title: Screening of indeno[1,2-b]indoloquinones by MALDI-MS: a new set of potential CDC25 phosphatase inhibitors brought to light.
abstract: Quinones and quinones-like compounds are potential candidates for the inhibition of CDC25 phosphatases. The combination of MALDI-MS analyses and biological studies was used to develop a rapid screening of a targeted library of indeno[1,2-b]indoloquinone derivatives. The screening protocol using MALDI-TOFMS and MALDI-FTICRMS highlighted four new promising candidates. Biological investigations showed that only compounds 5c-f inhibited CDC25A and -C phosphatases, with IC50values around the micromolar range. The direct use of a screening method based on MALDI-MS technology allowed achieving fast scaffold identification of a new class of potent inhibitors of CDC25 phosphatases. These four molecules appeared as novel molecules of a new class of CDC25 inhibitors. Assessment of 5c-e in an MRC5 proliferation assay provided an early indicator of toxicity to mammalian cells. Compound 5d seems the most promising hit for developing new CDC25 inhibitors.
authors.affiliation: a Université de Lyon, Université Lyon 1, Faculté de Pharmacie ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry , SFR Santé Lyon-Est CNRS UMS3453 INSERM US7, Lyon cedex 8 , France.|b Tishreen University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry and Drug Monitoring, Organic Chemistry Laboratory , Boulevard Aleppo , Latakia , Syria.
authors.forename: Faten
authors.initials: F
authors.lastname: Alchab
authors.affiliation: c Université de Lorraine, Laboratoire de Chimie et de Physique Approche Multiéchelle des Milieux Complexes (LCP-A2MC), UMR CNRS 7565, Institut Jean Barriol FR2843 , Metz cedex 3 , France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Sibille
authors.affiliation: a Université de Lyon, Université Lyon 1, Faculté de Pharmacie ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry , SFR Santé Lyon-Est CNRS UMS3453 INSERM US7, Lyon cedex 8 , France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Ettouati
authors.affiliation: d Université de Lorraine, Laboratoire de Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), UMR CNRS 7565, Institut Jean Barriol FR2843 , Metz cedex 3 , France , and.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bana
authors.affiliation: a Université de Lyon, Université Lyon 1, Faculté de Pharmacie ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry , SFR Santé Lyon-Est CNRS UMS3453 INSERM US7, Lyon cedex 8 , France.
authors.forename: Zouhair
authors.initials: Z
authors.lastname: Bouaziz
authors.affiliation: a Université de Lyon, Université Lyon 1, Faculté de Pharmacie ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry , SFR Santé Lyon-Est CNRS UMS3453 INSERM US7, Lyon cedex 8 , France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Mularoni
authors.affiliation: a Université de Lyon, Université Lyon 1, Faculté de Pharmacie ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry , SFR Santé Lyon-Est CNRS UMS3453 INSERM US7, Lyon cedex 8 , France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Monniot
authors.affiliation: d Université de Lorraine, Laboratoire de Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), UMR CNRS 7565, Institut Jean Barriol FR2843 , Metz cedex 3 , France , and.
authors.forename: Denyse
authors.initials: D
authors.lastname: Bagrel
authors.affiliation: e Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westfälische Wilhelms-University Münster , Münster , Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
authors.affiliation: a Université de Lyon, Université Lyon 1, Faculté de Pharmacie ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry , SFR Santé Lyon-Est CNRS UMS3453 INSERM US7, Lyon cedex 8 , France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.affiliation: d Université de Lorraine, Laboratoire de Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), UMR CNRS 7565, Institut Jean Barriol FR2843 , Metz cedex 3 , France , and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chaimbault
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007192:Indenes; D011809:Quinones; C000614228:indeno(1,2-b)indoloquinone; C517004:CDC25A protein, human; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases
keywords: CDC25 inhibitors; MALDI mass spectrometry; indeno[1,2-b]indoloquinones; irreversibility