Synthesis of 5-[1-hydroxy (or methoxy)-2,2-dihaloethyl]-2'- deoxyuridines with antiviral and cytotoxic activity.
The 5-[1-hydroxy (or methoxy)-2,2-dihaloethyl]-2'-deoxyuridines (3-12, Cl, Br and/or I) were synthesized by the addition of HOX or CH3OX (X = Cl, Br, I) to the vinyl substituent of the respective (E)-5-(2-halovinyl)-2'-deoxyuridines (1a-c). In vitro antiviral (HSV-1, HSV-2, HCMV, VZV, EBV) and cytotoxic (L1210) activities were determined. The 5-(1-hydroxy-2,2-dihaloethyl) series were generally more active than the 5-(1-methoxy-2,2-dihaloethyl) series against HSV-1, HSV-2, VZV and EBV. Anti-HSV-1 activity was dependent upon the steric orientation and/or hydrophobic properties of the halogen atom(s), with -CH(OH)CHBr(I) and -CH(OH)CHBr2 C-5 substituents providing the most potent activity. 5-(1-Hydroxy-2-bromo-2-iodoethyl)-2'-deoxyuridine (6), which exhibited the most potent anti-HSV-1 activity, was 12-fold less active than acyclovir. In contrast, the halogen atom(s) were not determinants of anti-VZV activity, where the approximately equipotent 5-(1-hydroxy-2,2-dihaloethyl) compounds (3, 4, 5, 6) exhibited anti-VZV activity comparable to that of acyclovir. All of the 5-(1-hydroxy (or methoxy)-2,2-dihaloethyl) analogs (3-12) were inactive against HCMV. The 5-(1-hydroxy-2-chloro-2-iodoethyl) compound (4) was an active cytotoxic agent as determined in the in vitro L1210 screen. The compounds 3-12 were non-toxic to uninfected host cells. The inhibitory effect on cell proliferation diminished upon replacement of the 5-(1-hydroxy-2,2-dihaloethyl) substituents of 3-6 with the corresponding 5-(1-methoxy-2,2-dihaloethyl) substituents (7-12).
Kumar
R
R
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Knaus
E E
EE
Wiebe
L F
LF
Allen
T M
TM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D006846:Hydrocarbons, Halogenated; D003857:Deoxyuridine