Solid-State Conformation of Anti-Human Immunodeficiency Virus Type-1 Agents: Crystal Structures of Three 3′-Azido-3′-deoxythymidine Analogues

The crystal structures of three anti-HIV 3′-azido-3′-deoxynucleosides have been determined to gain conformational information for structure-activity studies. The compounds 3′-azido-3'-deoxythymidine (AZT), 3'-azido-2',3'-dideoxyuridine (CS-87), and 3'-azido-2',3'-dideoxy-5-ethyluridine (CS-85) are all active inhibitors of HIV-1 replication. X-ray diffraction data for all three compounds were measured at 165 K. AZT: P2_1,a = 17.538 (1) Å, b = 12.021 (1) Å, c = 5.6435 (3). Å, β = 95.596 (8)°, Z = 4, R_a11 = 0.038. CS-87: P2₁, a = 9.7314 (8) Å, b = 6.7517 (6) Å, c = 8.3464 (7), Å, β = 91.854 (7)°, Z = 2, R_a11 = 0.046. CS-85: P2₁a = 5.567 (5) Å, b = 22.093 (9) Å, c = 21.149 (4) Å, β = 96.005 (9)°, Z = 8, R_a11= 0.036. Large differences are observed in the conformations of the seven independent observations, including four different conformations for the glycosyl link and three furanose ring geometries. The azido group is nonlinear and has a preferred conformation trans to the C2′-C3′ bond (four molecules). The azido group of one CS-85 molecule is disordered. Two positions, cis to C2′-C3′ and 26° from this position, are fully resolved. The three structures show extensive but distinct hydrogen-bonding patterns that include two different base-pairing geometries. AZT has one dimer formed by two molecules bonded by N3-02 hydrogen bonds. CS-85 has two dimers, one based on N3-02 hydrogen bonds and one based on N3-04 hydrogen bonds. The structure of CS-87 does not show base pairing but rather linear strands of molecules hydrogen bonded through the bases. The 5'-hydroxyl groups form additional strong hydrogen bonds with either the remaining carbonyl oxygens or 4' ether oxygens. Strong correlations between intramolecular conformational differences and intermolecular interactions are observed. Variations in the positions of the furanose ring substituents correlate not only with differences in the geometry of the ring but also with differences in base-pairing geometries. These correlations would suggest a long-range effect of the furanose substitution on the interactions of the bases.