Conformational Studies of Novel Antiretroviral Analogs of Zidovudine

Abstract

Conformational properties of three novel zidovudine analogs, namely 3′-azido-3′-deoxy-5′-O-isonicotinoylthymidine (AZT-Iso, 2), (−)-trans-(5S,6S)-5-bromo-6, 5′-epoxy-5,6-dihydro-3′-azido-3′-deoxythymidine (3) and (+)-trans-(5R,6R)-5-bromo-6,5′-epoxy-5,6-dihydro-3′-azido-3′-deoxythymidine (4), have been investigated by AM1 calculations and NMR studies, and compared with those of the parent nucleoside (AZT, 1). Based on the results obtained the following correlation may be established, a) AZT and AZT-Iso exhibit a conformational behavior analog to other pyrimidinic nucleosides, displaying a dynamic equilibrium in solution where the two conformers (North and South) undergo a constant transformation. b) Compounds 3 and 4 show a different conformational profile. The estimate of the pseudorotation phase angle reveals the rigid structures of the latter compounds, which do not evidence conformational equilibrium in solution; theazide group being the only group free to rotate. c) Diastereoisomers 3 and 4 exhibit an extra conformational parameter compared with other pyrimidinic nucleosides: the chair or boat conformation in the third ring formed between the sugar and the base. In all cases, a reasonable correlation was obtained between theoretical and NMR spectroscopic data.

Keywords:

• Antiretroviral analogs
• Novel AZT derivatives
• Conformational analysis
• AM1 calculations
• NMR studies

Acknowledgments

The authors thank the Agencia Córdoba Ciencia, the Agencia Nacional de Promoción Científica y Tecnológica (FONCyT), the Secretaria de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECyT-UNC), the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina, and Fundación Antorchas for financial support. The authors also wish to express their sincere thanks to Dra. L. Alassia (FILAXIS Laboratories, Buenos Aires, Argentina) for supplying zidovudine, Dr. C. Altona (State University Leiden, Gorlaeus Laboratories, The Netherlands) for PSEUROT calculations, and Dr. V. J. Kowalesky for recording NMR spectra in a 500 MHz apparatus (LANAIS RMN500).