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1. Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents

Author

Heinz-Herbert Fiebig, Markus Frieser, Siavosh Mahboobi, Harald Hufsky, Thomas Beckers, D. H. Paper, Jutta Bürgermeister, Herwig Pongratz, Frank-D. Böhmer, Jörg Hockemeyer, Angelika M. Burger, Alexei Lyssenko, and Silke Baasner

Subjects
G2 Phase, Indoles, Transplantation, Heterologous, Mice, Nude, Mitosis, Angiogenesis Inhibitors, Antineoplastic Agents, In Vitro Techniques, GTP Phosphohydrolases, HeLa, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Biopolymers, Microtubule, Allantois, Tubulin, Drug Discovery, Tumor Cells, Cultured, Animals, Humans, Cytotoxicity, Melanoma, biology, Chorion, Cell cycle, biology.organism_classification, Nocodazole, Biochemistry, chemistry, biology.protein, Molecular Medicine, Antimitotic Agent, Cattle, Drug Screening Assays, Antitumor
Abstract

A new class of simple synthetic antimitotic compounds based on 2-aroylindoles was discovered. (5-Methoxy-1H-2-indolyl)-phenylmethanone (1) as well as analogous 3-fluorophenyl- (36) and 3-methoxyphenyl (3) derivatives displayed high cytotoxicity of IC(50) = 20 to 75 nM against the human HeLa/KB cervical, SK-OV-3 ovarian, and U373 astrocytoma carcinoma cell lines. The inhibition of proliferation correlated with the arrest in the G2/M phase of the cell cycle. In in vitro assays with tubulin isolated from bovine brain, in general antiproliferative activity correlated with inhibition of tubulin polymerization. Thus, the antimitotic activity of 2-aroylindoles is explained by interference with the mitotic spindle apparatus and destabilization of microtubules. In contrast to colchicine, vincristine, nocodazole, or taxol, 1 did not significantly affect the GTPase activity of beta-tubulin. Interestingly, selected compounds inhibited angiogenesis in the chorioallantoic membrane (CAM) assay. In xenograft experiments, 1 was highly active after oral administration at 200 mg/kg against the human amelanocytic melanoma MEXF 989 in athymic nude mice. We conclude, that 2-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.

Published
2001

2. Structurally related immunological effects of triterpenoid saponins

Author

M, Bernhardt, C, Sturm, K H, Shaker, D H, Paper, G, Franz, and K, Seifert

Subjects
Immunity, Cellular, Plants, Medicinal, Macrophages, Tetrazolium Salts, In Vitro Techniques, Saponins, Lymphocyte Activation, Triterpenes, Cell Line, Mice, Structure-Activity Relationship, Thiazoles, Phagocytosis, Mice, Inbred DBA, Animals, Female, Cell Division, Cells, Cultured, Spleen
Abstract

The influence of the triterpenoid saponins 1-10 has been investigated on murine spleenocytes in the lymphocyte transformation test and on murine macrophages in an phagocytosis assay. The lymphocyte transformation test and the phagocytosis assay showed that the tested compounds have no stimulating effect. However, a significant inhibition of lymphocyte proliferation by the triterpenoid saponins 2, 6 and 10 was demonstrated.

Published
2001

3. [Polysaccharides from Nerium oleander: structure and biological activity]

Author

B M, Müller, F, Rosskopf, D H, Paper, J, Kraus, and G, Franz

Subjects
Male, Mice, Inbred C3H, Magnetic Resonance Spectroscopy, Plants, Medicinal, Cell Survival, Plant Extracts, Hydrolysis, Macrophages, In Vitro Techniques, Antineoplastic Agents, Phytogenic, Methylation, Mice, Structure-Activity Relationship, Phagocytosis, Polysaccharides, Tumor Cells, Cultured, Animals, Immunologic Factors, Female, Protease Inhibitors, Lymphocytes, Mitogens, Limulus Test
Abstract

A water extraction of crushed leaves of Nerium oleander yielded 2.3% of a crude polysaccharide. The main fraction (67%) represents a pectic polysaccharide mainly composed of galacturonic acid besides rhamnose, arabinose and galactose. The polysaccharide structure was characterized by NMR, mild acid- and pectinase treatment combined with GC-MS analyses. In vivo tests for a possible antitumor activity did not result in a significant action. Investigation of immunomodulating activity brought some indications for mitogenic activity and a weak macrophage-mediated cytotoxicity. Increase of phagocytosis could not be doubtlessly assigned to the polysaccharide due to the high amount of endotoxin in the homogenous fraction OLE 2.

Published
1991

4. Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

Author

Jelena Melesina, Wolfgang Sippl, Tino Heimburg, Christophe Romier, Martin Marek, Karin Schmidtkunz, E. Ramos-Morales, Julien Lancelot, C. Da Veiga, Manfred Jung, Takayoshi Suzuki, Dina Robaa, Eric Ennifar, Dmitrii V. Kalinin, T.B. Shaik, Raymond J. Pierce, Alokta Chakrabarti, Ralph Holl, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Martin-Luther-Universität Halle Wittenberg (MLU), Albert-Ludwigs-Universität Freiburg, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University of Münster, Kyoto Prefectural University of Medicine [Kyoto, Japon], Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), University of Hamburg, This work and the authors of this paper have been supported by funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreements nos. 241865 (SEtTReND) and 602080 (A-ParaDDisE) as well as the German Research Foundation (DFG) to W.S. (Si868/13-1) and M.J. (Ju295/13-1). This study was supported by the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. C.R., M.M., T.B.S., E.R.M., and R.J.P. are supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Strasbourg, the Institut Pasteur de Lille and the Université de Lille. W.S. was supported by the European Regional Development Fund of the European Commission. We acknowledge the support and the use of resources of the French Infrastructure for Integrated Structural Biology FRISBI ANR-10-INBS-05 and of Instruct-ERIC, We thank members of the ESRF-EMBL joint structural biology groups, the SOLEIL, and the Swiss Light Source (SLS) synchrotrons for the use of their beamline facilities and for help during data collection. We are grateful to Alastair McEwen (IGBMC) for his kind assistance during X-ray data collections., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), European Project: 241865,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,SETTREND(2010), European Project: 602080,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,A-PARADDISE(2014), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and Westfälische Wilhelms-Universität Münster = University of Münster (WWU)

Subjects
0301 basic medicine, Indoles, [SDV]Life Sciences [q-bio], Molecular Dynamics Simulation, Hydroxamic Acids, Isozyme, Histone Deacetylases, Substrate Specificity, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Catalytic Domain, Drug Discovery, Hydrolase, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, Amino Acid Sequence, Tyrosine, biology, Chemistry, Active site, HDAC8, Protein engineering, Triazoles, 3. Good health, Cell biology, Histone Deacetylase Inhibitors, Repressor Proteins, 030104 developmental biology, Histone, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine
Abstract

International audience; Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1–L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.

Published
2018