Fluorescent Tricyclic Analogues of Acyclovir and Ganciclovir. A Structure−Antiviral Activity Study

Golankiewicz, Bożenna; Ostrowski, Tomasz; Gośliński, Tomasz; Januszczyk, Piotr; Zeidler, Joanna; Baranowski, Daniel; Clercq, Erik De

doi:10.1021/jm010922s

Cited by 43 publications

(22 citation statements)

References 12 publications

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“…1) were shown to be effective inhibitors of HSV-1 thymidine kinase (TK) and are of interest as they maintain the inhibitory activity against the enzyme and, as they are more lipophilic than the current medications, may be valuable agents for the treatment of CNS infections. [11][12][13] Moreover, these tricyclic compounds were found to exhibit strong intrinsic fluorescent properties, which allows for sensitive concentration monitoring and optimal therapeutic dosing. [11][12][13] Penciclovir (PCV) and hydroxybutylguanine (HBG) (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives

Mohammed

Andrei

Hayallah

et al. 2019

Bioorganic & Medicinal Chemistry

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A B S T R A C TA series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-C 6 H 4 ) displayed good inhibitory activity (HSV-1 EC 50 1.5 μM, HSV-2 EC 50 0.8 μM) and retained inhibitory activity in HSV-1 TK − cells (EC 50 0.8 μM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds. 100:0 to 94:6 v/v to give the product as a white solid. Yield: 0.19 g62%), m.p. 288-290°C, TLC (CH 2 Cl 2 -MeOH 95:5 v/v) Rf 0.31. 1 H NMR (DMSO-d 6 ): δ 1.43 (quint, 2H, J = 7.5 Hz, H-3′), 1.85 (quint, 2H, J = 7.5 Hz, H-2′), 3.42 (q, 2H, J = 5.4 Hz, H-4′), 4.11 (t, 2H, J = 7.0 Hz, H-1′), 4.49 (t, 1H, J = 5.0 Hz, OH), 7.34 (t, 2H, J HF = 8.9 Hz, H-3″ and H-5″), 7.96 (dd, 2H, J HF = 5.0, 9.0 Hz, H-2″ and H-6″), 7.96 (s, 1H, H-2), 8.22 (d, 1H, J = 2.0 Hz, H-7), 13.09 (br.s,

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Section: Introductionmentioning

confidence: 99%

“…[11][12][13] Moreover, these tricyclic compounds were found to exhibit strong intrinsic fluorescent properties, which allows for sensitive concentration monitoring and optimal therapeutic dosing. [11][12][13] Penciclovir (PCV) and hydroxybutylguanine (HBG) (Fig. 1) are the carbocyclic analogues of GCV and ACV, respectively.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives

Mohammed

Andrei

Hayallah

et al. 2019

Bioorganic & Medicinal Chemistry

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“…A series of new guanine base modified tricyclic analogues of ACV and ganciclovir were evaluated for activity against herpes simplex virus type 1 and 2, showing similar antiherpetic potency as the parent compounds ACV and ganciclovir [8]. The antiherpetic activity was found to be strongly dependent on the nature and esteric demands of the substituents in the 6 and/or 7 positions [9]. …”

Section: Introductionmentioning

confidence: 99%

Conformational Analysis, Molecular Structure and Solid State Simulation of the Antiviral Drug Acyclovir (Zovirax) Using Density Functional Theory Methods

Álvarez-Ros

Palafox

2014

Pharmaceuticals

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The five tautomers of the drug acyclovir (ACV) were determined and optimised at the MP2 and B3LYP quantum chemical levels of theory. The stability of the tautomers was correlated with different parameters. On the most stable tautomer N1 was carried out a comprehensive conformational analysis, and the whole conformational parameters (R, β, Φ, φ1, φ2, φ3, φ4, φ5) were studied as well as the NBO Natural atomic charges. The calculations were carried out with full relaxation of all geometrical parameters. The search located at least 78 stable structures within 8.5 kcal/mol electronic energy range of the global minimum, and classified in two groups according to the positive or negative value of the torsional angle φ1. In the nitrogen atoms and in the O2' and O5' oxygen atoms of the most stable conformer appear a higher reactivity than in the natural nucleoside deoxyguanosine. The solid state was simulated through a dimer and tetramer forms and the structural parameters were compared with the X-ray crystal data available. Several general conclusions were emphasized.

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“…Recently, we designed a number of acyclovir and ganciclovir derivatives that are endowed with intrinsic strong fluorescent characteristics by synthesizing tricyclic ACV and GCV derivatives containing an additional aromatic entity attached to the purine system ( Figure 1). 10 These tricyclic purine nucleoside analogues (TPNAs) turned out to be potent and selective anti-herpesvirus agents, several of which were as potent antiviral agents as the parental ACV and GCV (Ref. 10 and manuscript submitted).…”

Section: Introductionmentioning

confidence: 99%

“…10 These tricyclic purine nucleoside analogues (TPNAs) turned out to be potent and selective anti-herpesvirus agents, several of which were as potent antiviral agents as the parental ACV and GCV (Ref. 10 and manuscript submitted). Encouraged by these observations, we also investigated these novel compounds for their potential to be used in the combined gene/chemotherapy of cancer cells transduced with the HSV-1 TK gene.…”

Section: Introductionmentioning

confidence: 99%

Pronounced cytostatic activity and bystander effect of a novel series of fluorescent tricyclic acyclovir and ganciclovir derivatives in herpes simplex virus thymidine kinase gene-transduced tumor cell lines

et al. 2002

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A number of tricyclic acyclovir (ACV) and ganciclovir (GCV) derivatives substituted with bulky lipophilic groups have been identified as potent and highly selective cytostatic agents against herpes simplex virus type 1 (HSV-1)-thymidine kinase (TK) gene-transduced human osteosarcoma and murine mammary carcinoma tumor cells. Although their affinity for HSV-1 TK was inferior to that of ACV or GCV, their cytostatic potency and selectivity was at least as high as observed for the parental ACV and GCV compounds. The tricyclic ACV and GCV derivatives were also endowed with

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Fluorescent Tricyclic Analogues of Acyclovir and Ganciclovir. A Structure−Antiviral Activity Study

Cited by 43 publications

References 12 publications

Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives

Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives

Conformational Analysis, Molecular Structure and Solid State Simulation of the Antiviral Drug Acyclovir (Zovirax) Using Density Functional Theory Methods

Pronounced cytostatic activity and bystander effect of a novel series of fluorescent tricyclic acyclovir and ganciclovir derivatives in herpes simplex virus thymidine kinase gene-transduced tumor cell lines

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