Abstract
The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N3-benzoylthymine afforded 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°) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (νmax) of N-MCD4T to 6.81°, and the superposition of both structures showed a RMS deviation of only 0.039 Å. The combined structural analysis of P and νmax shows that while the value of P may differ substantially, the low νmax resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase 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.
Original language | English |
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Pages (from-to) | 3292-3299 |
Number of pages | 8 |
Journal | Journal of Medicinal Chemistry |
Volume | 46 |
Issue number | 15 |
DOIs | |
Publication status | Published - 2003 Jul 17 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery