Synthesis of sugar-modified derivatives of the unusual nucleoside oxanosine and its carbocyclic analogs as potential inhibitors of HIV

摘要

Since the first description of AIDS (Acquired ImmunodeficiencynSyndrome) in 1981 and the discovery of the causativenagent, the human immunodeficiency virus (HIV), there hasnbeen intense research aimed at identifying substances effectivenagainst HIV. The drugs currently approved for the clinicalntreatment of AIDS and AIDS-related complex are AZT,nddI, ddC, d4T, (u0001)-3TC and 1592U89 (avacavirTM). However,nthe discovery of both clinical resistance and the expression ofntoxicity toward the used agents has emerged as a major concernnwith the effectiveness of long-term treatment. Thus, there is stillna need for a potent and safer drug to treat HIV infections alonenor in combination with other antiviral agents. Oxanosine 1,na novel guanosine analog antibiotic isolated from the culturenbroth of Streptomyces capreolus MG265-CF3, has beennreported to show antibacterial activity and to inhibit growth ofnHeLa cells in culture.2,3 Furthermore, 1 has been shown to alterntumor cell morphology into the normal morphology inntemperature-sensitive K-ras transformed rat kidney (K-rasts-nNRK) cells by inhibiting inosine monophosphate (IMP)ndehydrogenase.4nHowever, the antiviral effect of oxanosine has not yet beenninvestigated. In the search for effective, selective and nontoxicnantiviral agents, a variety of strategies have been devised tondesign nucleoside analogs. These strategies have involvednseveral formal modifications of the naturally occurring nucleosides,nespecially, alteration of the carbohydrate moiety. ThenFig. 1nsugar modifications make certain nucleosides acid stable andnincrease the metabolic stability by making them more resistantnto hydrolysis by adenosine deaminase, as well as resistantnto degradation by purine nucleoside phosphorylase. For anstructure–activity relationship study, as well as for the purposenof finding new anti-HIV agents, we set ourselves toward thensynthesis of a series of derivatives of oxanosine 1 and carbocyclicnoxanosine 2 (Fig. 1) starting from natural oxanosin