Structure-activity relationship of the affinity of 5-substituted uracil nucleoside analogues for varicella-zoster virus thymidine kinase and their activity against varicella-zoster virus

Ashida, Noriyuki; Watanabe, Yoko; Miura, Shinji; Kano, Fumitaka; Sakata, Shinji; Yamaguchi, Toyohumi; Suzutani, Tatsuo; Machida, Haruhiko

doi:10.1016/s0166-3542(97)00026-0

Cited by 15 publications

(11 citation statements)

References 20 publications

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“…Another practice is the replacement of a hydroxyl group with fluorine to generate a fluorinated enzyme substrate or inhibitor in a given enzymatic process. − Such a strategy is rationalized by electronic similarities between a fluorine atom and a hydroxyl group, with particular reference to polarity as well as the close isosteric relationship between fluorine and oxygen; thus, such substitution introduces a small structural disturbance. , Recently, nucleotides and nucleosides containing sugar fragments in which OH groups have been substituted with fluorine atoms are the focus of increasing interest. Some of these compounds are potential drugs, as they display anticancer activity. − Some are active against various viruses, including hepatitis B, − Epstein–Barr, varicella zoster, and HIV. − …”

Section: Introductionmentioning

confidence: 99%

“…Some of these compounds are potential drugs, as they display anticancer activity. 59−62 Some are active against various viruses, including hepatitis B, 63−65 Epstein−Barr, 66 varicella zoster, 67 and HIV. 68−71 Nowadays there are many drugs containing F and/or CF 3 as a substituent (in parentheses the kind of the substituent in shown), including the antipsychotics fluphenazine (CF 3 ), 72 flupentixol (CF 3 ), 73 haloperidol (F), 74 and risperidone (F); 75 the antidepressants fluoxetine (CF 3 ), 76 citalopram (F), 77 and fluvoxamine (CF 3 ); 78 and the anxiolytics 79 flunitrazepam (F) 80 and midazolam (F).…”

Section: Introductionmentioning

confidence: 99%

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Toward a Physical Interpretation of Substituent Effects: The Case of Fluorine and Trifluoromethyl Groups

et al. 2014

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The application of ab initio and DFT computational methods at six different levels of theory (MP2/cc-pVDZ, MP2/aug-cc-pVTZ, B3LYP/cc-pVDZ, B3LYP/aug-cc-pVTZ, M06/cc-pVDZ, and M06/aug-cc-pVTZ) to meta- and para-substituted fluoro- and trifluoromethylbenzene derivatives and to 1-fluoro- and 1-trifluoromethyl-2-substituted trans-ethenes allowed the study of changes in the electronic and geometric properties of F- and CF3-substituted systems under the impact of other substituents (BeH, BF2, BH2, Br, CFO, CHO, Cl, CN, F, Li, NH2, NMe2, NO, NO2, OH, H, CF3, and CH3). Various parameters of these systems have been investigated, including homodesmotic reactions in terms of the substituent effect stabilization energy (SESE), the π and σ electron donor-acceptor indexes (pEDA and sEDA, respectively), the charge on the substituent active region (cSAR, known earlier as qSAR), and bond lengths, which have been regressed against Hammett constants, resulting mostly in an accurate correspondence except in the case of p-fluorobenzene derivatives. Moreover, changes in the characteristics of the ability of the substituent to attract or donate electrons under the impact of the kind of moiety to which the substituent is attached have been considered as the indirect substituent effect and investigated by means of the cSAR model. Regressions of cSAR(X) versus cSAR(Y) for any systems X and Y allow final results to be obtained on the same scale of magnitude.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toward a Physical Interpretation of Substituent Effects: The Case of Fluorine and Trifluoromethyl Groups

et al. 2014

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“…Some of these compounds are potential medicines, as they have anticancer activity 58–63. Some are active against various viruses, including hepatitis B 64–66, Epstein–Barr 67, Varicella zoster 68, and HIV 69–72. Oligonucleotides whose sugar residues are modified by replacement of a OH group by a F atom were shown to be useful in gene therapy 73–76.…”

Section: Introductionmentioning

confidence: 99%

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Hoffmann

Rychlewski

2002

Int J of Quantum Chemistry

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ABSTRACT:In this article, we deal with the question of whether a fluorine atom can substitute a hydroxyl group in such a way that will lead to a compound showing a desired biologic activity, that is, a potential new drug. It is obvious that a fluorine atom differs from a hydroxyl group, as it cannot donate hydrogen bonds. However, it can accept them. Moreover, both fluorine and oxygen are of similar size and are the most electronegative elements. Therefore, a fluorine atom is thought to be a good substitute for a hydroxyl group. However, it was shown that for conformationally labile aliphatic compounds a replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorinecontaining aliphatic molecules are present in equilibrium at room temperature as a mixture of several different conformers. In contrast, for cyclic compounds the substitution of an OH group by an F atom does not much change shape and electrostatic potential around corresponding conformers. Moreover, these compounds are present in equilibrium at room temperature in aqueous solution as a mixture of the same most favored structures.

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“…For example, BVDU (De Clercq, 2004) has more than 10 3 -fold superiority in potency over acyclovir (Roberts et al, 1991;Ashida et al, 1997;Kussmann-Gerber et al, 1998;Sienaert et al, 2002). In the case of the Y21E thymidine kinase mutant, the IC 50 value for this class of inhibitors seems to be very similar to the wild type, whereas for Y21H thymidine kinase, the IC 50 value was increased approximately 10-fold.…”

Section: Resultsmentioning

confidence: 99%

Mutations Distal to the Substrate Site Can Affect Varicella Zoster Virus Thymidine Kinase Activity: Implications for Drug Design

Omari¹,

Liekens²,

Bird³

et al. 2006

Molecular Pharmacology

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Varicella zoster virus encodes a thymidine kinase responsible for the activation of antiherpetic nucleoside prodrugs such as acyclovir. In addition, herpes virus thymidine kinases are being explored in gene/chemotherapy strategies aimed at developing novel antitumor therapies. To investigate and improve compound selectivity, we report here structure-based site-directed mutagenesis studies of varicella zoster virus thymidine kinase (VZVTK). Earlier reports showed that mutating residues at the core of the VZVTK active site invariably destroyed activity; hence, we targeted more distal residues. Based on the VZVTK crystal structure, we constructed six mutants (E59S, R84V, H97Y/A, and Y21H/E) and tested substrate activity and competitive inhibition for several compound series. All VZVTK mutants tested retained significant phosphorylation activity with dThd as substrate, apart from Y21E (350-fold diminution in the k cat /K m ). Some mutations give slightly improved affinities: bicyclic nucleoside analogs (BCNAs) with a p-alkyl-substituted phenyl group seem to require aromatic ring stacking interactions with residue 97 for optimal inhibitory effect. Mutation Y21E decreased the IC 50 value for the BCNA 3-(2Ј-deoxy-␤-(Cf1368) 4-fold, whereas mutation Y21H increased the IC 50 value by more than 15-fold. These results suggest that residue 21 is important for BCNA selectivity and might explain why HSV1TK is unable to bind BCNAs. Other mutants, such as the E59S and R84V thymidine kinases, which in wild-type VZVTK stabilize the dimer interface, give opposite results regarding the level of sensitivity to BCNAs. The work described here shows that distal mutations that affect the VZVTK active-site may help in the design of more selective substrates for gene suicide therapy or as anti-varicella zoster virus drugs.

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Structure-activity relationship of the affinity of 5-substituted uracil nucleoside analogues for varicella-zoster virus thymidine kinase and their activity against varicella-zoster virus

Cited by 15 publications

References 20 publications

Toward a Physical Interpretation of Substituent Effects: The Case of Fluorine and Trifluoromethyl Groups

Toward a Physical Interpretation of Substituent Effects: The Case of Fluorine and Trifluoromethyl Groups

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Mutations Distal to the Substrate Site Can Affect Varicella Zoster Virus Thymidine Kinase Activity: Implications for Drug Design

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