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6. Intrinsic selectivity in capillary electrophoresis for chiral separations with dual cyclodextrin systems

Author

Lelievre, Frederic, Gareil, P., Bahaddi, Y., and Galons, H.

Subjects
Electrophoresis -- Research, Chirality -- Research, Cyclodextrins -- Research, Separation (Technology) -- Research, Chemistry
Abstract

Defined as the ratio of the affinity factors of the analytes for a complexing agent, the intrinsic selectivity is representative of the very nature of the complexing agent. When more than one complexing agent are present in the background electrolyte, it is possible to define several intrinsic selectivities according to whether completing agents are considered separately or all together. A theoretical model with respect to selectivity is presented for separations that involve two complexing agents, using the concept of apparent constant for complex formation. When only independent complexation occurs (absence of mixed complexes), then the intrinsic selectivity of a complexing agent X in the presence of a complexing agent Y can be easily related to the intrinsic selectivity of each complexing agent and to complex formation constants. Dual systems of cyclodextrins (CDs), implementing the cationic mono(6-amino-6-deoxy)-[Beta]-cyclodextrin ([Beta]-CD-N[H.sub.2]) and a neutral CD (trimethyl-[Beta]-CD (TM-[Beta]-CD) or dimethyl-[Beta]-CD (DM-[Beta]-CD)), were studied to illustrate this model and to offer an alternative to the separation of neutral enantiomers when [Beta]-CD-N[H.sub.2] shows no or insufficient stereoselectivity. With a dual [Beta]-CD-N[H.sub.2]/TM-[Beta]-CD system at pH 2.3, arylpropionic acid enantiomers were baseline resolved and benzoin derivatives were partially resolved. For the arylpropionic acids, [Beta]-CD-N[H.sub.2], which is not stereoselective, confers on them a nonzero mobility, while TM-[Beta]-CD allows the chiral recognition. A study of the respective influence of TM-[Beta]-CD and [Beta]-CD-N[H.sub.2] concentrations was performed to determine the optimal conditions with respect to resolution. This theoretical approach allowed characterization of the intrinsic selectivity of neutral CDs for pairs of neutral enantiomers and therefore identification of the potential of neutral chiral agents for neutral enantiomers.

Published
1997

9. From drug screening to target deconvolution: A target-based drug discovery pipeline using Leishmania casein kinase 1 isoform 2 to identify compounds with antileishmanial activity

Author

Durieu, E. Prina, E. Leclercq, O. Oumata, N. Gaboriaud-Kolar, N. Vougogiannopoulou, K. Aulner, N. Defontaine, A. No, J.H. Ruchaud, S. Skaltsounis, A.-L. Galons, H. Späth, G.F. Meijer, L. Rachidi, N.

Abstract

Existing therapies for leishmaniases present significant limitations, such as toxic side effects, and are rendered inefficient by parasite resistance. It is of utmost importance to develop novel drugs targeting Leishmania that take these two limitations into consideration. We thus chose a target-based approach using an exoprotein kinase, Leishmania casein kinase 1.2 (LmCK1.2) that was recently shown to be essential for intracellular parasite survival and infectivity. We developed a four-step pipeline to identify novel selective antileishmanial compounds. In step 1, we screened 5,018 compounds from kinase-biased libraries with Leishmania and mammalian CK1 in order to identify hit compounds and assess their specificity. For step 2, we selected 88 compounds among those with the lowest 50% inhibitory concentration to test their biological activity on host-free parasites using a resazurin reduction assay and on intramacrophagic amastigotes using a high content phenotypic assay. Only 75 compounds showed antileishmanial activity and were retained for step 3 to evaluate their toxicity against mouse macrophages and human cell lines. The four compounds that displayed a selectivity index above 10 were then assessed for their affinity to LmCK1.2 using a target deconvolution strategy in step 4. Finally, we retained two compounds, PP2 and compound 42, for which LmCK1.2 seems to be the primary target. Using this four-step pipeline, we identify from several thousand molecules, two lead compounds with a selective antileishmanial activity. © 2016, American Society for Microbiology. All Rights Reserved.

Published
2016

10. Abstracts of papers Symposium “new therapeutic developments in human infectious diseases”

Author

Compernolle, Frans, Saleh, Ashty, Hoornaert, Georges, Damianos, N., Galons, H., Miocque, M., Ouero, A. M., Cntto, J., De Clercq, E., Schols, D., Baba, M., Pauwels, R., De Meyer, N., Pandey, H. K., Mishra, L., Haemers, A., Vanden Berghe, D., Vlietinck, A. J., De Vos, E., Esmans, Ei., Van Dongen, W. F., Lepoivre, J. A., Alderweireldt, F. C., Balzarini, J., Herdewiin, P., Van Aerschot, A., Hiremath, S. P., Hooper, M., Mruthyunjayasuamy, B. H. M., Tounson, S., Kamerling, J. P., Jakobs, A., Christiaens, L., Renson, M., Joos, P., Esmans, E. L., Dommisse, R. A., Liepoivre, J. A., Marchand-Brynaert, J., Nasri, I., Auzeil, N., Bonaly, R., Loppinet, V., Opperdoes, F. R., Hol, W. G. J., Opio, J. Osuku, Labidalle, S., Galone, H., Bram, G., Plaum, L., Robaux, H., Monal, J. L., Schellekens, H., Schwabe, Carl H., Snippe, H., Verheul, A. F. M., Kamerlina, J. P., Slaghek, T. M., Koeman, F. A. W., Vlieqenthart, J. F. G., Vanden Bossche, Hugo, Vansterkenburg, Eugene L. M., Coppens, Isabelle, Opperdoes, Fred R., Wilting, Jaap, Bos, Octaaf J. M., Fischer, Marcel J. E., Janssen, Lambert H. M., Schepers, G., Herdewi in, P., Van Der Taelen, D., Verberckmoes, F., Wanner, M. J., v. Maarschalkerwaart, D. A. H., Koomen, G. J., Wigerinck, P., Claes, P., De Clercg, E., and Zhang, M. Q.

Published
1989
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11. 134 Rationale for evaluating (R)-roscovitine (Seliciclib) in patients with cystic fibrosis

Author

Meijer, L., primary, Nelson, D., additional, Riazanski, V., additional, Gabdulkhakova, A.G., additional, Hery-Arnaud, G., additional, Le Berre, R., additional, Loaëc, N., additional, Oumata, N., additional, Galons, H., additional, Nowak, E., additional, Guéganton, L., additional, Dorothée, G., additional, Gray, R.D., additional, Rossi, A.G., additional, Witko-Sarsat, V., additional, Norez, C., additional, Becq, F., additional, Ravel, D., additional, Mottier, D., additional, and Rault, G., additional

Published
2015
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12. Roscovitine-derived, dual-specificity inhibitors of cyclin-dependent kinases and casein kinases 1

Author

Oumata, N. Bettayeb, K. Ferandin, Y. Demange, L. Lopez-Giral, A. Goddard, M.-L. Myrianthopoulos, V. Mikros, E. Flajolet, M. Greengard, P. Meijer, L. Galons, H.

Abstract

Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK1) are involved in the two key molecular features of Alzheimer's disease, production of amyloid-β peptides (extracellular plaques) and hyper-phosphorylation of Tau (intracellular neurofibrillary tangles). A series of 2,6,9-trisubstituted purines, structurally related to the CDK inhibitor roscovitine, have been synthesized. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivatives displayed potent inhibition of both CDKs and CK1. In particular, derivative 13a was a potent inhibitor of CDK1/cyclin B (IC50: 220 nM), CDK5/p25 (IC50: 80 nM), and CK1 (IC 50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1δ provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of amyloid-β in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers. © 2008 American Chemical Society.

Published
2008

13. Screening the active constituents of Chinese medicinal herbs as potent inhibitors of Cdc25 tyrosine phosphatase, an activator of the mitosis-inducing p34cdc2 kinase

Author

Yang, H., Zheng, S., S. M., Li, Leclerc, S., L. L.Bach S., Yu, Knockaert, M., Reinhardt, J., Lozach, O., Schmitt, S., Baratte, B., Koken, M., S. P., Coburn, Tang, L., Jiang, T., D. C., Liang, Galons, H., J. F., Dierick, L. A., Pinna, Meggio, F., Totzke, F., Schachtele, C., Lerman, A. S., Carnero, A., Wan, Y., Gray, N., Meijer, L., J. Q., Cheng, S. Z., Zhang, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Myeloid, Chinese Herbal/analysis/*chemistry/*pharmacology Humans Lethal Dose 50 Leukemia, Chronic/drug therapy/*enzymology/pathology Medicine, Medicinal/chemistry cdc25 Phosphatase/*antagonists & inhibitors/*metabolism, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Chinese Traditional/methods Mitosis/*drug effects Phytotherapy/methods Plants, Tumor Cyclin-Dependent Kinases/*metabolism Dose-Response Relationship, Drug Drugs, Apoptosis/*drug effects Cell Cycle Proteins/*antagonists & inhibitors/*metabolism Cell Line
Abstract

OBJECTIVE: To screen and evaluate the active constituents of Chinese medicinal herbs as potent inhibitors of Cdc25 phosphatase. METHODS: The affinity chromatography purified glutashione-S-transferase/Cdc25A phosphatase fusion protein and Cdc2/cyclin B from the extracts of starfish M phase oocytes are used as the cell cycle-specific targets for screening the antimitotic constituents. We tested 9 extracts isolated from the Chinese medicinal herbs and vegetables including the agents currently used in cancer treatment by measuring the inhibition of Cdc25A phosphatase and Cdc2 kinase activity. The antitumor activity of the extracts was also evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry. RESULTS: Cdc25A inhibitory activity and antitumor activity are detected in the extracts isolated from three Chinese medicinal herbs Agrimona pilosa; Herba solani lyrati; Galla chinesis. CONCLUSION: We found three extracts isolated from Chinese medicinal herbs have potential inhibitory activity of Cdc25 phosphatase using a highly specific mechanism-based screen assay for antimitotic drug discovery.

Published
2005

14. CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

Author

Delehouzé, C, primary, Godl, K, additional, Loaëc, N, additional, Bruyère, C, additional, Desban, N, additional, Oumata, N, additional, Galons, H, additional, Roumeliotis, T I, additional, Giannopoulou, E G, additional, Grenet, J, additional, Twitchell, D, additional, Lahti, J, additional, Mouchet, N, additional, Galibert, M-D, additional, Garbis, S D, additional, and Meijer, L, additional

Published
2013
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