Abstract
Since the discovery of 3′-azido-3′-deoxythymidine (AZT) as the first drug for the treatment of AIDS, considerable efforts have been made to develop new nucleoside analogues that would be more active, less toxic inhibitors of the HIV-1 reverse transcriptase. Many novel compounds have been synthesized and tested, with only one general criterion for selection: the absence of a 3′-hydroxy 1 group so that the triphosphate nucleotide can inhibit HIV-1 reverse transcriptase by acting as a chain terminator. The molecular structures and conformations of many of these compounds have been examined in efforts to determine if structural or conformational features of the molecules can be correlated with activity.11-33 However, the diversity of compounds that show at least some activity and the fact that apparently very similar compounds can have extremely different activities indicate that identification of a single or a few structural parameters that would be required for activity is unlikely. The variations in activity are at least partially caused by the presence of several alternative metabolic pathways for the phosphorylation of the nucleoside to generate the active triphosphate nucleotide.2 This limits the utility of the study of the nucleoside conformation in analyzing the interaction of the nucleotide with reverse transcriptase. However, it may be possible to determine conditions required for efficient phosphorylation of the nucleoside. An additional factor complicating the development of structure-activity relationships is the inherent conformational flexibility of the nucleoside.34 For most nucleosides, several low-energy conformations can be identified and are accessible over low barriers to rotation. This precludes conclusions from the crystal structure determination of a single nucleoside but requires analysis of structural and conformational properties of a large group of related compounds with different activities. Most studies have focused on the modification of the deoxyribose unit rather than comparison of compounds with different bases for three reasons: (1) certain modification of the deoxyribose ring has been associated with high activity; (2) the conformation of the furanose ring determines the accessibility of the O5′-hydroxyl group; and, (3) nucleosides with different bases are frequently phosphorylated by different kinases.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
H. Mitsuya, R. Yarchoan, R. Kageyama, and S. Broder, Targeted therapy of human immunodeficiency virus-related disease, FASEB J., 5:2369 (1991).
R.F. Schinazi, J.R. Mead, and P.M. Feorino, Insights into HIV chemotherapy, AIDS Res. Human Retroviruses, 8:963 (1992).
M. Nasr, C. Litterst and J. McGowan, Computer-assisted structure-activity correlations of dideoxynucleoside analogues as potential anti-HTV drugs, J. Antiviral Res., 14:125 (1990).
H. Mitsuya, R. Yarchoan and S. Broder, Molecular targets for AIDS therapy, Science, 249:1533 (1990).
C.K. Chu, R.F. Schinazi, B.H. Arnold, D.L. Cannon, B. Doboszewski, V.B. Bhadti, and Z.P. Gu, Comparative activity of 2′,3′-saturated and unsaturated pyrimidine and purine nucleosides against human immunodeficiency virus type 1 in peripheral blood mononuclear cells, Biochem. Pharmacol., 37:3543 (1988).
C.K. Chu, R.F. Schinazi, M.K. Ahn, G.V. Ullas and Z.P. Gu, Structure-activity relationships of pyrimidine nucleosides as antiviral agents for human immunodeficiency virus type 1 in peripheral blood mononuclear cells, J. Med. Chem., 32:612 (1989).
J. Balzarini, G.-J. Kang, M. Dalai, P. Herdewijn, E. De Clercq, S. Broder and D.G. Johns, The anti-HTLV-III (anti-HIV) and cytotoxic activity of 2′,3′-didehydro-2′,3′-dideoxyribonucleosides: a comparison with their parental 2′,3′-dideoxyribonucleosides, Mol. Pharmacol., 32:162 (1987).
T.-S. Lin, R.F. Schinazi and W.H. Prusoff, Potent and selective in vitro activity of 3′-deoxythymdine-2′-ene (3′-deoxy-2′,3′-didehydrothymidine) against human immunodeficiency virus, Biochem. Pharmacol., 36:2713 (1987).
M.M. Mansuri, J.E. Starrett Jr., I. Ghazzouli, M.J.M. Hitchcock, R.Z. Sterzycki, V. Brankovan, T.-S. Lin, E.M. August, W.H. Prusoff, J.-P. Sommadossi and J.C. Martin, 1-(2,3-dideoxy-ß-D-glyceropent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent, J. Med. Chem., 32:461 (1989).
J. Balzarini, R. Pauwels, P. Herdewijn, E. De Clercq, D.A. Cooney, G.J. Kang, M. Dalai, D.G. Johns and S. Broder, Potent and selective anti-HTLV-III/LAV activity of 2′,3′-dideoxycytidine, the 2′,3′-unsaturated derivative of 2′,3′-dideoxycytidine, Biochem. Biophys. Res. Commun., 140:735 (1986).
G.I. Birnbaum, T.-S. Lin and W.H. Prusoff, Unusual structural features of 2′,3′-dideoxycytidine, an inhibitor of the HIV (AIDS) virus, Biochem. Biophys. Res. Commun., 151:608(1988).
P. Van Roey, J.M. Salerno, C.K. Chu and R.F. Schinazi, Correlation between preferred sugar ring conformation and activity of nucleoside analogues against human immunodeficiency virus, Proc. Natl. Acad. Sci. USA, 86:3929 (1989).
P. Van Roey and C.K. Chu, unpublished.
C.K. Chu, V.S. Bhadti, B. Doboszewski, Z.P. Gu, Y. Kosugi, K.C. Pullaiah and P. Van Roey, General synthesis of 2′,3′-dideoxynucleosides and 2′,3′-didehydro-2′,3′-dideoxynucleosides, J. Org. Chem., 54:2217 (1989).
P. Van Roey, J.M. Salerno, W.L. Duax, C.K. Chu M.K. Ahn and R.F. Schinazi, Solid-state conformation of anti-human immunodeficinecy virus type-1 agents: crystal structures of three 3′-azido-3′-deoxythymidine analogues, J. Am. Chem. Soc., 110:2277(1988).
G.I. Birnbaum, J. Giziewicz, E.J. Gabe, T.-S. Lin and W.H. Prusoff, Structure and conformation of 3′-azido-3′-deoxythymidine (AZT), an inhibitor of the HIV (AIDS) virus, Can. J. Chem., 65:2135 (1988).
A. Camerman, D. Mastropaolo, D. and N. Camerman, Azidothymidine: crystal structure and possible functional role of the azido group, Proc. Natl. Acad. Sci. USA, 84:8239 (1987).
R. Parthasarathy and H. Kim, Conformation and sandwiching of bases by azido groups in the crystal structure of 3′-azido-3′-deoxythymidine (AZT), an antiviral agent that inhibits HIV reverse transcriptase, Biochem. Biophys. Res. Commun., 152:351 (1988).
I. Dyer, J.N. Low, P. Tollin, H.R. Wilson and R.A. Howie, Structure of 3′-azido-3′-deoxythymidine, AZT, Acta Cryst. Ser. C, 44:767 (1988).
G.V. Gurskaya, E.N. Tsapkina, N.V. Skaptsova, A.A. Kracvskii, S.V. Lindeman and Y.T. Struchkov, Dokl. Akad. Nauk SSSR, 291:854 (1986).
J.N. Low and R.A. Howie, Structure of 3-(3-azido-2,3-dideoxy-ß-D-erythro-pentofuranosyl)cytosine hydrogen choloride, Acta Cryst. Ser. C, 46:84 (1990).
P. Van Roey and R.F. Schinazi, The crystal and molecular structure of 3′-fluoro-3′-deoxythymidine, a potent anti-HIV-1 nucleoside, Antiviral Chem. Chemother., 1:93(1990).
G.V. Gurskaya and E.N. Tsapkina, Dokl. Akad. Nauk. SSSR, 303:1378 (1988).
C.K. Chu, B. Doboszewski, W. Schmidt, G.V. Ullas and P. Van Roey, Synthesis of pyrimidine 3′-allyl-2′,3′-dideoxyribonucleosides by free-radical coupling, J. Org. Chem., 54:2767 (1989).
P. Van Roey, E.W. Taylor, C.K. Chu, and R.F. Schinazi, Conformational analysis of 2′,3′-didehydro-2′,3′-dideoxypyrimidine nucleosides, J. Am. Chem. Soc., in press.
W.E. Harte Jr., J.E. Starrett Jr., J.C. Martin and M.M. Mansuri, Structural studies of the anti-HTV agent 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T), Biochem. Biophys. Res. Comm., 175:298 (1991).
G.I. Birnbaum, J. Giziewicz, T.-S. Lin, and W.H. Prusoff, Structural features of 2′,3′-dideoxy-2′,3′-didehydrocytidine, a potent inhibitor of the HIV (AIDS) virus, Nucleosides Nucleotides, 8:1259 (1989).
P. Van Roey and C.K. Chu, The crystal and molecular structure of the complex of 2′,3′-didehydro-2′,3′-dideoxyguanosine with pyridine, Nucleosides Nucleotides, 11:1229 (1992).
H.O. Kim, S.K. Ahn, A J. Alves, J.W. Beach, L.S. Jeong, B.G. Choi, P. Van Roey, R.F. Schinazi and C.K. Chu, Asymmetric synthesis of 1,3-dioxolane-pyrimidine nucleosides and their anti-HIV activity, J. Med. Chem., 35:1987 (1992).
C.K. Chu, S.K. Ahn, H.O. Kim, J.W. Beach, A.J. Alves, L.S. Jeong, Q. Islam, P. Van Roey and R.F. Schinazi, Asymmetric synthesis of enantiomerically pure (-)-(1’R,4’R)-dioxolane-thymidine and its anti-HIV activity, Tetrahedron Lett., 32:3791 (1991).
D.W. Norbeck, S. Spanton, S. Broder and H. Mitsuya, A new 2′,3′-dideoxynucleoside prototype with in vitro activity against HIV, Tetrahedron Lett., 30:6263 (1989).
E.W. Taylor, P. Van Roey, R.F. Schinazi and C.K. Chu, A stereochemical rationale for the activity of anti-HIV nucleosides, Antiviral Chem. Chemother., 1:163 (1990).
P. Van Roey, E.W. Taylor, C.K. Chu and R.F. Schinazi, Correlation of molecular conformation and activity of reverse transcriptase inhibitors, Ann. N. Y. Acad. Sci., 616:29 (1990).
W. Saenger, “Principles of Nucleic Acid Structure”, Springer-Verlag, New York, (1984).
L.H. Koole, S. Neidle, M.D. Crawford, A.A. Krayevski, G.V. Gurskaya, A. Sandstroem, J.-C. Wu, W. Tong and J. Chattopadhyaya, Comparative structural studies of [3.1.0]-fiised 2′,3′-modified ß-D-nucleosides by X-ray crystallography, NMR spectroscopy, and molecular mechanics calculations, J. Org. Chem., 56:6884(1991).
V.E. Marquez, C.K.-H. Tseng, J.A. Kelley, H. Mitsuya, S. Broder, J.S. Roth and J.S. Driscoll, 2′,3′-dideoxy-2′-fluoro-ara-A. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV), Biochem. Pharmacol., 36:2719 (1987).
M. Sundaralingam, in: “Structure and Conformation of Nucleic Acid and Protein-Nucleic Acid interactions” M. Sundaralingam and S.T. Rao, eds. 487–536, University Park Press, Baltimore, MD (1975).
D. Pearlman and S.-H. Kim, Conformational studies of nucleic acids. II. The conformational energetics of commonly occuring nucleosides, J. Biomol. Ster. Dynam., 3:99 (1985).
G.I. Birnbaum and D. Shugar, Biologically active nucleosides and nucleotides: conformational features and interactions with enzymes, in: “ Nucleic Acid Structure”, S. Neidle, ed., Part 3,1, VCH, New York (1987).
A.L. Spek, 1992 American Crystallographic Association Meeting, Pittsburgh, PA, Abstract J05 (1992).
W.K. Olson, How flexible is the furanose ring? II. An updated potential energy estimate, J. Am. Chem. Soc., 104:278 (1982).
C.K. Johnson, ORTEP-II, Report ORNL-5138 (Oak Ridge Natl. Lab., Oak Ridge, TN) (1976).
J.W. Beach, L.S. Jeong, AJ. Alves, D. Pohl, H.O. Kim, C.-N. Chang, S.-L. Doong, R.F. Schinazi, Y.-C. Cheng and C.K. Chu, Synthesis of enantiomerically pure (2′R,5′S)-(-)-l-[2-(hydroxymethyl)oxothiolan-5-yl]cytosine as a potent antiviral agent against hepatitis B virus (HBV) and human immunodeficiency virus (HIV) J. Org. Chem., 57:2217 (1992).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer Science+Business Media New York
About this chapter
Cite this chapter
Van Roey, P., Chu, C.K. (1993). Crystal Structures and Molecular Conformations of Anti-HIV Nucleosides. In: Chu, C.K., Baker, D.C. (eds) Nucleosides and Nucleotides as Antitumor and Antiviral Agents. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2824-1_15
Download citation
DOI: https://doi.org/10.1007/978-1-4615-2824-1_15
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6221-0
Online ISBN: 978-1-4615-2824-1
eBook Packages: Springer Book Archive