The development of nucleoside analogues with novel mechanisms of action capable of overcoming HIV resistance is the main focus of this project. Current emphasis include two main classes of structures: 1) 4'-Ethynyl-2',3'-dideoxynucleosides. While the first target made, (+/-)-1-(2',3'-dideoxy-4-C-ethynyl-ribopentofuranosyl)cytosine, was inactive in cell culture, the 5'-triphosphate was a potent inhibitor of HIV reverse transcriptase (RT) in vitro. Lipase-catalyzed resolution revealed that the D-enantiomer with the natural configuration was the more potent compound. The less potent L-enantiomer lost all activity against the M184V mutant while the D-enantiomer retained activity. The ability of HIV RT to discriminate between 5'-triphosphate enantiomeric substrates is seen only in very few instances. The chiral synthesis of the active (2R,5R)-6-Amino-3-[5-ethynyl-5-(hydroxymethyl)oxolan-2-yl]-3-hydropyrimidin-2-one enantiomer is nearly completed and plans to explore other nucleobases, particularly purines, are underway with the aim of synthesizing pro-drugs suitable to by-pass the first kinase activation. 2) 2',3'-Dideoxybicyclo[3.1.0]hexene nucleosides. In this family of conformationally locked analogues we have identified N-MCD4T as a very effective anti-HIV agent. The corresponding guanosine analogue, structurally similar to carbovir, was inactive. Similarly, the isomeric S-MCD4T was also inactive. Current synthetic studies are directed to the understanding of the differences between these North (N) and South (S) families at the molecular level.
