Dideoxynucleosides as Potential Anti-AIDS Drugs

Basic Sciences

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Abstract

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.