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Fluorinated Molecules and Medicinal Chemistry

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From left to right, in front: Julia Kaffy, Leyla Vahdati, Sandrine Ongeri, Sophie Decamps, Katia Fera, Thierry Milcent.
Behind: Marius Mamone, Benoît Crousse, Guillaume Bernadat, Dimitri Brinet, Shu Tao, Tâp Ha Duong and Jean-Louis Soulier.

The research pursued in our group focuses on new synthetic methodologies, involving organofluorine and peptide chemistry, devoted to medicinal chemistry and effort towards new processes respectful of environment. The group has a long lasting experience in biologically active molecules where the introduction of fluoroalkyl substituents can improve the pharmacological profile of drugs. Typical examples are fluorinated peptidomimetics and analogs of natural products: artemisinin derivatives (anti-malaria and anti-cancer) and styryl lactone analogs (anti-tumor). Our group has also a long experience in the peptidomimetic units design and synthesis as inhibitors of protein-protein interactions: anti-infectious (anti HIV), anti-tumor drugs (proteasome) and inhibition of amyloide aggregation. Here are depicted the main research thematics of the group:


Directors

Pr. S. Ongeri and Dr. B. Crousse


Expertises area

  • anti-Alzheimer’s agents (mimics of β-strands and β-sheets, β-sheet breakers)
  • anti-tumor agents (proteasome inhibitors)
  • anti-infectious agents (HIV-1 protease, cabapenemase inhibitors)
  • Protein-protein interaction
  • Fluorine chemistry, fluorous phase
  • Peptidic and peptidomimetic synthesis


Collaborations

  • UMR 8612, University Paris Sud, France: Pr. M. Taverna (capillary electrophoresis)
  • P. & M. Curie University, Paris, France: Pr. Reboud (HIV-1 PR, proteasome); Pr. Lequin, Dr. Khemtemourian (NMR conformational studies, fluorescence spectroscopy, CD)
  • University Insubria and Università degli Studi di Milano, Italy (Pr. Piarulli, Pr. Gennari, Pr. Gelmi)
  • Central Glass Ltd, Japan (fluorinated reagents)
  • Tosoh Ltd, Japan (fluorinated reagents)
  • Fiocruz, Rio de Janeiro, Brazil (natural products, medicinal chemistry)


Permanent people

  • Dr. Danièle Bonnet-Delpon - Director of research CNRS “Emerite”
  • Dr. Benoît Crousse – Director of research CNRS
  • Pr. Tâp Ha-Duong - Professor in Molecular Modelling
  • Dr. Julia Kaffy - Assistant Professor in Medicinal Chemistry
  • Dr.Thierry Milcent - Assistant Professor in Medicinal Chemistry
  • Pr. Sandrine Ongeri - Professor in Medicinal Chemistry
  • Dr. Jean-Louis Soulier - Research Engineer CNRS
  • in sept 2013 - Assistant Professor in Molecular Modelling


Students/Post-docs/Non permanent people:

  • D. Brinet - Ph D. Student
  • S. Decamps - Ph D. student
  • J. Hao - Ph D. Student
  • M. Mamone - Ph D. Student
  • L. Thi-Thuy - Ph D. Student
  • M. N. Tonali - Ph D. Student
  • L. Vahdati – Ph D. Student (Co-tutoring with Università Insubria University, Italy)
  • Y. Xu - Ph D. Student


Fluorinated molecules of biological interest, natural products (artemisinin, goniothalamin)

One of the big program of the team these last years was the improvement of the pharmacological profile of natural products and their by-products by introduction of fluoroalkyl groups. In particular two molecules have attracted our interest: the antimalarial artemisinin and the antitumoral goniothalamine, but which suffer from a bad oral bioavailability (artemisinin) and from side effects like genotoxicity and embryotoxicity (goniothalamin). The introduction of a fluoroalkyl group on the strategic positions allowed the development of new generations of molecules possessing better pharmacological properties.

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Fluorous phase, fluorinated alcohols, supramolecular associations

Fluoroalkyl alcohols TFE and HFIP possessed particular properties (acidity, polarity, high H-Bond donor, …), and allowed to perform clean and selective reactions without external promotor (Lewis acid, or Brönsted acid).

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Fluorinated scaffolds and peptidomimetics (Physicochemical and Biological properties, New Methodologies of synthesis)

Fluorine has become a fundamental tool in the development of drugs. Trifluoromethylated compounds are particularly important, as shown by the number of CF3-containing drugs and drug-candidates in clinical use or in development.

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Design and synthesis of fluorinated Carbapenemase inhibitors (LabEx LERMIT)

http://www.labex-lermit.fr/fr/recherche/projets/resistance/r1

Targeting carbapenemases for fighting antibiotic-resistant Gram-negative bacteria

Multidrug resistant (MDR) gram-negative pathogens, especially Enterobacteriaceae, are emerging worldwide. The MDR pattern is relatively common with resistance appearing to all major classes of anti-gram-negative agents (e.g. β-lactams, fluoroquinolones, and aminoglycosides), and in some cases, resistance to all available drugs. This is particularly worrisome in view of the current dearth of new compounds active against MDR gram-negatives in the pipeline.

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Peptidomimetics as modulators of Protein-Protein Interactions (PPIs) involving β-sheets (mimics of β-strands and β-sheets, β-sheet breakers)

Physiological or aberrant, protein-protein interactions can be associated to a large number of pathologies. Small protein fragments are involved in these interactions, called “hot-spot”. They are well defined secondary structure (α-helices, β-turn and/or β-sheets).

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Biophysicochemistry

The biophysicochemistry tools are particularly important for the evaluation of the activity on different targets of our molecules and also in the comprehension at the molecular level of the mechanism of the pathological aggregation process.

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Molecular modelling

The goal of the “molecular modelling” team is to support rational design of new compounds targetting biological molecules and complexes, using various up-to-date in silico techniques, including quantum molecular calculations, all-atom molecular dynamics simulations, and coarse-grained modelling.

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Publications (2008-)

Structure-activity Relationships of Sugar-based peptidomimetics as modulators of amyloid B-peptide early oligomerization and fibrillization; J. Kaffy, D. Brinet, J-L Soulier, L. Khemtémourian, O. Lequin, M. Taverna, B. Crousse, S. Ongeri, Eur. J. Med. Chem. 2014,in press. An improved CE method for the In vitro monitoring of the challenging early steps of the Aβ1-42 peptide oligomerization: application to anti-Alzheimer’s drug discovery. D. Brinet, J. Kaffy, F. Oukacine, S. Glumm, S. Ongeri, (...)

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A Cover paper

Novel regioisomers of trifluoromethylated cyclopropanes have been synthesized by Michael addition and nucleophilic cyclization process. The reaction was carried out with the trifluoromethylcrotonate and nucleophilic reagents. Fluorinated cyclopropanes were obtained with good to excellent diastereoselectivities. Furthermore, interesting constrained building blocks have emerged from this methodology.

Access to novel amino trifluoromethyl cyclopropane carboxylic acid derivatives. Massaba Keita, Rocco De Bona, Mickael Dos Santos, Olivier Lequin, Sandrine Ongeri, Thierry Milcent, Benoit Crousse Tetrahedron 2013 69 (15), 3308.

http://dx.doi.org/10.1016/j.tet.2013.02.012

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Bioorganic and Medicinal Chemistry of Fluorine (Book)
J.-P. Bégué et D. Bonnet-Delpon

Edition - June 2008
72.90 Euro
2008. 366 Pages, Hardcover
ISBN-10: 0-470-27830-7
ISBN-13: 978-0-470-27830-7 - John Wiley & Sons

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Publications 2008-06/2014 - 455.4 kb