METHYLENECYCLOPROPANE ANALOGS AND PRODRUGS FOR HCMV

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Selected 6-amino- and 2-amino-6-substituted purine Z- methylenecyclopropane nucleoside analogues (mostly S-enantiomers) will be prepared for biological evaluation as potential drugs against human cytomegalovirus (HCMV). New 2,6-disubstituted purine methylenecyclopropanes will be synthesized for studies of structure- activity relationships. Several types of prodrugs of enantiomeric Z- methylenecyclopropane analogues will also be prepared for a detailed in vitro and in vivo evaluation. The major aim of the project is to provide multigram quantities of analogues in enantiopure form (lipophilic phosphate prodrugs as two diastereoisomers each) to permit (i) their evaluation in vitro against wild type and mutated forms of cytomegalovirus (CMV), (ii) in vivo studies in animals infected with CMV, (iii) investigation of cross-resistance with current drugs and (iv) studies of mechanism of action of these analogues. These studies are relevant for preclinical development of methylenecyclopropane analogues of nucleosides as anti-HCMV drugs.