Solid-State and Solution Conformations of the Potent HIV Inhibitor, 4'-Azidothymidine

• Published in: Journal of medicinal chemistry 1994-02, Vol.37 (4), p.431-438
• Main Authors: Maag, Hans, Nelson, Janis T, Steiner, Jorge L. Rios, Prisbe, Ernest J
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Atomic and molecular physics; Conformation (statistics and dynamics); Crystallography, X-Ray; Exact sciences and technology; General molecular conformation and symmetry; stereochemistry; HIV - drug effects; human immunodeficiency virus; Macromolecules and polymer molecules; Magnetic Resonance Spectroscopy; Molecular Conformation; Physics; Stereoisomerism; Studies of special atoms, molecules and their ions; clusters; Zidovudine - analogs & derivatives; Zidovudine - chemistry; Zidovudine - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00030a001

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, PA = 13.7 degrees, PB = 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 13C NMR experiment was used to determine the 1H-13C 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.