SOLID-STATE AND SOLUTION CONFORMATIONS OF THE POTENT HIV INHIBITOR, 4'-AZIDOTHYMIDINE

The three-dimensional structure of 4'-azidothymidine has been determined for the solid state and in solution. X-ray crystal analysis indicates the presence of two independent molecules (A and B) having the following conformational parameters: Phase angles, P-A = 13.7 degrees, P-B = 12.6 degrees (C3'-endo envelope); puckering amplitude Psi(MA) = 32.4 degrees, Psi(MB) = 37.2 degrees; glycosyl torsion angle (chi A) = -88.2 degrees, (chi B) = -71.2 degrees; 4'-5' torsion angle (gamma A) = 58.5 degrees, (gamma B) = 36.0 degrees. The solution conformation was determined from NMR coupling constants in D2O. Analysis using the computer programs PSEUROT and DAERM yielded phase angles (P) of 53.2 degrees (C4'-exo envelope) (major conformer) and 63 degrees (C4'-exo envelope), respectively, with corresponding puckering amplitudes (Psi(M)) of 34.9 degrees and 45.8 degrees. A gated C-13 NMR experiment was used to determined the H-1-C-13 vicinal coupling constants used to calculate the solution glycosyl torsion angle ((chi)) to be either -80 degrees or -160 degrees and a 4'-5' torsion angle, gamma, of ca. 180 degrees. These studies show that 4'-azidothymidine is conformationally exceptional among the antiretroviral nucleosides both as a solid and in solution. The C3'-endo (northern) conformation determined by X-ray crystallography is rare among HIV-inhibitory nucleosides which usually exist in the solid state in a southern conformation. The solution structure is even more peculiar in that it exists in the extremely rare 4'-exo envelope conformation.