Stereoelectronic properties of five anti-HSV-1 2′-deoxynucleosides analogues with heterocyclic substituents in the 5-position: A comparison with BVDU

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

doi:10.1016/0166-3542(94)90076-0

Cited by 8 publications

(7 citation statements)

References 19 publications

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“…Anti-HSV-1 Activity and Affinity for HSV-I Thymidine Kinase of Different 2'-Deoxyuridines with a Heteroaryl Substituent in the 5-Position [3-51 [7] 5-Substituent HSV-1 (Kos) HSV-1 Thymi- has been confirmed by minimum-energy calculations (data not shown). Moreover, a correlation could be found between the electrostatic potential energy map, 1.75 8, above the plane of the bisheterocyclic system, of the compounds and their affinity for the enzyme [6]. This is illustrated in Fig.…”

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confidence: 96%

“…The products that were most intensively studied could be divided in a group of compounds with high affinity for the HSV-1 TK (i.e., 2'-deoxy-5-(thien-2-yl)uridine (l), 5-(5-bromothien-2-y1)-2'-deoxyuridine (2), 5-(5-chlorothien-2-yl)-2'-deoxyuridine (5), and 2'-deoxy-5-(furan-Zyl)uridine (15)) and a group of compounds with low affinity for the enzyme (k, 5-(3-bromothien-2-~1)-2'-deoxyuridine (4), 5-( 5-bromofuran-2-yl)-2'-deoxyuridine (16), 2'-deoxy-5-(isoxazol-5-y1)uridine (19), and 5-(3-bromoisoxazo1-5-y1)-2'-deoxyuridine (20)). This study led to the conclusion that the conformation of the molecules is highly influenced by possible S/C=O interactions [6] (Fig, I ), and that a substitution zone exists for unfavourable interactions Table 1. Anti-HSV-1 Activity and Affinity for HSV-I Thymidine Kinase of Different 2'-Deoxyuridines with a Heteroaryl Substituent in the 5-Position [3-51 [7] 5-Substituent HSV-1 (Kos) HSV-1 Thymi- has been confirmed by minimum-energy calculations (data not shown).…”

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confidence: 98%

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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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confidence: 96%

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confidence: 98%

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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“…For furanyl analogues (II, IV), the substituent in the 5-position is oriented in such a way that the oxygen atoms of the uracil moietyand of the furanyl ring are pointed away from each other. Energy calculations (Olivier et al, 1994) confirm the favourable crystallographic conformation (about 4.0 kcal/mol) with the sulphur atom (I, III, V) located in the neighbourhood of the carbonyl function and the furanyl oxygen atom (II, IV) located at the opposite side. Fig.…”

Section: Fig 2 Atomic Numbering and Bond Lengths (ǻ) For (A) Compoumentioning

confidence: 59%

“…Other substituents (chlorine or methyl group) placed in that same position also lead to active compounds with the same structural properties: the 5-(5-chlorothien-2-yl)-2'-dUrd (Olivier et al, 1994) and the 5-(5-methylthien-2-yl)-2'-dUrd (Creuven et al, 1995). If, however, the bromine atom is shifted from C 1 to C 3 of the thienyl ring (V), the affinity for HSV-1 TK decreases (61.4 µM) and the affinity is comparable with the affinity of the bromofuranyl congener (IV).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1996

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The crystal structures of 5-(5-furan-2-yl)-2'-deoxyuridine (II), 5-(5-bromofuran-2-yl)-2'-deoxyuridine (IV) and 5-(3-bromothien-2-yl)-2'-deoxyuridine (V) have been studied in order to explain the different affinity of the compounds for the herpes simplex virus type 1 (HSV-1) thymidine kinase. These compounds present a variable affinity according to the position of the heteroatom substituting the five-membered ring. An unfavourable substitution in the five-membered ring for interaction with the HSV-1 thymidine kinase has been identified.

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“…Previous results by others also show that uridines substituted with a bromoaryl (Herdewijn, 1994;Olivier et et., 1994) or with a 2-bromovinyl (Machida et sl., 1993;Herdewijn, 1994;Yokota et al, 1994) in the 5-position of the uracil, are biologically active. These results prompted us to further study the structure-activity relationships of bromophenyl substituted 2'-deoxyuridines by introducing a second meta-substituent in the phenyl ring.…”

Section: Introductionmentioning

confidence: 64%

Synthesis of Various 5-(5″-Substituted-3″-Bromophenyl)-2′-β-Deoxyuridines

Persson

Hörnfeldt

Gronowitz

et al. 1996

Antivir Chem Chemother

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SummaryA series of 5-(511-substituted-311-bromophenyl)-2'-~ deoxyuridines were prepared and investigated for their activity against HCMV and HIV. None of the compounds exhibited any activity against HIV at the highest concentration, 100 J.lg rnr". In the HCMV ELISA assay the EO so and COso values of the 5-(5 11-substituted-3 11-bromophenyl)-2'-deoxyuridines were about 60 J.lg rnr" and 150 J.lg rnr", respectively.

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Stereoelectronic properties of five anti-HSV-1 2′-deoxynucleosides analogues with heterocyclic substituents in the 5-position: A comparison with BVDU

Cited by 8 publications

References 19 publications

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

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

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

Synthesis of Various 5-(5″-Substituted-3″-Bromophenyl)-2′-β-Deoxyuridines

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