Thymidine kinase inhibitors

We will discuss small molecule inhibitors of three main classes of nonprotein kinases sugar kinases, nucleoside kinases and lipid kinases. This chapter will be limited to discussion of the inhibition of human kinases. Several non-human non-protein kinases have been the focus of drug development efforts as well, including choline kinase for inhibition of Plasmodium, uridine-cytidine kinase as an anti-parasitic target and thymidine kinase inhibitors as an anti-mycobacterial treatment or for treatment of Herpes simplex viral infections. These applications will not be discussed in this chapter. Peptide... 

Various N-acyl and N-sulphonyl derivatives of 5 -amino-5 -deoxythym-idine and 5 -amino-2 ,5 -dideo3y-5-lodourIdIne have been prepared as viral thymidine kinase inhibitors. The N-acyl derivative (30). and the corresponding compound with the enantiomeric li acyl group, have been synthesized as lipophilic analogues of ATP each compound has a geometrical similarity to one of the preferred conformations for a metal-chelated triphosphate chain.74 a number of stable nitrogen analogues of -adenosylmethionine, such as (31). have been reported. ... 

The 5 -alkylaminoadenosine (67) has been synthesised from adenosine, and found to be a potent irreversible inhibitor of S-adenosyl-L-methlonine decarboxylase. 119 A range of N-acyl derivatives (68), and corresponding N-sulphonyl compounds, have been prepzired as virzil thymidine kinase inhibitors. 120... 

The Case Study Herpes Simplex Virus Type 1 Thymidine Kinase Substrates and Inhibitors... 

Exploration of Bulk Tolerance at ATP Sites. Non-covalent type inhibitors have also been used to study bulk tolerance around the ATP binding sites. In this vein Hampton and co-workers have both synthesized and tested as inhibitors a large number of adenine nucleotide analogs (Figure 2f) to probe the bulk tolerance at a number of positions on the parent compound (28-31) These compounds have been used to study systematically the isoenzyme selectivity of adenylate kinases, hexokinases, thymidine kinases and pyruvate kinases with respect to bulk tolerance at many sites on the ATP molecule. Some of the most isoenzyme specific results were obtained with pyruvate kinase isoenzymes K,L and M using ADP derivatives. Here 3 -0Me-ADP was found to inhibit pyruvate kinase preferentially with a ratio of inhibitory potency of 7.6 6.0 1.0 for the K,M and L isoenzymes, respectively. Another compound, 8-NHEt-ADP, was selective for the M isoenzyme, giving a ratio of 7.1 1.2 1.0 for the M, K and L forms, respectively. 

Famciclovir (Famvir) is the diacetyl ester prodrug of the acyclic guanosine analogue 6-deoxypenciclovir Dena-vir). Penciciovir has activity against HSV-1, HSV-2, VZV, and HB V. After oral administration, famciclovir is converted to penciciovir by first-pass metabolism. Penciciovir has a mechanism of action similar to that of acyclovir. It is first monophosphorylated by viral thymidine kinase then it is converted to a triphosphate by cellular kinases. Penciciovir triphosphate acts as a competitive inhibitor of viral DNA polymerase, but unlike acyclovir, it does not cause chain termination. 

L D. The conversion of penciclovir to its active form requires initial monophosphorylation by viral thymidine kinases, then conversion to its active triphosphate form by cellular enzymes. Thus, the concentration of penciclovir triphosphate is particularly high in cells infected with its target viruses (e.g., HSV, VZV, HBV). Foscarnet is a pyrophosphate analogue that does not require activation. Oseltamivir is a neuraminidase inhibitor that is con-... 

In the host cell, viruses induce the formation of enzymes that they themselves cannot produce. The most important group of such enzymes is that of the DNA polymerases, but thymidine kinase is also essential. Interference with these enzymes by either enzyme inhibitors or through fraudulent antimetabolites is the basis of the activity of many antiviral drugs. In this respect, antiviral compounds and cytostatics used in the treatment of malignant tumors have much in common and indeed overlap each other in their activity. 

Acyclovir (ACV) is not a true nucleoside, because the guanine residue is attached to an open-chain structure, but it mimics deoxyribose well enough for the compound to be accepted as a substrate by a thymidine kinase specified by certain herpes-type viruses. The normal thymidine kinase in mammalian cells does not recognize ACV as a substrate, however, so only virus-infected cells convert ACV to its monophosphate. Once the first phosphate has been added, the second phosphate is added by cellular guanylate kinase several other cellular kinases can add the third phosphate. The triphosphate is a more potent inhibitor of the viral DNA polymerases than of cellular DNA polymerases and also inactivates the former but not the latter. The net result is that ACV has been an effective treatment of, and prophylaxis for, genital herpes. Also it can result in dramatic relief of pain associated with shingles caused by reactivation of latent varicella-zoster virus, and has been successful in many patients with herpes encephalitis. 

Thirty 5 -thiourea-substituted a-thymidine analogues used to develop receptor-independent 4D-QSARmodels ( 3 = 0.83) for thymidine monophosphate kinase inhibitors. The model was also put into the context of reported crystallographically characterized inhibitor/enzyme interactions... 

UNITY pharmacophore, FlexXd docking, and structure interaction fingerprint approaches were used to identify compounds in the Maybridge database (59,275 compounds) as potential thymidine monophosphate kinase inhibitors... 

Aparna V, Jeevan J, Ravi M et al (2006) 3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods. Bioorg Med Chem Lett 16 1014-1020... 

Gopalakrishnan B, Aparna V, Jeevan J et al (2005) A virtual screening approach for thymidine monophosphate kinase inhibitors as... 

In particular, acyclovir 1 has become important because of its potent antiherpes activity. Interest in this compound was further enhanced by the finding that, in HS V infected cells, its mechanism of action is due to its specific phosphorylation by the viral-encoded (but not cellular) thymidine kinase to acyclo GMP followed by further phosphorylation by cellular GMP and GDP kinases to the triphosphate, acyclo GTP, which is a selective and potent inhibitor of the HSV DNA polymerase.DHPA (3) and DHPG (2) "" also show significant antiviral activity. These findings have stimulated a widespread interest in. and led to the synthesis of. a large number of purine (and pyrimidine) acyclo nucleosides. " "... 

The deoxyuridine analogue 5-azidomethyl-2 -deoxyuridine (159) was one of a large number of compounds investigated as inhibitors of thymidylate synthase and thymidine kinase from L1210 cells, but the compound was... 

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