STRUCTURAL-ANALYSIS OF 2',3'-DIDEOXYINOSINE, 2',3'-DIDEOXYADENOSINE, 2',3'-DIDEOXYGUANOSINE AND 2',3'-DIDEOXYCYTIDINE BY 500-MHZ H-1-NMR SPECTROSCOPY AND ABINITIO 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 ddl (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: P(N) = 0.1-degrees, P(S) = 161-degrees and psi(m) = 34.1-degrees for ddI (1); P(N) = 1.4-degrees, P(S) = 160-degrees and psi(m) = 34.2-degrees for ddA (2) and P(N) = 2.4-degrees, P(S) = 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 ddl (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 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. A van 't Hoff plot of (ln (%S/%N)) as a function of reciprocal of temperature shows a clear straight line through all seven observed data points for each of 2',3'-dideoxynucleosides (1-4). Note that this van 't Hoff plot gave the thermodynamics of the North and South conformational states of the pentofuranose moiety. The slope of the curve gave the values for enthalpies (DELTAH) for ddI (1), ddA (2), ddG (3) and ddC (4) which are 5.5, 4.1, 4.2 and 6.9 kJ/mol, respectively; corresponding values for entropies (AS) derived from the point of interception on the ordinate are 8.2, 5.2, 5.2 and 12.7 J/mol K, respectively. Finally, independent ab-initio MO studies (GAUSSIAN 92) on the conformation of ddl (1) have been performed using HF/3-21G level of theory. Results of these MO calculations have been compared with the experimental NMR data which show excellent agreement.