Synthesis and anti-HIV evaluation of 2',3'-dideoxyribo-5-chloropyrimidine analogues: reduced toxicity of 5-chlorinated 2',3'-dideoxynucleosides.
In view of the selective anti-HIV activity of 2',3'-dideoxy-3'-fluoro-5-chlorouridine (11), a series of eight 2',3'-dideoxy-5-chloropyrimidines were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus type 1 (HIV-1) replication in MT-4 cells. A marked improvement in selectivity was noted for the 5-chlorouracil derivatives of 2,3-dideoxyribofuranose, 3-azido-2,3-dideoxyribofuranose, and 3-fluoro-2,3-dideoxyribofuranose, mainly due to decreased toxicity of the compounds for the host cells. While chlorination of 2',3'-dideoxycytidine removed the anti-HIV activity, introduction of a chlorine at the C-5 position of 3'-fluoro-, 3'-azido- or 2',3'-didehydro-2',3'-dideoxycytidine led to reduced cytotoxicity with only slightly reduced anti-HIV activity. X-ray analysis showed compound 11 to have two molecules in the asymmetric unit with chi = -168.8 (3) degrees and -131.3 (3) degrees and P = 179 (1) degree and 163 (1) degree, respectively; thus revealing no close resemblance to 3'-azido-3'-deoxythymidine (AZT).
Van Aerschot
A
A
Laboratories of Pharmaceutical Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
Everaert
D
D
Balzarini
J
J
Augustyns
K
K
Jie
L
L
Janssen
G
G
Peeters
O
O
Blaton
N
N
De Ranter
C
C
De Clercq
E
E
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006678:HIV / Q000187:drug effects*; D006801:Humans; D008968:Molecular Conformation; D014961:X-Ray Diffraction
D000998:Antiviral Agents; D015224:Dideoxynucleosides