Novel selective human mitochondrial kinase inhibitors: Design, synthesis and enzymatic activity

Ciliberti, Nunzia; Manfredini, Stefano; Angusti, Angela; Durini, Elisa; Solaroli, Nicola; Vertuani, Silvia; Buzzoni, Lisa; Bonache, M C; Ben-Shalom, Efrat; Karlsson, Anna; Saada, Ann; Balzarini, Jan

doi:10.1016/j.bmc.2007.01.049

Cited by 8 publications

(10 citation statements)

References 38 publications

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“…A variety of TK-2 inhibitors have been described in the literature and include 3Ј-hexanoylamino-dThd (Kierdaszuk et al, 1999), pyrimidine ribofuranosyl nucleosides, 3Ј-spiroribonucleosides , and arabinosyl nucleosides containing long-chain acyl substituents at the C-2Ј position of the sugar ring (Balzarinia et al, 2001;Manfredini et al, 2001;Ciliberti et al, 2007). 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).…”

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confidence: 99%

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

Balzarini

Daele²,

Negri³

et al. 2009

Mol Pharmacol

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Substituted 3Ј-thiourea derivatives of ␤-thymidine (dThd) and 5Ј-thiourea derivatives of ␣-dThd have been evaluated for their inhibitory activity against recombinant human cytosolic dThd kinase-1 (TK-1), human mitochondrial TK-2, herpes simplex virus type 1 (HSV-1) TK, and varicella-zoster virus TK. Several substituted 3Ј-thiourea derivatives of ␤-dThd proved highly inhibitory to and selective for TK-2 (IC 50 value, 0.15-3.1 M). The 3Ј-C-branched p-methylphenyl (compound 1) and 3-CF 3 -4-Cl-phenyl (compound 7) thiourea derivatives of ␤-dThd showed competitive inhibition of TK-2 when dThd was used as the variable substrate (K i values, 0.40 and 0.05 M, respectively), but uncompetitive inhibition in the presence of variable concentrations of ATP (K i values, 15 and 2.0 M, respectively). These kinetic properties of compounds 1 and 7 against TK-2 could be accounted for by molecular modeling showing that two hydrogen bonds can be formed between the thiourea nitrogens of compound 7 and the oxygens of the ␥-phosphate of ATP. The importance of several active-site residues was assessed by site-directed mutagenesis experiments on TK-2 and the related HSV-1 TK. The low K i /K m ratios for compounds 1 and 7 (0.38 and 0.039 against dThd, and 0.75 and 0.12 against ATP, respectively) indicate that these compounds are among the most potent inhibitors of TK-2 described so far. In addition, a striking close correlation was found between the inhibitory activities of the test compounds against TK-2 and Mycobacterium tuberculosis thymidylate kinase that is strongly indicative of close structural and/or functional similarities between both enzymes in relation to their mode of interaction with these nucleoside analog inhibitors.

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confidence: 99%

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

Balzarini

Daele²,

Negri³

et al. 2009

Mol Pharmacol

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“…Manfredini et al 49 communicated in 2001 the first compounds within this series, and a full report on these derivatives has recently been published. 50 It is interesting to note that while AraT (8) shows significant affinity for HSV-1 TK and a 10-fold lower affinity for TK2, introduction of long chain acyl substituents at the 2 0 -OH, as in the decanoyl and dodecanoyl esters (compounds 14 and 15, respectively) ( Fig. 5), enhanced the affinity for TK2 by 10-fold (Table I).…”

Section: S T R U C T U R E S O F T K 2 I N H I B I T O R Smentioning

confidence: 98%

“…49,50 By shortening the 2 0 -O-acyl chain to a pentanoyl moiety, or by replacing the acyl chain by an alkyl moiety, an important decrease in the inhibitory activity was observed. 49,50 A similar approach has been applied to BVAraU derivatives. Thus, introduction of an octanoyl or decanoyl chain (compounds 16 and 17) ( Fig.…”

Section: S T R U C T U R E S O F T K 2 I N H I B I T O R Smentioning

confidence: 99%

“…5) increased the inhibitory potency of the BVAraU derivatives against TK2-catalysed dThd phosphorylation by 7-fold (IC 50 values of $6 mM) (Table I). 49,50 None of the araT and BVaraU derivatives showed appreciable inhibitory activity against cytosolic TK-1. Interestingly, when the acyl chain incorporates an NHBoc at the distal site as in compound 18, TK2 inhibition is further slightly enhanced (IC 50 ¼ 3.8 AE 0.2 mM).…”

Section: S T R U C T U R E S O F T K 2 I N H I B I T O R Smentioning

confidence: 99%

“…Interestingly, when the acyl chain incorporates an NHBoc at the distal site as in compound 18, TK2 inhibition is further slightly enhanced (IC 50 ¼ 3.8 AE 0.2 mM). 50 However, when the pentanoyl chain is functionalized with a free NH 2 as in compound 19, TK2 inhibition is lost. It should be mentioned that when the corresponding 2 0 -O-acyl-AraG and 2 0 -O-acyl-AraC derivatives were explored for TK2 inhibition, no inhibitory activity was observed.…”

Section: S T R U C T U R E S O F T K 2 I N H I B I T O R Smentioning

confidence: 99%

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Structure, physiological role, and specific inhibitors of human thymidine kinase 2 (TK2): Present and future

Pérez‐Pérez

Priego

Hernández

et al. 2008

Medicinal Research Reviews

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Human mitochondrial thymidine kinase (TK2) is a pyrimidine deoxynucleoside kinase (dNK) that catalyzes the phosphorylation of pyrimidine deoxynucleosides to their corresponding deoxynucleoside 5'-monophosphates by gamma-phosphoryl transfer from ATP. In resting cells, TK2 is suggested to play a key role in the mitochondrial salvage pathway to provide pyrimidine nucleotides for mitochondrial DNA (mtDNA) synthesis and maintenance. However, recently the physiological role of TK2turned out to have direct clinical relevance as well. Point mutations in the gene encoding TK2 have been correlated to mtDNA disorders in a heterogeneous group of patients suffering from the so-called mtDNA depletion syndrome (MDS). TK2 activity could also be involved in mitochondrial toxicity associated to prolonged treatment with antiviral nucleoside analogues like AZT and FIAU. Therefore, TK2 inhibitors can be considered as valuable tools to unravel the role of TK2 in the maintenance and homeostasis of mitochondrial nucleotide pools and mtDNA, and to clarify the contribution of TK2 activity to mitochondrial toxicity of certain antivirals. Highly selective TK-2 inhibitors having an acyclic nucleoside structure and efficiently discriminating between TK-2 and the closely related TK-1 have already been reported. It is actually unclear whether these agents efficiently reach the inner mitochondrial compartment. In the present review article,structural features of TK2, MDS-related mutations observed in TK2 and their role in MDS will be discussed. Also, an update on novel and selective TK2 inhibitors will be provided.

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Photoreactivities of 5-Bromouracil-containing RNAs

Morinaga

Kizaki

Takenaka

et al. 2013

Bioorganic & Medicinal Chemistry

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5-Bromouracil ((Br)U) was incorporated into three types of synthetic RNA and the products of the photoirradiated (Br)U-containing RNAs were investigated using HPLC and MS analysis. The photoirradiation of r(GCA(Br)UGC)(2) and r(CGAA(Br)UUGC)/r(GCAAUUCG) in A-form RNA produced the corresponding 2'-keto adenosine ((keto)A) product at the 5'-neighboring nucleotide, such as r(GC(keto)AUGC) and r(CGA(keto)AUUGC), respectively. The photoirradiation of r(CGCG(Br)UGCG)/r(C(m)GCAC(m)GCG) in Z-form RNA produced the 2'-keto guanosine ((keto)G) product r(CGC(keto)GUGCG), whereas almost no products were observed from the photoirradiation of r(CGCG(Br)UGCG)/r(C(m)GCAC(m)GCG) in A-form RNA. The present results indicate clearly that hydrogen (H) abstraction by the photochemically generated uracil-5-yl radical selectively occurs at the C2' position to provide a 2'-keto RNA product.

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Novel selective human mitochondrial kinase inhibitors: Design, synthesis and enzymatic activity

Cited by 8 publications

References 38 publications

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

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

Structure, physiological role, and specific inhibitors of human thymidine kinase 2 (TK2): Present and future

Photoreactivities of 5-Bromouracil-containing RNAs

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