Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells

Clemens Zwergel; Brigitte Czepukojc; Emilie Evain-Bana; Zhanjie Xu; Giulia Stazi; Mattia Mori; Alexandros Patsilinakos; Antonello Mai; Bruno Botta; Rino Ragno; Denise Bagrel; Gilbert Kirsch; Peter Meiser; Claus Jacob; Mathias Montenarh; Sergio Valente

doi:10.1016/j.ejmech.2017.04.012

Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells

Eur J Med Chem. 2017 Jul 7:134:316-333. doi: 10.1016/j.ejmech.2017.04.012. Epub 2017 Apr 10.

Authors

Affiliations

¹ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Division of Bioorganic Chemistry, School of Pharmacy, Saarland State University, Campus, Bld. B2.1, 66123, Saarbrücken, Germany; Université de Lorraine, UMR CNRS 7565, Structure et Réactivité des Systèmes Moléculaires Complexes, Equipe 3 (HECRIN), 1 Boulevard Arago, 57078, Metz Technopôle, France.
² Medical Biochemistry and Molecular Biology, Saarland University, 66421, Homburg/Saar, Germany; Division of Bioorganic Chemistry, School of Pharmacy, Saarland State University, Campus, Bld. B2.1, 66123, Saarbrücken, Germany.
³ Université de Lorraine, UMR CNRS 7565, Structure et Réactivité des Systèmes Moléculaires Complexes, Equipe 5 (MIC), Campus Bridoux, rue du Général Delestraint, 57070, Metz Cedex, France.
⁴ Université de Lorraine, UMR CNRS 7565, Structure et Réactivité des Systèmes Moléculaires Complexes, Equipe 3 (HECRIN), 1 Boulevard Arago, 57078, Metz Technopôle, France; Division of Bioorganic Chemistry, School of Pharmacy, Saarland State University, Campus, Bld. B2.1, 66123, Saarbrücken, Germany; Ursapharm Arzneimittel GmbH, Industriestraße 35, 66129, Saarbrücken, Germany.
⁵ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.
⁶ Italian Institute of Technology, Center for Life Nano Science@Sapienza, Via Regina Elena 291, 00161, Rome, Italy.
⁷ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Alchemical Dynamics srl, P. le A. Moro 5, 00185, Rome, Italy.
⁸ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Istituto Pasteur- Fondazione Cenci Bolognetti, Sapienza University of Rome, Via Regina Elena 291, 00161, Rome, Italy.
⁹ Université de Lorraine, UMR CNRS 7565, Structure et Réactivité des Systèmes Moléculaires Complexes, Equipe 3 (HECRIN), 1 Boulevard Arago, 57078, Metz Technopôle, France. Electronic address: gilbert.kirsch@univ-lorraine.fr.
¹⁰ Ursapharm Arzneimittel GmbH, Industriestraße 35, 66129, Saarbrücken, Germany.
¹¹ Division of Bioorganic Chemistry, School of Pharmacy, Saarland State University, Campus, Bld. B2.1, 66123, Saarbrücken, Germany.
¹² Medical Biochemistry and Molecular Biology, Saarland University, 66421, Homburg/Saar, Germany. Electronic address: Mathias.Montenarh@uniklinikum-saarland.de.
¹³ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address: Sergio.valente@uniroma1.it.

PMID: 28431339
DOI: 10.1016/j.ejmech.2017.04.012

Abstract

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.

Keywords: 3DQSAR; Apoptosis; CDC25; Cancer; Phosphatases; Quinone-polycycles.

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Coumarins / chemistry*
Coumarins / pharmacology*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Neoplasms / drug therapy
Neoplasms / metabolism
Quantitative Structure-Activity Relationship
Quinolones / chemistry
Quinolones / pharmacology
cdc25 Phosphatases / antagonists & inhibitors*
cdc25 Phosphatases / metabolism

Substances

Antineoplastic Agents
Coumarins
Enzyme Inhibitors
Quinolones
CDC25A protein, human
CDC25C protein, human
cdc25 Phosphatases