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Keywords:

dideoxynucleosides, 2'-substituted, 2'-azt, activity anti-hiv, aids, solid state conformation, human immunodeficiency virus, anti-hiv agents, 2',3'-dideoxynucleoside analogs, htlv-iii/lav, inhibitors, invitro, 3'-fluoro-2',3'-dideoxy-5-chlorouridine, 3'-azido-3'-deoxythymidine, derivatives, infectivity, Antiviral Agents, Crystallography, Dideoxynucleosides, HIV, Humans, Molecular Structure, Structure-Activity Relationship, Virus Replication, X-Ray Diffraction, Zidovudine, Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, Virology, DIDEOXYNUCLEOSIDES, 2'-SUBSTITUTED, 2'-AZT, ACTIVITY ANTI-HIV, AIDS, SOLID STATE CONFORMATION, HUMAN IMMUNODEFICIENCY VIRUS, ANTI-HIV AGENTS, 2',3'-DIDEOXYNUCLEOSIDE ANALOGS, HTLV-III/LAV, INHIBITORS, INVITRO, 3'-FLUORO-2',3'-DIDEOXY-5-CHLOROURIDINE, 3'-AZIDO-3'-DEOXYTHYMIDINE, DERIVATIVES, INFECTIVITY, In Vitro Techniques, 0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology and Pharmaceutical Sciences, 3107 Microbiology, 3207 Medical microbiology, 3214 Pharmacology and pharmaceutical sciences

Abstract:

1-(2-Azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl) thymine (2'-NN3ddThd) was synthesized from 1-(5-O-trityl-2,3-anhydro-beta-D-lyxofuranosyl) thymine by two different procedures. Method A prepared the title compound by opening of the oxirane ring with LiEt3BH followed by mesylation of the 2'-hydroxyl function, introduction of the 2'-azido substituent and deblocking of the 5'-function. In method B nucleophilic opening of 3'-deoxy-5'-O-(tert-butyldimethylsilyl)-5-methyl-2,2'-anhydrouridine was carried out with sodium azide in hexamethylphosphoramide in the presence of benzoic acid. Single X-ray crystallographic studies indicated a solid state conformation (3T2), which was opposite to that of the A form of AZT (2T3) but closely resemble that of 1-(2-fluoro-2,3-dideoxy-beta-D-ery thropentofuranosyl)thymine (2'FddThd) (3T2) and of 3'-azido-2',3'-dideoxy-2,6-diaminopurine riboside (3'-N3ddDAP) (3T2). Whereas the latter displayed significant inhibitory activity against human immunodeficiency virus (HIV) replication, 2'-FddThd and 2'-N3ddThd were essentially inactive.