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tains 15 L-leucine residues it is both sufficiently hydrophobic to be incorporated in lipid bilayers[41 and favors u-helical conformation. ['] In this form the crown ether rings in I are perfectly aligned (Figure 1). Herein we present the results of studies on the conformation of 1 and its incorporation in planar C.

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MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine) is a novel nucleoside analog that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved NRTIs. Herein, we describe our recent efforts to explore the impact of structural changes to the properties of MK-8591 through the synthesis and antiviral evaluation of carbocyclic derivatives. Synthesized analogs were evaluated for their antiviral activity, and the corresponding triphosphates were synthesized and evaluated in a biochemical assay. 4′-Ethynyl-G derivative (±)-29 displayed a promising IC 50 of 33 nM in a hPBMC cell-based antiviral assay, and its triphosphate (TP), (±)-29-TP, displayed an IC 50 of 324 nM in a biochemical RT-polymerase assay. Improved TP anabolite delivery resulting in improved in vitro potency was achieved by preparing the corresponding phosphoramidate prodrug of single enantiomer 29b, with 6-ethoxy G derivative 34b displaying a significantly improved IC 50 of 3.0 nM, paving the way for new directions for this novel class of nucleoside analogs.