DEPARTMENT OF PHARMACEUTICAL CHEMISTRY - RESEARCH

 

Research Areas

I.                Antibiotic chemistry

 

1.     Modification of semisynthetic glycopeptide antibiotics with lipophilic side chains

 

Csávás, M.,  Miskovics A.,  Szűcs, Zs.,  Rőth E., Nagy, Zs. L.,  Bereczki, I.,  Herczeg, M., Batta, Gy.,  Nemes-Nikodém, É., Ostorházi, E.,  Rozgonyi, F.,  Borbás, A., Herczegh, P.:

Synthesis and antibacterial evaluation of some teicoplanin pseudoaglycon derivatives containing alkyl- and arylthiosubstituted maleimides

 

Journal of Antibiotics, 68 (9) 579-585 (2015). DOI: 10.1038/ja.2015.33

Abstract: Bis-alkylthio maleimido derivatives have been prepared from teicoplanin pseudoaglycon by reaction of its primary amino group with N-ethoxycarbonyl bis-alkylthiomaleimides. Some of the new derivatives displayed excellent antibacterial activity against resistant bacteria.

 

2.     Synthesis of glycopeptides having antiviral effect

 

Ilona Bereczki, Máté Kicsák, Laura Dobray, Anikó Borbás, Gyula Batta, Sándor Kéki, Éva Nemes Nikodém, Eszter Ostorházi, Ferenc Rozgonyi, Evelien Vanderlinden, Lieve Naesens, Pál Herczegh

Semisynthetic teicoplanin derivatives as new influenza virus binding inhibitors: Synthesis and antiviral studies

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3251–3254.

 

 

 

 

Abstract: In order to obtain new, cluster-forming antibiotic compounds, teicoplanin pseudoaglycone derivatives containing two lipophilic n-octyl chains have been synthesized. The compounds proved to be poor antibacterials, but, surprisingly, they exhibited potent anti-influenza virus activity against influenza A strains. This antiviral action was related to inhibition of the binding interaction between the virus and the host cell. Related analogs bearing methyl substituents in lieu of the octyl chains, displayed no anti-influenza virus activity. Hence, an interaction between the active, dually n-octylated compounds and the lipid bilayer of the host cell can be postulated, to explain the observed inhibition of influenza virus attachment.

 

3.     Preparation of chimeric antibiotics containing fluoroquinolone carboxylic acid

 

 

II.              Carbohydrate chemistry

 

1.     Synthesis of thio-linked glycomimetics by photoinduced hydrothiolation of unsaturated carbohydrates

 

Lázár, L., Csávás, M, Herczeg, M, Herczegh, P., Borbás, A.:

Synthesis of S-Linked Glycoconjugates and S-Disaccharides by Thiol-Ene Coupling Reaction of Enoses.

Organic Letters, 14, 4650-4653 (2012)

Abstract: Free-radical hydrothiolation of the endocyclic double bond of enoses is reported. Reaction between 2-acetoxy-D-glucal and a range of thiols including amino acid, peptide, glycosyl thiols, and sugars with primary or secondary thiol functions gave S-linked a-glucoconjugates and S-disaccharides with full regio- and stereoselectivity. Addition of glycosyl thiols to a 2,3-unsaturated glycoside also proceeded with good

selectivity and afforded a series of 3-deoxy-S-disaccharides.

 

 

 

2.     Synthesis of multivalent carbohydrates as potential ligands of bacterial lectins

 

Magdolna Csávás, Lenka Malinovská, Florent Perret, Milán Gyurkó, Zita Tünde Illyés, Michaela Wimmerová, Anikó Borbás:

Tri- and tetravalent mannoclusters cross-link and aggregate BC2L-A lectin from Burkholderia cenocepacia

Carbohydr. Res., 437, (2017) 1-8.

Abstract:The opportunistic Gram-negative bacterium Burkholderia cenocepacia causes lethal infections in cystic fibrosis patients. Multivalent mannoside derivatives were prepared as potential inhibitors of lectin BC2LA, one of the virulence factors deployed by B. cenocepacia in the infection process. An (a1/2)-thiolinked mannobioside mimic bearing an azide functionalized aglycon was conjugated to different multivalent scaffolds such as propargylated calix[4]arenes, methyl gallate and pentaerythritol by azidealkyne 1,3-dipolar cycloaddition. The interaction between the glycoclusters and the mannose binding BC2L-A lectin from B. cenocepacia was examined by isothermal microcalorimetry, surface plasmon resonance, inhibition of yeast agglutination and analytical ultracentrifugation.

  

3.     Preparation of carbohydrate-antibiotic chimeras

 

4.     Novel synthesis of idose/iduronic acid monosaccharide building blocks  and heparinoid oligosaccharides

Herczeg, M., Lázár, L., Bereczky, Z., Köver, K. E., Timári, I., Kappelmayer, J., Lipták, A., Antus, S., Borbás, A.:

Synthesis and Anticoagulant Activity of Bioisosteric Sulfonic-Acid Analogues of the Antithrombin-Binding Pentasaccharide Domain of Heparin.

Chem. Eur. J., 18, 10643-10652 (2012)

Abstract: Two pentasaccharide sulfonic acids that were related to the antithrombin-binding domain of heparin were prepared, in which two or three primary sulfate esters were replaced by sodium-sulfonatomethyl moieties. The sulfonic-acid groups were formed on a monosaccharide level and the obtained carbohydrate sulfonic-acid esters were found to be excellent donors and acceptors in the glycosylation reactions. Throughout the synthesis, the hydroxy groups to be methylated were masked in the form of acetates and the hydroxy groups to be sulfated were masked with benzyl groups. The disulfonic-acid analogue was prepared in a [2+3] block synthesis by using a trisaccharide disulfonic acid as an acceptor and a glucuronide disaccharide as ma donor. For the synthesis of the pentasaccharide trisulfonic acid, a more-efficient approach, which involved elongation of the trisaccharide acceptor with a non-oxidized precursor of the glucuronic acid followed by post-glycosidation oxidation at the tetrasaccharide level and a subsequent [1+4] coupling reaction, was elaborated. In vitro evaluation of the anticoagulant activity of these new sulfonic-acid derivatives revealed that the disulfonate analogue inhibited the blood-coagulation-proteinase factor Xa with outstanding efficacy; however, the introduction of the third sulfonic-acid moiety resulted in a notable decrease in the anti-Xa activity. The difference in the biological activity of the disulfonic- and trisulfonicacid counterparts could be explained by the different conformation of their L-iduronic-acid residues.

 

5.     Synthesis of sulfonic acid analogues of sialic acid and investigation of their antiviral effect

 

6.     Synthesis and characterisation of carbohydrate based nitrogen-containing tricycles

 

7.     Synthesis of nucleic acid analogues

 

III.            Others

 

1.     Synthesis of aspirin-hybrids

 

2.     Development of protecting group strategies

Máté Kicsák, Miklós Bege,  Ilona Bereczki, Magdolna Csávás, Mihály Herczeg, Zoltán Kupihár, Lajos Kovács, Anikó Borbás, Pál Herczegh:

A three-component reagent system for rapid and mild removal of O-, N- and S-trityl protecting groups.

Org. Biomol. Chem., 14 (12) (2016) 3190-3192.

A new reagent system consisting of a Lewis acid such as BF3·Et2O or Cu(OTf)2, the mild protic acid hexafluoroisopropanol and the reducing quenching agent triethylsilane was elaborated for O-, N- and S-detritylation of nucleoside, carbohydrate and amino acid derivatives. The method is compatible with acetyl, silyl, acetal and Fmoc groups.

RESEARCH GRANTS:

OTKA K109208 2013-2017.

Thio-click approach for the synthesis of peptide-oligonucleosides , oligomannoside mimetics and chiral crown ethers

PI: Prof. Borbás Anikó

NKFIH K16 K119509 2016-2020

Synthesis and antibacterial evaluation of semisynthetic glycopeptides and multivalent carbohydrates

PI: Dr. Csávás Magdolna

NKFIH Indiai-magyar TÉT pályázat 2016-2020

Thio-click approach for the synthesis of stable glycomimetics and chiral oxathiocrown ethers

PI: Dr. Borbás Anikó

DECHEM GINOP-2.3.2-15-2016-00008 2016-2020

Participants: Prof. Anikó Borbás, Prof. Pál Herczegh, Dr. Magdolna Csávás, Dr. Mihály Herczeg, Dr. Erika Mező, Dr. Máté Kicsák, Dr. Miklós Bege, Dr. Zsolt Szűcs, Dániel Eszenyi

PHARMPROT GINOP-2.3.2-15-2016-00044 2016-2020

Participants: Prof. Pál Herczegh, Prof. Anikó Borbás

OTKA PD 115645 2015-2018

Synthesis of 6-deoxy-L-talopyranoside-containing Idraparinux derivatives with potential anticoagulant activity

PI: Dr. Herczeg Mihály

INTERNATIONAL COLLABORATIONS

 

1.     Florent Perret

University Claude Bernard

Institut  de Chimie et de Biochimie Moleculaire et Supramoléculaire

 

2.     Lenka Malinovska, Gita Jancarikova

Masaryk University

Central European Institute of Technology (CEITEC)

 

3.     Gabriela Novotna

Academy of Sciences of the Czech Republic         

Institute of Microbiology

 

4.     Lieve Naesens

Rega Institute for Medical Research

 

5.     Margaret Dah-Tsyr Chang

National Tsing Hua University

Institute of Molecular and Cellular Biology

 

6.     Cheng Hsun-Chiu

Chang Gung University        

Molecular Infectious Diseases Research Center, Chang Gung Memorial Hospital

 

7.     Andrey E. Shchekotikhin

Gause Institute of New Antibiotics Russian Academy of Sciences           

Head of Laboratory of Chemical Transformations of Antibiotics

 

8.     Michaela Wimmerová

Masaryk University  

National Centre for Biomolecular Research, Faculty of Science

 

9.     Yuan-Chuan Lee

Johns Hopkins University

Department of Biology

 

10.  Mark von Itzstein

Griffith University

Institute for Glycomics