Acyclic Nucleoside Analogues as Novel Inhibitors of Human Mitochondrial Thymidine Kinase

Abstract

A series of acyclic nucleoside analogues of 5'-O-tritylthymidine have been synthesized and evaluated as potential human mitochondrial thymidine kinase (TK-2) inhibitors. In this series, the sugar moiety of the parent 5'-O-tritylthymidine has been replaced by aliphatic chains including (E)- and (Z)-butenol, butynol, or butanol. Among them the (Z)-butenyl derivative (10) showed an IC(50) against TK-2 of 1.5 microM, being 1 order of magnitude more potent than the parent 5'-O-tritylthymidine. This lead compound has been further modified by replacing the thymine base by other pyrimidine bases such as 5-iodouracil, 5-ethyluracil, 5-methylcytosine, 3-N-methylthymine, or 5,6-dihydrothymine, as well as by the purine base guanine. The trityl group has also been replaced by different aliphatic and aromatic acyl moieties including tert-butylacetyl, hexanoyl, decanoyl, and diphenylacetyl moieties. The evaluation of the compounds against TK-2 and the phylogenetically close HSV-1 TK has shown that the base moiety plays a crucial role in their interaction against these pyrimidine nucleoside kinases. Also, the presence of a lipophilic substituent, preferentially an aromatic moiety such as diphenylmethyl or triphenylmethyl, is required for efficient TK-2 inhibition. Whereas some compounds showed marked specificity for either TK-2 (i.e, the 5,6-dihydrothymine derivative, 26) or HSV-1 TK (i.e., the butynyl derivative, 11), some others, including the (Z)-and (E)-butenyl derivatives 10 and 12, showed significant inhibition against both enzymes. They also proved to be inhibitory against HSV-1 TK in intact human osteosarcoma cells that were transduced with the HSV-1 TK gene.

Non-Nucleoside Inhibitors of Mitochondrial Thymidine Kinase (TK-2) Differentially Inhibit the Closely Related Herpes Simplex Virus Type 1 TK andDrosophila melanogasterMultifunctional Deoxynucleoside Kinase

“…In fact, we could demonstrate that KIN-52, KIN-12, and KIN-39 could virtually completely suppress remaining TK activity in extracts of human lymphocytic CEM/TK Ϫ cells that were deficient for TK-1 but kept mitochondrial TK-2 activity, whereas the TK-2 inhibitors hardly affected TK activity in extracts from wild-type CEM/0 cells that were competent in both TK-1 and TK-2 activities (data not shown). Also, KIN-12 and related derivatives were shown to be able to enter intact human osteosarcoma cells and were not cytotoxic at 20 M (Herná ndez et al, 2002). However, it is unclear whether these compounds were also able to enter the mitochondrial compartment in intact mammalian cells.…”

“…1) have been described recently (Herná ndez et al, 2002). BVDU was from the Rega Institute (Leuven, Belgium).…”

Human Mitochondrial Thymidine Kinase Is Selectively Inhibited by 3′-Thiourea Derivatives of β-Thymidine: Identification of Residues Crucial for Both Inhibition and Catalytic Activity

“…It is noteworthy that pyrimidine 2Ј-deoxynucleoside analogs containing a trityl moiety at the 5Ј-position of the deoxyribose have also been shown to act as potent and selective inhibitors of TK-2 (Herná ndez et al, 2002). Further synthetic efforts subsequently led to the identification of and detailed studies on tritylated acyclic pyrimidine nucleoside analogs as TK-2 inhibitors .…”

“…Further synthetic efforts subsequently led to the identification of and detailed studies on tritylated acyclic pyrimidine nucleoside analogs as TK-2 inhibitors . These compounds act as non-nucleosidic inhibitors and are endowed with a pronounced inhibitory activity against the enzyme (50% inhibitory concentrations as low as 0.3 M) (Herná ndez et al, 2002Balzarini et al, 2003;Priego et al, 2004;Hernandez et al, 2006;Pérez-Pérez et al, 2008). In this study, we report on the discovery of a series of substituted 3Ј-or 5Ј-thiourea derivatives of ␤-and ␣-dThd, respectively, as TK-2 inhibitors and the identification of several derivatives that were highly potent in their anti-TK-2 action.…”

Σύνθεση Μιας Νέας Τάξης Φθορο - Θειο - Νουκλεοζιτών Με Πιθανή Αντιϊκή Και Αντικαρκινική Δράση

“…The above acyclic nucleosides were also evaluated against HSV-1, and the highest activity was achieved by furanopyrimidine derivative 148b (Fig. 71) Hernandez et al [158] synthesized and tested against human mitochondrial thymidine kinase (TK-2) and HSV-1 TK, a series of acyclic nucleoside analogues 149-153 (Fig. 72,73) of 5 -O-tritylthymidine (Tr-dThd).…”