Synthesis, antiviral and cytotoxic activity of 2'-deoxyuridines, 2'-fluoro-2'-deoxyuridines and 2'-arabinouridines containing 5-(1-hydroxy-2-halo-2-ethoxycarbonylethyl)-, 5-(1-hydroxy-2-iodo-2- carboxyethyl)- and 5-[1-hydroxy (or methoxy)-2-iodoethyl] substituents.
The 5-[1-hydroxy-2-chloro-2-(ethoxycarbonyl)ethyl]-2'-deoxyuridine (7) and 5-[1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl]-2'- fluoro-2'-deoxyuridine/uridine nucleosides (8, 9) were synthesized by the regiospecific addition of HOX (X = Br or Cl) to the vinyl substituent of the respective (E)-5-[2-(ethoxycarbonyl)-vinyl]-2'-deoxyuridines (6a-b) and uridine (6c). A related reaction of (E)-5-(2-carboxyvinyl)-2'-deoxyuridines (10a-b) and uridine (10c) with iodine and potassium iodate afforded the 5-(1-hydroxy-2-iodo-2-carboxyethyl) derivatives (11-13). 5-(1-Hydroxy-2-iodoethyl)-arabinouridine (18) was obtained by the reaction of (17) with iodine in the presence of the oxidizing agent iodic acid. Treatment of (18) with methanolic sulfuric acid afforded 5-(1-methoxy-2-iodoethyl)-arabinouridine (19) in 65% yield. Of the newly synthesized compounds, 7, 11 and 12 showed activity in vitro against HSV-1. The most active compound (12, ID50 = 0.1 microgram/ml) was 10 times less active than acyclovir (ID50 = 0.01 microgram/ml) against HSV-1. Compounds 7 and 11 were cytotoxic to L1210 cells in culture, exhibiting an ED50 of 7.2 and 4.7 micrograms/ml respectively, relative to melphalan (ED50 = 0.15 microgram/ml), but were inactive against the KB cell line.
Kumar
R
R
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Wiebe
L I
LI
Knaus
E E
EE
Allen
T M
TM
Tempest
M L
ML
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D005467:Floxuridine; D001086:Arabinofuranosyluracil; D003857:Deoxyuridine