Anti-influenza virus activity and structure–activity relationship of aglycoristocetin derivatives with cyclobutenedione carrying hydrophobic chains

Naesens, Lieve; Vanderlinden, Evelien; Rőth, Erzsébet; Jekő, József; Andrei, Gracíela; Snoeck, Robert; Pannecouque, Christophe; Illyés, Eszter; Batta, Gyula; Herczegh, Pál; Sztaricskai, Ferenc

doi:10.1016/j.antiviral.2009.01.003

Cited by 51 publications

(52 citation statements)

References 26 publications

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“…The following control compounds were included: ribavirin (Virazole), obtained from ICN Pharmaceuticals; rimantadine (Sigma); and oseltamivir carboxylate (GS-4071) (a kind gift from T. Cihlar, Gilead Sciences, Foster City, CA). The test compounds were evaluated for anti-influenza virus activity by a multicycle cytopathic effect (CPE) reduction assay (28). MDCK cells were seeded into 96-well plates at 7,500 cells per well 16 h prior to infection and incubated at 35°C.…”

Section: General Synthesis Of 2 (Series Ii)mentioning

confidence: 99%

Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin

Vanderlinden

Göktaş

Cesur

et al. 2010

J Virol

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147

175

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Currently available drugs for the prevention and treatment of seasonal influenza virus infections are the M2 ion channel blockers (amantadine and rimantadine) and the neuraminidase (NA) inhibitors (oseltamivir and zanamivir) (9). The clinical usefulness of amantadine and rimantadine is limited due to the increasing incidence of adamantane-resistant viruses in the population (3, 11). Moreover, the M2 ion channel blockers inhibit only influenza A virus replication and are associated with neurological side effects. NA inhibitors are favored clinically, since they are effective against all NA subtypes, are well tolerated, and have a higher barrier for resistance (27). However, drug-resistant isolates have been detected in A/H3N2-and A/H5N1-infected patients receiving oseltamivir treatment (10, 16). Even more reason for concern is the recent and worldwide isolation of oseltamivir-resistant A/H1N1 mutants, even among untreated patients (17, 46). Oseltamivir and, to a lesser extent, zanamivir have been stockpiled as part of pandemic preparedness plans and form the cornerstone of the response to the recent outbreak of the swine flu A/H1N1 virus (39, 40). However, it is unclear whether these antivirals will be sufficient to deal with larger influenza epidemics, so there is an urgent need to develop antivirals that act on a novel influenza virus target.An attractive antiviral strategy is to block influenza virus entry into the host cell, a process in which the viral hemagglutinin (HA) plays a key role (42). HA is a trimeric envelope glycoprotein that contains two disulfide-linked polypeptide chains, HA1 and HA2. After attachment of the receptor binding domain in the HA1 subunit to sialic acid-containing cell surface glycans, the virion is internalized by endocytosis. The acidic pH of the endosome leads to an extensive and irreversible conformational change of the HA protein, resulting in exposure of the fusion peptide, which inserts into the endosomal target membrane of the host cell (18). After fusion of the viral and endosomal membranes, the viral ribonucleoproteins are released into the cytosol and transported into the nucleus, where replication occurs (6). Crystallographic studies have provided detailed insight into the processes of HA refolding and extrusion of the fusion peptide (4). The latter is a sequence of hydrophobic amino acids located at the N terminus of the HA2 subunit, which is, in the prefusogenic conformation, sequestered in a pocket of ionizable residues at the monomer interface of the HA trimer (48). In order to exploit the HA protein as an antiviral target, several small-molecule inhibitors that block the acid-induced conformational change of HA have been identified (2,19,21,30,49). For many of these, development has been hindered by their subtype-dependent activities. On the other hand, these diverse fusion inhibitors represent excellent tools to identify the HA amino acid residues involved in the fusion process and/or delineate the structural differences among HA subtypes (36). We report here the i...

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Section: General Synthesis Of 2 (Series Ii)mentioning

confidence: 99%

Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin

Vanderlinden

Göktaş

Cesur

et al. 2010

J Virol

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147

175

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“…11 Briefly, the antiviral activity was expressed as the 50% effective concentration (EC 50 ), or compound concentration producing 50% inhibition of influenza virus replication (as determined by microscopic or spectrophotometric assays). These experiments also allowed to estimate the cytotoxicity of the test compounds.…”

Section: Introductionmentioning

confidence: 99%

Click reaction synthesis of carbohydrate derivatives from ristocetin aglycon with antibacterial and antiviral activity

Pintér

Bereczki

Batta

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tNew sugar derivatives of ristocetin were prepared by copper-catalyzed 1,3-dipolar cycloaddition reaction using azido-ristocetin aglycon and various propargyl glycosides. Some of them were found to be active against Gram-positive bacteria and showed favorable antiviral activity against the H1N1 subtype of influenza A virus.Ó 2010 Elsevier Ltd. All rights reserved. rhamnose from ristocetin A removes this aggregating property. In a systematic study with aglyco-ristocetin 5 (2) (Scheme 1) derivatives we found that deglycosylation of 1 retains the antibacterial activity, however 2 is not suitable for platelet aggregation tests due to its very low solubility in water. To improve solubility, we prepared derivatives of 2 containing b-D-glucopyranosyl and b-Dmaltosyl substituents attached through an N-glycosylthiourea moiety. 6 These derivatives possessed good antibacterial activity and did not induce platelet aggregation. These promising results prompted us to perform a systematic study on the influence of various sugar substituents on the biological activity of derivatives of 2. In this work we here report on the synthesis and biological activity of several new sugar derivatives of 2. For conjugation of 1 we have chosen D-glucose, D-mannose and L-rhamnose, since the ristocetin molecule also contains these saccharides. Another glycopeptide antibiotic, teicoplanin has N-acetyl-D-glucosamine substituent, consequently this sugar was also chosen for the derivatisation of 1. Following our diazo-transfer-click reaction sequence 7 3 was chosen as the starting compound. Copper-catalyzed 1,3-dipolar cycloaddition reaction ('click reaction') 8 of the latter with per-O-acetylated propargyl glycosides 9 resulted in the carbohydrate-substituted aglycons 4a-8a. Zemplén deacetylation 10 of the sugar acetate moieties led to the glycosyl-oxymethyl-triazolyl derivatives of the ristocetin aglycon carrying saccharides with a-D-Evaluation of the biological properties of these derivatives (including the per-O-acetates) against Gram-positive bacteria demonstrated that introduction of the sugar moieties at the N-terminus into the ristocetin A aglycon molecule had a beneficial effect on the antibacterial activity. From an analysis of the data summarized in Table 1, it can be seen that the most of the new derivatives displayed higher activity than 1. The sugar derivatives 4-7 had good to excellent bacteriostatic activity against the test organisms, including glycopeptide-resistant enterococci. Interestingly, in this small group of compounds, the configuration of the sugar part (D-sugars) exhibited only a slight influence on the MIC values.0960-894X/$ -see front matter Ó

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“…The anti-influenza virus activity and cytotoxicity were investigated as described previously by Naesens et al [8]. As expected, the reference compounds oseltamivir carboxylate (the active form of Tamiflu ® ; a kind gift from Dr. T. Cihlar, Gilead Sciences) and ribavirin (ICN Pharmaceuticals) were active against influenza virus; their EC 50 values were clearly lower than their MCC values (concentrations causing minimal cytotoxicity) (l " Table 3).…”

Section: Anti-influenza Virus and Cytotoxicity Testmentioning

confidence: 99%

“…The new compounds are related to the other isolated compounds which are characterized by the presence of xanthone moieties functionalized with hydroxy groups. We report herein the structure of the isolated compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) and their cytotoxic, anti-influenza and HIV replication activities.…”

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confidence: 99%

Cytotoxicity of Natural Compounds Isolated from the Seeds ofGarcinia afzelii

Lannang¹,

Louh²,

Biloa³

et al. 2009

Planta Med

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The new compounds guttiferone O ( 1) and 3-methoxycheffouxanthone ( 2) have been isolated from the seeds of Garcinia afzelii Engl., together with nine known compounds: 2-hydroxy-1,7-dimethoxyxanthone ( 3), smeathxanthone A ( 4), 1,5-dihydroxyxanthone ( 5), 1,6-dihydroxy-5-methoxyxanthone ( 6), cheffouxanthone ( 7), 1,3,5-trihydroxyxanthone ( 8), smeathxanthone B ( 9), isoxanthochymol ( 10) and guttiferone E ( 11). Their structures were elucidated by means of 1D and 2D-NMR techniques. All the isolates showed high cytotoxic activity and were found inactive when tested against HIV and influenza viruses.

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Anti-influenza virus activity and structure–activity relationship of aglycoristocetin derivatives with cyclobutenedione carrying hydrophobic chains

Cited by 51 publications

References 26 publications

Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin

Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin

Click reaction synthesis of carbohydrate derivatives from ristocetin aglycon with antibacterial and antiviral activity

Cytotoxicity of Natural Compounds Isolated from the Seeds ofGarcinia afzelii

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