STEREOSELECTIVE SYNTHESIS OF ISO-CARBOCYCLIC NUCLEOSIDE ANALOGUES AS POTENTIAL ANTIVIRAL DRUGS

ABSTRACT A series of iso-carbocyclic nucleoside analogues were prepared starting from a chiral cyclopentanol, by using a convergent approach. In the key step, an enantiomerically pure cyclopentanol was condensed with N3- protected pyrimidine nucleobases using a modified Mitsunobu protocol. INTRODUCTION Over the last few decades, carbocyclic nucleosides represent an attractive approach for the development of new antiviral drugs. Due to their hydrolytic and enzymatic stability in comparison to the natural nucleosides they show important biological properties. Carbocyclic nucleoside analogues like carbovir and entecavir were found to be potent inhibitors of HIV´s reverse transcriptase and recently the carbocyclic 2’- deoxythymidine analogue carba-dT has shown high in vitro activity against HIV replication (Fig.1). This compound shows a unique mechanism of inhibition termed delayed chain termination, resulting in the blocking of DNA synthesis.[ 1] Moreover, the synthesis of carba-iso-dT was reported. This isomer showed a 20-fold decrease of the antiviral activity (EC50 = 10 M) compared to carba-dT, but surprisingly without exhibiting any cytotoxicity.[2]On the basis of these results, the interest is directed to the investigation of new carbocyclic nucleosides against the hepatitis C virus (HCV), a RNA virus that uses a RNAdependent RNA-polymerase (RdRp) for the viral replication. The current standard treatment for HCV-infections is a combination of subcutaneous interferon- with oral admission of the nucleoside drug ribavirin. Because of the low response rates as well as toxic side effects, these therapies are inadequate. Moreover, there is no established vaccineagainst HCV and there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection. RESULTS AND DISCUSSION We report on the synthesis of a series of iso-carbocyclic nucleoside analogues as potential inhibitors of RdRp (Fig.2). A convergent approach was used for the synthesis, offering the formation of a variety of nucleoside analogues by the direct coupling of a cyclopentanol derivative and different heterocyclic bases. We decided to start from enantiomerically pure (1R,2S)- 2-(benzyloxymethyl)cyclopent-3-enol, which was used for the preparation of a cyclopentanol derivate. The coupling with N3-protected pyrimidine nucleobases under standard Mitsunobu conditions presented a critical step; unfortunately, the nucleobases react as ambident nucleophiles, leading to a mixture of N1- and O2-isomers. In order to maximizethe reaction yields and to control the regioselective coupling, different reactions conditions were tested [3] and the results will be presented. Figure 2. Structures of the new iso-carbocyclic nucleosides. CONCLUSION We successfully synthesized new iso-carbocyclic nucleoside analogues. These will be evaluated as potential antiviral compounds. REFERENCES 1. Boyer, P.L., Vu, B.C., Ambrose Z., Julias, J.G., Warnecke, S., Liao, C., Meier, C., Marquez, V.E., Hughes, S.H. J. Med. Chem. 2009, 52, 5356-5364. 2. Ludek, O.L., Krämer, T., Balzarini, J., Meier, C. Synthesis 2006, 8, 1313-1324. 3. Radi M., Rao J.R., Jha A.K, Chu C.K. Nucl. Nucl. &Nucl. Acids 2009, 28, 504–518.