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 |
|---|---|
| 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 |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude. / Choi, Yongseok; George, Clifford; Comin, Maria J.; Barchi, Joseph J.; Kim, Hak Sung; Jacobson, Kenneth A.; Balzarini, Jan; Mitsuya, Hiroaki; Boyer, Paul L.; Hughes, Stephen H.; Marquez, Victor E.
In: Journal of Medicinal Chemistry, Vol. 46, No. 15, 17.07.2003, p. 3292-3299.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude
AU - Choi, Yongseok
AU - George, Clifford
AU - Comin, Maria J.
AU - Barchi, Joseph J.
AU - Kim, Hak Sung
AU - Jacobson, Kenneth A.
AU - Balzarini, Jan
AU - Mitsuya, Hiroaki
AU - Boyer, Paul L.
AU - Hughes, Stephen H.
AU - Marquez, Victor E.
PY - 2003/7/17
Y1 - 2003/7/17
N2 - 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.
AB - 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.
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U2 - 10.1021/jm030116g
DO - 10.1021/jm030116g
M3 - Article
C2 - 12852759
AN - SCOPUS:0037479917
VL - 46
SP - 3292
EP - 3299
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -