Contact info:

Coordinator of the Marie Curie Early Stage Training Site sEnDiChem:
"Sensing Endocrine Disrupting Chemicals: development of novel solid phase extraction systems"
http://www.sendichem.ugent.be (photos of the Yearly Progress Meeting 2007, not active yet)

Department of Organic Chemistry
Laboratorium for Organic and Biomimetic Chemistry
Ghent University
Krijgslaan 281, S4
B-9000 Gent
Belgium
Tel: +32 9 264 44 72
Fax: +32 9 264 49 98

email Prof. dr. Annemieke Madder: annemieke.madder@Ugent.be

• Design and synthesis of serine-protease mimics
  Oligopeptide Approach and Oligonucleotide Approach
  
• Novel techniques for cross-linking of biomacromolecules
  
• Construction of conformationally restricted multipodal peptide architectures
  Peptide vaccins, DNA binding ligands, oestrogen receptor mimics for EDC solid phase extraction
  

Nucleic acids on the other hand are uniquely suited for sequence-specific recognition of nucleic acids through Watson-Crick base pairing in oligonucleotides, even in very short sequences. This capability allows nucleic acid enzymes to carry out chemical transformations on nucleic acid substrates with high sequence specificity. A major drawback in using oligonucleotides in the design of synthetic catalysts is that they cannot provide functional groups with such diversity and properties as proteins in order to act as bases or Lewis acids. However, with the event of antisense research, a lot of functional group modified nucleoside building blocks have become known and available to synthetic organic chemists. Thus, it is tempting to equip oligonucleotides with the functional tools of peptide chains by building block modification. This should result in a powerful combination of both predefined structural organization (cf. duplex formation) and presence of catalytic entities. Depending on the specific site of incorporation of the functionalities in the nucleoside building blocks, different spatial positions within the duplex grooves can be reached.

The high specificity of nucleic acid - nucleic acid recognition has prompted significant interest in the design of modified oligonucleotides (ONs) that bind irreversibly to their complementary sequence via a covalent cross-link. Such ONs have been shown to interfere with natural nucleic acids and their fragments. This enables selective control of gene expression, leading to the development of potential therapeutics for cancer and a number of other diseases and even allows envisioning chemical alteration of genetic information.

The strategy of interstrand cross-linking is based on the use of ONs incorporating a reactive functionality which, upon hybridization, forms (a) covalent link(s) with the nucleic acid.

The furan moiety is also an interesting group for the postsynthetic modification of ONs. Once a convertible nucleoside unit is introduced into the ON, the ON can be modified with a variety of functional groups. In this case, the easily available and very reactive a,b -unsaturated aldehyde can be used in reactions with a number of nucleophiles. The possibility of converting the unreactive furan into a reactive enal moiety in aqueous conditions adds to the potential of the proposed method for the labeling of oligonucleotides with other hydrophilic entities such as peptides or carbohydrates. Finally, the oxidised furan moiety can also be used for DNA - protein cross-linking.

Proteins are implicated in almost all biological processes and represent some of the most potent and selective agents known. Yet the use of proteins as drugs is still significantly compromised by poor bioavailability characterised by poor penetration of membranes and low cellular uptake, instability of three dimensional protein structures, which unfold under a variety of conditions, antigenicity, and unfavourable pharmacokinetics due to instability of peptide bonds to degradation by peptidases.

It occurred to us that both templates 1 and 2 ( vide supra) are ideally suited for the construction of complex peptide architectures with defined structural preorganisation. Steroid derivative 1 will impose a rigid parallel orientation on the peptide chains. It is further known that many steroids are drugs with excellent oral bioavailability. Template 2 will result in a more flexible orientation that can be conformationally restrained by binding of a ligand in the cavity created by the three aromatic units. This molecule is easily accessible via a short synthetic sequence starting from simple and cheap starting materials.

We therefore concentrate on the use of these scaffolds in the follwing areas:

• Design and synthesis of new DNA-binding peptides:

Inclusion of the natural DNA binding sequences of the Leucine zipper proteins into 1 in order to construct dipodal DNA-binding ligands.

• Design and synthesis of a new type of peptide vaccins:

• Design and synthesis of oestrogen receptor mimics for EDC solid phase extraction:

In recent years the potential role of environmental pollutants with suspected endocrine activity (so-called endocrine disrupting chemicals or EDCs) in a variety of reproductive system-related abnormalities in humans and animals, has strongly been emphasized by the media. Fast and easy methods with low detection limits for the quantitative analysis of EDCs are urgently requested because more exposure data for risk assessment are necessary and synergistic effects of different EDCs are not ruled out. Of the various steps in a sample preparation procedure, the extraction/purification/separation step, which is present in almost all the known analytical procedures described in literature, is the most critical.

Based on the known structure of the receptor and the available data for the numerous receptor-ligand complexes, we aim at the synthesis of model compounds for the ER receptors based on the use of scaffold molecule 2 that allows for the generation of small to medium sized multipodal peptidomimetics with preferred conformation.

• Catherine Bodé (2007): “ Evaluation of a steroidal scaffold for the conformational restriction of peptides in the development of peptide vaccins."
  
  
• An Gea (2008): “Synthesis and evaluation of a new tripodal scaffold for use in combinatorial chemistry”

• Paulina Bloch (2008): “Synthesis of multipodal peptides as miniature protein models”
  
  
• Marta Gonzalez Gomez (2007): “Synthesis of active esters as new N-terminal peptide derivatising agents for use in the COFRADIC method”
  
  
• Marta Tarrés I Deulofeu (2006): “Synthetic efforts towards the construction of a new steroid scaffold for dipodal peptides”
  
  
• Marieke Op de Beeck (2006): “Synthese van hydroxyl-gefunctionaliseerde nucleosiden voor incorporatie in oligonucleotide-gebaseerde serineproteasen”
  
  
• Annelies Deceuninck (2005): “Bereiding van furan-gederivatiseerde peptiden voor DNA crosslinking via selectieve furan-oxidatie”
  
  
• Kristof Stevens (2004): Ontwikkeling van nieuwe hypericinederivaten voor toepassingen in fotodynamische therapie”
  
  
• Steven Van der Plas (2004): “Synthese van nucleoside-dieen bouwstenen voor incorporatie in gemodificeerde oligonucleotiden”
  
  
• Karel Aelvoet (2003): Studie naar de ontwikkeling van een nieuwe kleurtest voor de detectie van vrije alcoholfuncties op vaste fase”
  
  
• Nuria Roque I Rosell (2003): “Efforts towards the synthesis of a tripodal library for the discovery of serine-protease mimics”
  
  
• Stefan Meeus (2001): “Reactiviteitsstudie van een gekleurde paranitrofenylester, ontwikkeld voor de visuele detectie van op vaste fase gebonden amines”
  
  

• Up to date synthesis apparatus
• Automated analytical/semi-prep RPHPLC (Agilent 1100)
• HPLC facilities for very small, small and medium scale purification
• Extended mass spectrometry facilities: ESI, API, CI, EI, MALDI-TOF
• Extended NMR facilities: 300 MHz, 500 MHz, 700 MHz

Professor of Organic Chemistry
Faculty of Sciences
Ghent University

• July 1992
  Master in Chemistry, State University of Gent , Belgium, Faculty of Sciences.
  Undergraduate Thesis : "Synthesis of bridgehead compounds through hexatriene-cyclohexadiene electrocyclizations"
  Promotor: Prof. Dr. A. Lera;
  University of Santiago de Compostela; Spain
  
  
• February 1997 Doctor in Sciences, chemistry, State University of Gent, Belgium, Faculty of Sciences.
  Ph.D Thesis : "Stepwise development of non-enzymatic hydrolases"
  Promotor: Prof. Dr. P. J. De Clercq; Ghent University; Belgium

• 1992-1993
  IWONL PhD Grant
  
  
• 1993-1997
  Research Assistant of the belgian National Fund for Scientific Research at the Ghent University
  
  
• 1997
  Postdoctoral stay in the laboratory of Prof. Dr. C. Gennari, Dipartimento di Chimica Organica e Industriale Milano, Universita' di Milano, Italy
  "Synthesis of ligands for a library of b-turn mimetics"
  
  
• 1998-2002 Postdoctoral Research Assistant of the belgian National Fund for Scientific Research
  2000-2001; postdoctoral stay in the laboratory of Prof. Dr. R. Strömberg
  Division of Organic and Bioorganic Chemistry, Karolinska Institute, Stockholm, Zweden
  
  
• Since 1/10/2002 Professor of Organic Chemistry, Faculty of Sciences
  Ghent University

• 1996 VJC-prize : first prize awarded by the Royal Young Chemists Society (KVCV)
• 1996 DSM-prize in Chemistry and Technology : second prize awarded by DSM
• 1996 Varian Award for Analytical Chemistry : first prize awarded by Varian

• Evans pK a List ( http://daecr1.harvard.edu/pdf/evans_pKa_table.pdf )
• Bordwell pK a table (http://www.chem.wisc.edu/areas/reich/pkatable/)
• Name Reactions Index (http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/rindex.htm)
• Name Reactions (Merck Index) (http://themerckindex.cambridgesoft.com/TheMerckIndex/NameReactions/TOC.asp)
• Name Reactions (http://orgchem.chem.uconn.edu/namereact/named.html)
• Named Reagents (http://www.chem.wisc.edu/areas/reich/handouts/NameReagents/namedreag.htm)
• NMR Solvents (http://www.chem.wisc.edu/areas/reich/Handouts/nmr/NMR-Solvents.htm)