Novel 3'-C/N-substituted 2',3'-beta-D-dideoxynucleosides as potential chemotherapeutic agents. 1. Thymidine derivatives: synthesis, structure, and broad spectrum antiviral properties.
A synthetic scheme for the 3'-oxime derivatives 3E, 5E, 5Z, 7E and 7Z of 1-(2,3-dideoxy-beta-D-glycero-pentofuranosyl)thymine and for 1-(2,3-dideoxy-3-nitro-beta-D-erythro-pentofuranosyl)-thymine (10) has been developed starting from appropriately 5'-protected 3'-ketothymidine. X-ray analysis showed that 3'-N-hydroxyimino 3E and 3'-N-methoxyimino 5Z derivatives have close molecular conformations: anti about the N1-C1' bond, and gauche+ about the C4'-C5' exocyclic bond. Their sugar conformations are C1'-exo-O4'-endo and C1'-exo-C2'-endo, respectively. The antiviral assays in cell cultures demonstrated that 3'-N-hydroxyimino 3E and 3'-N-acetoxyimino 7E + 7Z derivatives are endowed with significant activity against human immunodeficiency virus (HIV) with EC50 values ranging between 0.02 and 0.40 microgram/mL for both HIV-1 and HIV-2. The other compounds 5E + 5Z and 10 were at least 2 orders of magnitude less active. The 3'-N-hydroxyimino derivative 3E also shows promising activity against hepatitis B virus (HBV) (EC50 = 0.25 microgram/mL) and against herpes simplex virus type 1 (HSV-1) and HSV-2.
Fedorov
I I
II
Moscow Medical Sechenov Academy, Russia.
Kazmina
E M
EM
Gurskaya
G V
GV
Jasko
M V
MV
Zavodnic
V E
VE
Balzarini
J
J
De Clercq
E
E
Faraj
A
A
Sommadossi
J P
JP
Imbach
J L
JL
Gosselin
G
G
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007536:Isomerism; D008956:Models, Chemical; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D013936:Thymidine