A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude

Yongseok Choi, Clifford George, Maria J. Comin, Joseph J. Barchi, Hak Sung Kim, Kenneth A. Jacobson, Jan Balzarini, Hiroaki Mitsuya, Paul L. Boyer, Stephen H. Hughes, Victor E. Marquez

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)3292-3299
Number of pages8
JournalJournal of Medicinal Chemistry
Volume46
Issue number15
DOIs
Publication statusPublished - 2003 Jul 17
Externally publishedYes

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Stavudine
Anti-HIV Agents
Carbasugars
HIV Reverse Transcriptase
HIV-2
Poisons
Nucleosides
Structural analysis
Inhibitory Concentration 50
Conformations
HIV-1
1-(5-(hydroxymethyl)bicyclo(3.1.0)hex-3-en-2-yl)-5-methyl-1,3-dihydropyrimidine-2,4-dione
Molecules

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 journalArticle

Choi, Y, George, C, Comin, MJ, Barchi, JJ, Kim, HS, Jacobson, KA, Balzarini, J, Mitsuya, H, Boyer, PL, Hughes, SH & Marquez, VE 2003, 'A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude', Journal of Medicinal Chemistry, vol. 46, no. 15, pp. 3292-3299. https://doi.org/10.1021/jm030116g
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. / A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 15. pp. 3292-3299.
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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.

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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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