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:
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.
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).
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.
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.
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).
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.
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.
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, (...)
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.
Edition - June 2008
2008. 366 Pages, Hardcover
ISBN-13: 978-0-470-27830-7 - John Wiley & Sons
Publications 2008-06/2014 - 455.4 kb