Structural analysis of 2',3'-dideoxyinosine, 2',3'-dideoxyadenosine, 2',3'-dideoxyguanosine and 2',3'-dideoxycytidine by 500-MHz 1H-NMR spectroscopy and ab-initio molecular orbital calculations.

Solution structure of anti-AIDS drug, 2',3'-dideoxyinosine (ddI) has been assessed by NMR spectroscopy and pseudorotational analysis in conjunction with its analogues: 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG) and 2',3'-dideoxycytidine (ddC). The absence of 3'-hydroxyl groups in these compounds has prompted us to establish the relationship between proton-proton and corresponding endocyclic torsion angles in the 2',3'-dideoxyribofuranose moiety on the basis of five available crystal structures of 2',3'-dideoxynucleosides. A subsequent pseudorotational analysis on ddI (1), ddA (2), ddG (3) and ddC (4) shows that the twist C2'exo-C3'-endo forms of sugar are overwhelmingly preferred (75-80%) over the C2'-endo envelope forms. The phase angles (P) for North and South conformers with the corresponding puckering amplitude (psi m) for ddI (1), ddA (2) and ddG (3) are as follows: PN = 0.1 degrees, PS = 161 degrees and psi m = 34.1 degrees for ddI (1); PN = 1.4 degrees, PS = 160 degrees and psi m = 34.2 degrees for ddA (2) and PN = 2.4 degrees, PS = 163 degrees and psi m = 33.6 degrees for ddG (3). The predominant North conformer of ddC (4) is intermediate between twist C2'-exo-C3'-endo and C3'-endo envelope (P = 10.9 degrees) with a psi m of 34.7 degrees. Note that these preponderant North-sugar structures (approx. 75-80%) found in the solution studies of ddI (1), ddA (2), dG (3) and ddC (4) are not reflected in the X-ray crystal structures of 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine. The constituent sugar residues in both of these crystal structures denosine and 2',3'-dideoxycytidine. The constituent sugar residues in both of these crystal structures are found to be in the South-type geometry (ddA crystalizes in C3'-exo envelope form, while ddC adopts the form intermediate between the C3'-exo envelope and C3'-endo-C4'-exo twist form). This means that X-ray structures of ddA (2) and ddC (4) only represent the minor conformer of the overall pseudorotamer population in solution. An assumption that the structure of the pentofuranose sugar (i.e. P and psi m) participating in conformational equilibrium described by the two-state model remains unchanged at different temperatures has been experimentally validated by assessing five unknown pseudorotational parameters with eight unique observables (3J1'2', 3J1'2", 3J2'3', 3J2'3", 3J2"3', 3J2"3", 3J3'4' and 3J3"4') for 2',3'-dideoxynucleosides.(ABSTRACT TRUNCATED AT 400 WORDS)

[1]  Cornelis Altona,et al.  Empirical Correlations Between Conformational Parameters in β‐D‐Furanoside Fragments Derived from a Statistical Survey of Crystal Structures of Nucleic Acid Constituents Full Description of Nucleoside Molecular Geometries in Terms of Four Parameters , 1980 .

[2]  F. D. Leeuw,et al.  The relationship between proton-proton NMR coupling constants and substituent electronegativities—I : An empirical generalization of the karplus equation , 1980 .

[3]  W. Prusoff,et al.  Unusual structural features of 2',3'-dideoxycytidine, an inhibitor of the HIV (AIDS) virus. , 1988, Biochemical and biophysical research communications.

[4]  William L. Duax,et al.  Solid-state conformation of anti-human immunodeficiency virus type-1 agents: Crystal structures of three 3'-azido-3'-deoxythymidine analogs , 1988 .

[5]  M. Sundaralingam,et al.  Conformational analysis of the sugar ring in nucleosides and nucleotides. Improved method for the interpretation of proton magnetic resonance coupling constants. , 1973, Journal of the American Chemical Society.

[6]  E. De Clercq,et al.  3'-substituted 2',3'-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. , 1987, Journal of medicinal chemistry.

[7]  H. Mitsuya,et al.  Potential anti-AIDS drugs. 2',3'-Dideoxycytidine analogues. , 1987, Journal of medicinal chemistry.

[8]  W. Prusoff,et al.  Structure and conformation of 3′-azido-3′-deoxythymidine (AZT), an inhibitor of the HIV (AIDS) virus , 1987 .

[9]  S. Larson,et al.  Synthesis of 2′,3′-Dideoxyribavirin , 1987 .

[10]  B. Jagannadh,et al.  1H NMR study of the sugar pucker of 2',3'-dideoxynucleosides with anti-human immunodeficiency virus (HIV) activity. , 1991, Biochemical and biophysical research communications.

[11]  A. Katritzky,et al.  Ab initio and semiempirical calculations on the tautomeric equilibria of N-unsubstituted and N-substituted benzotriazoles , 1990 .

[12]  Warren J. Hehre,et al.  AB INITIO Molecular Orbital Theory , 1986 .

[13]  M. Sundaralingam,et al.  Conformational analysis of the sugar ring in nucleosides and nucleotides. A new description using the concept of pseudorotation. , 1972, Journal of the American Chemical Society.

[14]  Ernst Anders,et al.  A MO theoretical study on the rearrangements of 1-hyroxy- and 1-(acyloxy)-1,2,3-triazoles and their benzotriazole analogues : comparison of ab initio and semiempirical calculations , 1992 .

[15]  L. Vrang,et al.  An analysis of the inhibition of replication of HIV and MuLV by some 3'-blocked pyrimidine analogs. , 1989, Biochemical pharmacology.

[16]  P. Roey,et al.  General syntheses of 2',3'-dideoxynucleosides and 2',3'-didehydro-2',3'-dideoxynucleosides , 1989 .

[17]  J. C. Martin,et al.  Structural studies of the anti-HIV agent 2',3'-didehydro-2',3'-dideoxythymidine (D4T). , 1991, Biochemical and biophysical research communications.

[18]  C. Altona,et al.  Through‐Space effects on vicinal proton spin–spin coupling constants mediated via hetero atoms: Nonequivalence of cis couplings in five‐membered rings , 1983 .

[19]  F. D. Leeuw,et al.  The relationship between proton–proton NMR coupling constants and substituent electronegativities. II—conformational analysis of the sugar ring in nucleosides and nucleotides in solution using a generalized Karplus equation , 1981 .

[20]  J. Plavec,et al.  Structural studies of anti-HIV 3′-(α-fluorothymidine & 3′-(α-azidothymidine by 500 MHz 1H-NMR spectroscopy & molecular mechanics (MM2) calculations , 1991 .

[21]  E. De Clercq,et al.  Investigations on the anti-HIV activity of 2',3'-dideoxyadenosine analogues with modifications in either the pentose or purine moiety. Potent and selective anti-HIV activity of 2,6-diaminopurine 2',3'-dideoxyriboside. , 1988, Biochemical pharmacology.

[22]  L. Vrang,et al.  Inhibition of the reverse transcriptase from HIV by 3'-azido-3'-deoxythymidine triphosphate and its threo analogue. , 1987, Antiviral research.

[23]  L. Vrang,et al.  Different patterns of inhibition of avian myeloblastosis virus reverse transcriptase activity by 3'-azido-3'-deoxythymidine 5'-triphosphate and its threo isomer , 1987, Antimicrobial Agents and Chemotherapy.

[24]  J. Chermann,et al.  Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). , 1983, Science.

[25]  Transition Structures of Hydrocarbon Pericyclic Reactions , 1992 .

[26]  C. Altona,et al.  Conformational analysis of the deoxyribofuranose ring in DNA by means of sums of proton-proton coupling constants: a graphical method. , 1987, Journal of biomolecular structure & dynamics.

[27]  R. Parthasarathy,et al.  Conformation and sandwiching of bases by azido groups in the crystal structure of 3'-azido-3'-deoxy-thymidine (AZT), an antiviral agent that inhibits HIV reverse transcriptase. , 1988, Biochemical and biophysical research communications.