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N-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors

Journal of Medicinal Chemistry, ISSN: 0022-2623, Vol: 49, Issue: 26, Page: 7766-7773
2006
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Article Description

Novel N-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 (IC = 0.3-0.5 μM). 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-(β-D-arabinofuranosyl) thymine (Ara-T) and ganciclovir in HSV-1 TK-expressing OST-TK/HSV-1 TK cell cultures. © 2006 American Chemical Society.

Bibliographic Details

Hernandez, Ana-Isabel; Familiar, Olga; Negri, Ana; Rodríguez-Barrios, Fatima; Gago, Federico; Karlsson, Anna; Camarasa, María-José; Balzarini, Jan; Pérez-Pérez, María-Jesús

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

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