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, 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.
Maag
H
H
Institute of Bio-Organic Chemistry, Syntex Discovery Research, Palo Alto, California 94304.
Nelson
J T
JT
Steiner
J L
JL
Prisbe
E J
EJ
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006678:HIV / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013237:Stereoisomerism; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; C072200:4'-azidothymidine; D015215:Zidovudine