| Abstract
| - The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as aconformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturatedmethanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substitutedprecursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N3-benzoylthymineafforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N)hemisphere of the pseudorotational cycle but 70° away from a perfect N (P = 0°) conformationtoward the East and West hemispheres, respectively. Despite this large difference, the doublebond reduces the puckering amplitude (νmax) of N-MCD4T to 6.81°, and the superposition ofboth structures showed a RMS deviation of only 0.039 Å. The combined structural analysis ofP and νmax shows that while the value of P may differ substantially, the low νmax resolves thedifferences and becomes the dominant pseudorotational parameter. N-MCD4T is active againstHIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent thanD4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reversetranscriptase with a 10-fold higher IC50 than D4TTP. By virtue of its carbocyclic nature,N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.
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