Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells
| Autor: | Claus Jacob, Denise Bagrel, Bruno Botta, Brigitte Czepukojc, Zhanjie Xu, Gilbert Kirsch, Clemens Zwergel, Peter Meiser, Rino Ragno, Alexandros Patsilinakos, Mattia Mori, Mathias Montenarh, Emilie Evain-Bana, Antonello Mai, Sergio Valente, Giulia Stazi |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Programmed cell death CDC25A Cdc25 Quantitative Structure-Activity Relationship Antineoplastic Agents Apoptosis Quinolones 3DQSAR 03 medical and health sciences 0302 clinical medicine Coumarins Cell Line Tumor Neoplasms Drug Discovery cancer drug discovery3003 pharmaceutical science Humans cdc25 Phosphatases phosphatases Enzyme Inhibitors Cell Proliferation Pharmacology CDC25 biology Cell growth Chemistry Organic Chemistry Cell Cycle General Medicine Cell cycle apoptosis quinone-polycycles pharmacology organic chemistry Cell biology 030104 developmental biology Biochemistry Cell culture 030220 oncology & carcinogenesis Cancer cell biology.protein |
| Zdroj: | European journal of medicinal chemistry. 134 |
| ISSN: | 1768-3254 |
| Popis: | Cell division cycle phosphatases CDC25 A, B and C are involved in modulating cell cycle processes and are found overexpressed in a large panel of cancer typology. Here, we describe the development of two novel quinone-polycycle series of CDC25A and C inhibitors on the one hand 1a-k, coumarin-based, and on the other 2a-g, quinolinone-based, which inhibit either enzymes up to a sub-micro molar level and at single-digit micro molar concentrations, respectively. When tested in six different cancer cell lines, compound 2c displayed the highest efficacy to arrest cell viability, showing in almost all cell lines sub-micro molar IC50 values, a profile even better than the reference compound NCS95397. To investigate the putative binding mode of the inhibitors and to develop quantitative structure-activity relationships, molecular docking and 3-D QSAR studies were also carried out. Four selected inhibitors, 1a, 1d, 2a and 2c have been also tested in A431 cancer cells; among them, compound 2c was the most potent one leading to cell proliferation arrest and decreased CDC25C protein levels together with its splicing variant. Compound 2c displayed increased phosphorylation levels of histone H3, induction of PARP and caspase 3 cleavage, highlighting its contribution to cell death through pro-apoptotic effects. |
| Databáze: | OpenAIRE |
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