N1-Substituted Thymine Derivatives as Mitochondrial Thymidine Kinase (TK-2) Inhibitors
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- 作者：Ana-Isabel Herná ; ndez ; Olga Familiar ; Ana Negri ; Fá ; tima Rodrí ; guez-Barrios ; Federico Gago ; Anna Karlsson ; Marí ; a-José ; Camarasa ; Jan Balzarini ; Marí ; a-Jesú ; s
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：December 28, 2006
- 年：2006
- 卷：49
- 期：26
- 页码：7766 - 7773
- 全文大小：292K
- 年卷期：v.49,no.26(December 28, 2006)
- ISSN：1520-4804
文摘
Novel N1-substituted thymine derivatives related to 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine have beensynthesized and evaluated against thymidine kinase-2 (TK-2) and related nucleoside kinases [i.e., Drosophilamelanogaster deoxynucleoside kinase (Dm-dNK) and herpes simplex virus type 1 thymidine kinase (HSV-1TK)]. The thymine base has been tethered to a distal triphenylmethoxy moiety through a polymethylenechain (n = 3-8) or through a (2-ethoxy)ethyl spacer. Moreover, substitutions at position 4 of one of thephenyl 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 
M). Compound 26bcompetitively inhibited TK-2 with respect to thymidine and uncompetitively with respect to ATP. A rationalefor the biological data was provided by docking some representative inhibitors into a homology-based modelof human TK-2. Moreover, two of the most potent TK-2 inhibitors (18 and 26b) that also inhibit HSV-1TK were able to reverse the cytostatic activity of 1-(
-D-arabinofuranosyl)thymine (Ara-T) and ganciclovirin HSV-1 TK-expressing OST-TK-/HSV-1 TK+ cell cultures.
M). Compound 26bcompetitively inhibited TK-2 with respect to thymidine and uncompetitively with respect to ATP. A rationalefor the biological data was provided by docking some representative inhibitors into a homology-based modelof human TK-2. Moreover, two of the most potent TK-2 inhibitors (18 and 26b) that also inhibit HSV-1TK were able to reverse the cytostatic activity of 1-(-D-arabinofuranosyl)thymine (Ara-T) and ganciclovirin HSV-1 TK-expressing OST-TK-/HSV-1 TK+ cell cultures.