Chemistry

Chemical Libraries description

U1177 holds the regional screening library of 90500 chemical structures, aliquoted in single use copies stored at -20░C (10ÁL 10mM in DMSO). Original samples are stored in dry form in individual 2D barcoded tubes (MatrixTM).

We also have a library of 2000 compounds of the Pharmacopeia and a continuously growing library of fragments.

Data Management / Molecular Modeling

Data management is performed thanks to a  web-based information system and used in multiple collaborative projects. The system is based on complementary databases interfaced with state of the art softwares:

Accelrys BioRegTM, ChemRegTM,  ISIS base TM for compound identification and structures, MS Access TM and Oracle TM for data storage and addressing (alphanumeric data, vectors, images)

Data are entered and manipulated and using Accelrys Pipeline pilot TM, a user-friendly interface developed initially for drug discovery in the pharmaceutical industry. 

We use iLabber TM as ELN.

For molecular modeling and 3D-structures viewing we use MOE TM and Pymol TM softwares.

Chemistry Tools (See our representative publications using these tools):

Fragment synthesis and use

Prevet, H., Flipo, M., Roussel, P., Deprez, B., & Willand, N. Microwave-assisted synthesis of functionalized spirohydantoins as 3-D privileged fragments for scouting the chemical space. Tetrahedron Letters,2016, 57(26): 2888-2894.doi:10.1016/j.tetlet.2016.05.065

Tran, N. C., Dhondt, H., Flipo, M., Deprez, B., & Willand, N. Synthesis of functionalized 2-isoxazolines as three-dimensional fragments for fragment-based drug discovery. Tetrahedron Letters,2015, 56(27): 4119-4123. doi:10.1016/j.tetlet.2015.05.035

Villemagne, B., Flipo, M., Blondiaux, N., Crauste, C., Malaquin, S., Leroux, F., Piveteau, C., Villeret, V., Brodin, P., Villoutreix, B. O., Sperandio, O., Soror, S. H., Wohlkonig, A., Wintjens, R., Deprez, B., Baulard, A. R., & Willand, N. Ligand efficiency driven design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging and linking approaches. Journal of Medicinal Chemistry,2014 57(11): 4876-4888.10.1021/jm500422b

Parallel Synthesis

Flipo, M., Willand, N., Lecat-Guillet, N., Hounsou, C., Desroses, M., Leroux, F., Lens, Z., Villeret, V., Wohlkönig, A., Wintjens, R., Christophe, T., Jeon, H. K., Locht, C., Brodin, P., Baulard, A., & Deprez, B. Discovery of novel N-phenyl-phenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining High-Throughput Screening and Synthesis. Journal of Medicinal Chemistry,2012, 55(14): 6391–6402. doi:10.1021/jm300377g

Flipo, M., Beghyn, T., Charton, J., Leroux, V. A., Deprez, B. P., & Deprez-Poulain, R. F. A library of novel hydroxamic acids targeting the metallo-protease family: design, parallel synthesis and screening. Bioorganic and Medicinal Chemistry,2007, 15(1): 63-76. doi:10.1016/j.bmc.2006.10.010

Deprez-Poulain, R. F., Charton, J., Leroux, V., & Deprez, B. P. Convenient synthesis of 4H-1,2,4-triazole-3-thiols using di-2-pyridylthionocarbonate. Tetrahedron Letters,2007, 48(46): 8157-8162. doi:10.1016/j.tetlet.2007.09.094

Charton, J., Leroux, F., Delaroche, S., Landry, V., Deprez, B. P., & Deprez-Poulain, R. F. Synthesis of a Library of 200-Member Squaric Acid N-Hydroxylamide Amides. Bioorganic & Medicinal Chemistry Letters,2008, 18(18): 4968-4971. doi:10.1016/j.bmcl.2008.08.025

Solid phase

Cousaert, N., Willand, N., Gesquiere, J.-C., Tartar, A., Deprez, B., & Deprez-Poulain, R. Original loading and Suzuki conditions for the solid-phase synthesis of biphenyltetrazoles. Application to the first solid-phase synthesis of irbesartan. Tetrahedron Letters,2008, 49: 2743-2747. doi:10.1016/j.tetlet.2008.02.147

Charton, J., Cousaert, N., Bochu, C., Willand, N., Deprez, B., & Deprez-Poulain, R. A versatile solid-phase synthesis of 3-aryl-1,2,4-oxadiazolones and analogues. Tetrahedron Letters,2007, 48(8): 1479-1483. doi:10.1016/j.tetlet.2006.12.050

Green chemistry, microwave and solvent free techniques

Malaquin, S., Jida, M., Courtin, J., Laconde, G., Willand, N., Deprez, B., & Deprez-Poulain, R. Water-based conditions for the microscale parallel synthesis of bicyclic lactams. Tetrahedron Letters,2013, 54(6): 562-567.doi:10.1016/j.tetlet.2012.11.082

Jida, M., Malaquin, S., Deprez-Poulain, R., Laconde, G., & Deprez, B. Synthesis of five- and six-membered lactams via solvent-free microwave Ugi reaction. Tetrahedron Letters,2010, 51(39): 5109-5111. doi:10.1016/j.tetlet.2010.07.021

Jida, M., Deprez-Poulain, R., Malaquin, S., Roussel, P., Agbossou-Niedercorn, F., Deprez, B., & Laconde, G. Solvent-free microwave-assisted Meyers’ lactamization. Green Chemistry,2010, 12: 961 - 964. doi:10.1039/B924111F

Metal-catalyzed reactions

Dequirez, G., Bourotte, M., Porras de Francisco, E., Remuiñan, Blanco, M. J., Deprez, B., & Willand, N. Microwave-Assisted Suzuki-Miyaura Cross Coupling using Nickel as Catalyst to Rapidly Access to 3-Arylazetidine. ChemistrySelect,2017, 2(28): 8841-8846.10.1002/slct.201702101. 10.1002/slct.201702101

Probst, N. P., Deprez, B., & Willand, N. Palladium-free Sonogashira-type cross-coupling reaction of bromoisoxazolines or N-alkoxyimidoyl bromides and alkynes. Tetrahedron Letters,2016, 57(10): 1066-1070. doi:10.1016/j.tetlet.2016.01.070

Deprez-Poulain, R., Cousaert, N., Toto, P., Willand, N., & Deprez, B. Application of Ullmann and Ullmann-Finkelstein reactions for the synthesis of N-aryl-N-(1H-pyrazol-3-yl) acetamide or N-(1-aryl-1H-pyrazol-3-yl) acetamide derivatives and pharmacological evaluation. Eur J Med Chem, 2011, 46: 3867-3876. doi:10.1016/j.ejmech.2011.05.056

Toto, P., Gesquiere, J.-C., Cousaert, N., Deprez, B., & Willand, N. UFU (Ullmann-Finkelstein-Ullmann): a new multicomponent reaction. Tetrahedron Letters,2006, 47(28): 4973-4978. doi:10.1016/j.tetlet.2006.04.041

Toto, P., Gesquiere, J.-C., Deprez, B., & Willand, N. Synthesis of N-(iodophenyl)-amides via an unprecedented Ullmann-Finkelstein tandem reaction. Tetrahedron Letters,2006, 47(7): 1181-1186. doi:10.1016/j.tetlet.2005.12.022

Nicolas Cousaert, Patrick Toto, Nicolas Willand, and Benoît Déprez. Efficient, Protection-Free Suzuki-Miyaura Synthesis of ortho-biphenyltetrazoles. Tet Let, 2005, 46, 6529-6532. doi:10.1016/j.tetlet.2005.07.082

Special chemical templates (See our representative publications ):

Acidic compounds:

Acidic compounds are under-represented in chemical libraries. Nevertheless, these compounds present interesting bioactivities. Among commercially available drugs, one can notice that acidic functions are essential for several important therapeutic classes like NSAIDs (Non Steroidal Anti-Inflammatory Drugs), sartans and glitazones. Interestingly, these drugs target very different protein classes: enzymes, GPCRs (G-protein coupled receptors) and nuclear hormone receptors. Carboxylic acid and bioisosters are thus important pharmacophoric groups. We have developed and studied new acidic compounds in that perspective.

  • Maingot, L., Leroux, F., Landry, V., Dumont, J., Nagase, H., Villoutreix, B., Sperandio, O., Deprez-Poulain, R., & Deprez, B. New non-hydroxamic ADAMTS-5 inhibitors based on the 1,2,4-triazole-3-thiol scaffold. Bioorganic & Medicinal Chemistry Letters,2010, 21: 6213-6216. doi:10.1016/j.bmcl.2010.08.108
  • Flipo, M., Charton, J., Hocine, A., Dassonneville, S., Deprez, B., & Deprez-Poulain, R. Hydroxamates: Relationships between structure and plasma-stability. J Med Chem,2009, 52(21): 6790-6802. doi:10.1021/jm900648x
  • Charton, J., Deprez-Poulain, R., Hennuyer, N., Tailleux, A., Staels, B., & Deprez, B. Novel non-carboxylic acid retinoids: 1,2,4-Oxadiazol-5-one derivatives. Bioorganic & Medicinal Chemistry Letters,2009, 19(2): 489-492.doi:10.1016/j.bmcl.2008.11.040
  • Charton, J., Charruault, L., Deprez-Poulain, R., & Deprez, B. Alkylsquarates as key intermediates for the rapid preparation of original drug-inspired compounds. Combinatorial Chemistry and High Throughput Screening,2008, 11(4): 294-303.

Priviledged structures:

To synthesize these compounds, we are developing condensation reactions that have a high CsEI (Complexity of synthesis Efficiency Index), derived from Meyers' work or IMCRs (Isonitrile Multi-Component Reactions). Using the repertoire of green protocols we have developed new chemical series that are bioinspired. A strong focus is put on the study of enantio and dia-stereoselectivities and heterocycles.

  • Lasalle, M., Picon, S., Boulahjar, R., Hoguet, V., Van Obbergen, J., Roussel, P., Deprez, B., & Charton, J. Access to newly functionalized imidazole derivatives: efficient synthesis of novel 5-amino-2-thioimidazoles using propylphosphonic anhydride (®T3P). Tetrahedron Letters,2015, 56(8): 1011-1014. doi:10.1016/j.tetlet.2015.01.046
  • Malaquin, S., Jida, M., Courtin, J., Laconde, G., Willand, N., Deprez, B., & Deprez-Poulain, R. Water-based conditions for the microscale parallel synthesis of bicyclic lactams. Tetrahedron Letters,2012: in press. doi:10.1016/j.tetlet.2012.11.082
  • Wen, X., Bakali, J. E., Deprez-Poulain, R., & Deprez, B. Efficient propylphosphonic anhydride (®T3P) mediated synthesis of benzothiazoles, benzoxazoles and benzimidazoles. Tetrahedron Letters,2012, 53(19): 2440-2443 doi:10.1016/j.tetlet.2012.03.007
  • Jida, M., Laconde, G., Soueidan, O.-M., Lebegue, N., Revelant, G., Pelinski, L., Agbossou-Niedercorn, F., Deprez, B., & Deprez-Poulain, R. Stereoselective synthesis of enantiopure N-protected-3-arylpiperazines from keto-esters. Tetrahedron Letters,2012, 53(39) 5215–5218. doi: 10.1016/j.tetlet.2012.07.031
  • Aknin, K., Gauriot, M., Totobenazara, J., Deguine, N., Deprez-Poulain, R., Deprez, B., & Charton, J. Squaric acid is a suitable building-block in 4C-Ugi reaction: access to original bivalent compounds.,2011 53: 458-461. doi:10.1016/j.tetlet.2011.11.077
  • Soueidan, M., Jida, M., Bousquet, T., Niedercorn, F. A., & Pelinski, L. Efficient access to new chiral ferrocenyl [gamma]-lactams from amino alcohols. New Journal of Chemistry,2011, 35(5): 991-993. doi: 10.1039/C1NJ20059C
  • Bousquet, T., Jida, M., Soueidan, M., Deprez-Poulain, R., Agbossou-Niedercorn, F., & Pelinski, L. Fast and Efficient solvent-free Passerini reaction. Tetrahedron Letters,2011: in press. doi:10.1016/j.tetlet.2011.11.028
  • Jida, M., Soueidan, M., Willand, N., Agbossou-Niedercorn, F., Pelinski, L., Laconde, G., Deprez-Poulain, R., & Deprez, B. A facile and rapid synthesis of N-benzyl-2-substituted piperazines. Tetrahedron Letters,2011, 52(14): 1705-1708. doi:10.1016/j.tetlet.2011.02.011
  • Soueidan, M., Jida, M., Bousquet, T., Niedercorn, F. A., & Pelinski, L. Efficient access to new chiral ferrocenyl [gamma]-lactams from amino alcohols. New Journal of Chemistry,2011, 35(5): 991-993. doi: 10.1039/C1NJ20059C
  • Deprez-Poulain, R., Cousaert, N., Toto, P., Willand, N., & Deprez, B. Application of Ullmann and Ullmann-Finkelstein reactions for the synthesis of N-aryl-N-(1H-pyrazol-3-yl) acetamide or N-(1-aryl-1H-pyrazol-3-yl) acetamide derivatives and pharmacological evaluation. Eur J Med Chem,2011, 46: 3867-3876. doi:10.1016/j.ejmech.2011.05.056
  • Malaquin, S., Jida, M., Gesquiere, J.-C., Deprez-Poulain, R., Deprez, B., & Laconde, G. Ugi reaction for the synthesis of 4-aminopiperidine-4-carboxylic acid derivatives. Application to the synthesis of carfentanil and remifentanil. Tetrahedron Letters,2010, 51(22): 2983-2985. doi:10.1016/j.tetlet.2010.03.120
  • Jida, M., Deprez-Poulain, R., Malaquin, S., Roussel, P., Agbossou-Niedercorn, F., Deprez, B., & Laconde, G. Solvent-free microwave-assisted Meyers’ lactamization. Green Chemistry,2010, 12: 961 - 964. doi:10.1039/B924111F
  • Reynes, C., Host, H., Camproux, A.-C., Laconde, G., Leroux, F., Mazars, A., Deprez, B., Fahraeus, R., Villoutreix, B. O., & Sperandio, O. Designing Focused Chemical Libraries Enriched in Protein-Protein Interaction Inhibitors using Machine-Learning Methods. Plos Computational Biology,2010, 6(3): e1000695. doi:10.1371/journal.pcbi.1000695
  • Beghyn, T., Deprez-Poulain, R., Willand, N., Foleas, B., & Deprez, B. Natural compounds: leads or ideas? Bioinspired molecules for drug discovery. Chemical Biology and Drug Design,2008, 72: 3-15. doi:10.1111/j.1747-0285.2008.00673.x
  • Willand, N., Folléas, B., Boutillon, C., Verbraeken, L., Gesquiere, J.-C., Tartar, A., & Deprez, B. Efficient, Two-Step Synthesis O N-Substituted Nortropinone Derivatives. Tetrahedron Letters,2007, 48(29): 5007-5011.doi:10.1016/j.tetlet.2007.05.110
  • Déprez-Poulain R, Willand N, Boutillon C, Nowogrocki G, Azaroual N, Déprez B. A simple reaction to produce small structurally complex and diverse molecules. Tetrahedron Lett. 2004; 45 (27): 5287-5290.doi:10.1016/j.tetlet.2004.05.008 
  • Willand N, Beghyn T, Nowogrocki G, Gesquière J-C, Déprez B. Synthesis and structural studies of a novel scaffold for drug discovery: a 4,5-dihydro-3 H-spiro[1,5-benzoxazepine-2,4 '-piperidine]. Tetrahedron Lett. 2004; 45 (5): 1051-1054. doi:10.1016/j.tetlet.2003.11.079
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