5-Substituted pyrimidines with a 1,5-anhydro-2, 3-dideoxy-D-arabino-hexitol moiety at N-1: synthesis, antiviral activity, conformational analysis, and interaction with viral thymidine kinase.
A new series of anhydrohexitol nucleosides are described. These compounds have a pyrimidine base moiety substituted in the 5-position with a chloro (1b), trifluoromethyl (1c), vinyl (1d), 2-thienyl (1e), ethynyl (1f) or propynyl (1g) substituent. The vinyl, propynyl, and, in particular, the 5-trifluoromethyl analogue showed potent activity against herpes simplex virus (HSV), 1c with a selectivity index of >16000 against HSV-1 and >1000 against HSV-2. Conformational analysis of anhydrohexitol nucleosides using computational methods indicates that these nucleosides occur in an equilibrium between the C1 and 1C form with a DeltaE of 5.9 kJ/mol. When the anhydrohexitol nucleoside is cocrystallized with the HSV-1 thymidine kinase it adopts a 1C conformation, which is opposite to the conformation found for the small molecule alone. The enzyme, apparently, induces a conformational change, and conformational flexibility of an anhydrohexitol nucleoside may be advantageous for recognition by viral enzymes.
Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
T
T
Ostrowski
B
B
Wroblowski
R
R
Busson
J
J
Rozenski
E
E
De Clercq
M S
MS
Bennett
J N
JN
Champness
W C
WC
Summers
M R
MR
Sanderson
P
P
Herdewijn
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001087:Arabinonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000737:chemistry
D000998:Antiviral Agents; D001087:Arabinonucleosides; D011743:Pyrimidines; D013937:Thymidine Kinase