2'-Azido-2',3'-dideoxythymidine: synthesis and crystal structure of a 2'-substituted dideoxynucleoside.
1-(2-Azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (2'-N3ddThd) 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 resembled that of 1-(2-fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)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.
Van Aerschot
A
A
Laboratory of Pharmaceutical Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
Everaert
D
D
Gosselin
G
G
Peeters
O
O
Blaton
N
N
De Ranter
C
C
Imbach
J L
JL
Balzarini
J
J
De Clercq
E
E
Herdewijn
P
P
D000998:Antiviral Agents / Q000138:chemical synthesis*; D003461:Crystallography; D015224:Dideoxynucleosides / Q000737:chemistry / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D014961:X-Ray Diffraction; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C068377:2'-azido-2',3'-dideoxythymidine; D015215:Zidovudine; C002854:alovudine