaluation against HIV in H9 T‐lymphoid cell culture showed the nucleosides to be devoid of significant antiviral activity compared to DDA. The 3‐deazaadenosine analog also demonstrated weak suppression of mouse splenic NK activity toward YAC cells (mouse lymphoma cell targets). The imidazo[1,2‐α]pyrazine analog of 3‐deazaadenosine showed antiinflammatory activity in vivo in the rat pleurisy carrageenan model in the same range with 3‐deazaadenosine.