Relationship between structural properties and affinity for herpes simplex virus type 1 thymidine kinase of bromine substituted 5-heteroaromatic 2′-deoxyuridines

Creuven, Isabelle; Evrard, C.; Olivier, Anne; Evrard, G.; Wigerinck, Piet; Herdewijn, Piet; Durant, François

doi:10.1016/0166-3542(95)00838-1

Cited by 6 publications

(2 citation statements)

References 17 publications

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“…Crystal structures for 1 and 6 match previously published unit cell and space group data. 57,58 Crystallographic data (excluding structure factors) for compounds 1, 2, 6, 8 and 9 in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 627723, 627722, 627725, 627724 and 632875 respectively. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).…”

Section: X-ray Structuresmentioning

confidence: 99%

Furan decorated nucleoside analogues as fluorescent probes: synthesis, photophysical evaluation, and site-specific incorporation

2007

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The synthesis and photophysical evaluation of modified nucleoside analogues in which a five-membered heterocycle (furan, thiophene, oxazole and thiazole) is attached to the 5 position of 2'-deoxyuridine are reported. The furan containing derivative is identified as the most promising responsive nucleoside of this family due to its emission quantum efficiency and degree of sensitivity to its microenvironment. The furan moiety was then attached to the 5 position of 2'-deoxycytidine as well as the 8 position of adenosine and guanosine. Photophysical evaluation of these four furan containing nucleoside analogues reveal distinct differences in the absorption, emission and quantum efficiency depending upon the class of nucleoside (pyrimidine or purine). Comparing the photophysical properties of all furan containing nucleosides, identifies the furan thymidine analogue, 5-(fur-2-yl)-2'-deoxyuridine, as the best candidate for use as a responsive fluorescent probe in nucleic acids. 5-(fur-2-yl)-2'-deoxyuridine was then converted to the corresponding phosphoramidite and site specifically incorporated into DNA oligonucleotides with greater than 88% coupling efficiency. Such furan-modified oligonucleotides form stable duplexes upon hybridization to their complementary DNA strands and display favorable fluorescent features.

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Section: X-ray Structuresmentioning

confidence: 99%

Furan decorated nucleoside analogues as fluorescent probes: synthesis, photophysical evaluation, and site-specific incorporation

2007

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“…Clearly, there is a difference between both classes of molecules. Crystal structure analysis revealed that all compounds have a quasi-coplanar geometry between the five-membered heterocyclic ring and the uracil base (Figure ). − Intramolecular interactions stabilize this coplanarity. Interestingly, in the 2-thienyl series of compounds, coplanarity is stabilized by an interaction between the O4 carbonyl group of the uracil base and the sulfur atom of the thiophene ring (Figure , structure A ).…”

Section: The Playersmentioning

confidence: 99%

Understanding the Binding of 5-Substituted 2‘-Deoxyuridine Substrates to Thymidine Kinase of Herpes Simplex Virus Type-1

Winter

Herdewijn

1996

J. Med. Chem.

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Thymidine kinase from HSV-1 (HSV-1 TK) is a key enzyme in the metabolic activation of antiviral nucleosides. High affinity of such compounds for the enzyme is required for efficient phosphorylation. In this study, affinity data from a series of 5-substituted 2'-deoxyuridine substrates in combination with the crystal structure of the viral enzyme were used to investigate the structural factors influencing the affinity of these compounds for the enzyme. Calculations showed that the binding energetics and conformations of thymidine and the 5-substituted 2'-uridine analogues are similar. The major part of the binding energy arises from interactions involving sugar and base moieties. Small differences in affinity for the enzyme are explained by the hydrophobicity of the 5-substituent or by its energetic complementarity with the active site pocket. In designing high-affinity nucleoside substrates of HSV-1 TK, care should be taken to maintain the geometry of the base moiety and sugar hydroxyl functionalities. Substitutions at the 5-position of the nucleobase should be lipophilic and characterized by well-defined geometrical properties. The present study represents a first quantitative explanation for HSV-1 TK affinity of 5-substituted 2'-deoxyuridines which are historically the first group of selective antivirals. The results may be used to design new and more potent compounds.

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Synthesis of 2′‐Deoxy‐5‐(isothiazol‐5‐yl)uridine and Its Interaction with the HSV‐1 Thymidine Kinase

Luyten

Winter

Busson

et al. 1996

Helvetica Chimica Acta

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(1 3.11.96) 2'-Deoxy-5-(isothiazol-5-yl)uridine (12) was synthesized starting from 2'-deoxy-5-iodouridine using a Pdcatalysed cross-coupling reaction with propiolaldehyde diethyl acetal followed by deprotection and ring closure using thiosulfate. 2'-Deoxyuridine 12 has a particular place among the 5-heteroaryl-substituted 2'-deoxyuridines in that it has a high affinity for herpes simplex virus type 1(HSV-1)-encoded thymidine kinase (TK) without antiviral activity. Biochemical studies revealed that 12 is a substrate for viral TK. We further investigated the interaction of 12 with the HSV-1 thymidine kinase. The conformation of 12 in solution was established by NMR spectroscopy. The most stable conformer 12A has the S-atom of the isothiazole ring placed in the neighbourhood of the C(4)=0 group of the pyrimidine moiety. The compound was docked in its most stable conformation in the active site of HSV-1 TK and subjected to energy minimization. This demonstrated that the isothiazole moiety binds in a cavity lined by the side chains ofTyr-132, Arg-163, Ala-167, and Ala-168 and that the C(3) atom of the isothiazole moiety is located in close proximity of the phenolic 0-atom of Tyr-132 and the aliphatic part of the Arg-163 side chain.Introduction. -The structure-activity-relationship study of 5-substituted 2'-deoxyuridines started with the historical discovery of 2'-deoxy-5-iodouridine as an anti-herpes agent [l]. The mode of action of 5-substituted 2'-deoxyuridines has since long been studied, and it is well documented that these compounds have to be phosphorylated to their mono-, di-, and triphosphate and that these metabolites are responsible for the biological activity. In their monophosphate form, some 5-substituted 2'-deoxyuridines are efficient inhibitors of thymidylate synthase [2]. In their triphosphate form, these nucleosides interfere with DNA synthesis by inhibiting DNA polymerases and/or by functioning as alternative substrates thus being incorporated into DNA. Whatever the mechanism, the first step in the anabolism to the active metabolite is the phosphorylation by nucleoside kinases. With respect to the 5-substituted 2'-deoxyuridines that are active against HSV-1, this phosphorylation is carried out by the viral thymidine kinase. The thymidine kinase (TK) encoded by herpes simplex virus type 1 (HSV-1) has a broader substrate specificity than the human enzymes so that modified nucleosides can be selectively activated in the HSV-1-infected cells.Recently, a study was undertaken to analyse the affinity of several 5-substituted 2'-deoxyuridines for the HSV-1-encoded TK and to relate this affinity with structural data [3-81. In Table I , an overview is given of the compounds synthesized (see Scheme for general Formula), together with their TK affinity. Compounds with a low affinity for the

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Relationship between structural properties and affinity for herpes simplex virus type 1 thymidine kinase of bromine substituted 5-heteroaromatic 2′-deoxyuridines

Cited by 6 publications

References 17 publications

Furan decorated nucleoside analogues as fluorescent probes: synthesis, photophysical evaluation, and site-specific incorporation

Furan decorated nucleoside analogues as fluorescent probes: synthesis, photophysical evaluation, and site-specific incorporation

Understanding the Binding of 5-Substituted 2‘-Deoxyuridine Substrates to Thymidine Kinase of Herpes Simplex Virus Type-1

Synthesis of 2′‐Deoxy‐5‐(isothiazol‐5‐yl)uridine and Its Interaction with the HSV‐1 Thymidine Kinase

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