N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors.
Novel N1-substituted thymine derivatives related to 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine have been synthesized and evaluated against thymidine kinase-2 (TK-2) and related nucleoside kinases [i.e., Drosophila melanogaster deoxynucleoside kinase (Dm-dNK) and herpes simplex virus type 1 thymidine kinase (HSV-1 TK)]. The thymine base has been tethered to a distal triphenylmethoxy moiety through a polymethylene chain (n = 3-8) or through a (2-ethoxy)ethyl spacer. Moreover, substitutions at position 4 of one of the phenyl rings of the triphenylmethoxy moiety have been performed. Compounds with a hexamethylene spacer (18, 26b, 31) displayed the highest inhibitory values against TK-2 (IC50 = 0.3-0.5 microM). Compound 26b competitively inhibited TK-2 with respect to thymidine and uncompetitively with respect to ATP. A rationale for the biological data was provided by docking some representative inhibitors into a homology-based model of human TK-2. Moreover, two of the most potent TK-2 inhibitors (18 and 26b) that also inhibit HSV-1 TK were able to reverse the cytostatic activity of 1-(beta-D-arabinofuranosyl)thymine (Ara-T) and ganciclovir in HSV-1 TK-expressing OST-TK-/HSV-1 TK+ cell cultures.
Hernandez
Ana-Isabel
AI
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
Familiar
Olga
O
Negri
Ana
A
Rodríguez-Barrios
Fatima
F
Gago
Federico
F
Karlsson
Anna
A
Camarasa
María-José
MJ
Balzarini
Jan
J
Pérez-Pérez
María-Jesús
MJ
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001087:Arabinonucleosides / Q000494:pharmacology; D001667:Binding, Competitive; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004331:Drosophila melanogaster / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015774:Ganciclovir / Q000494:pharmacology; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*; D013941:Thymine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000998:Antiviral Agents; D001087:Arabinonucleosides; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C010032:thymine arabinoside; D015774:Ganciclovir; D013941:Thymine; D013936:Thymidine