title: Phenolic indeno[1,2-b]indoles as ABCG2-selective potent and non-toxic inhibitors stimulating basal ATPase activity.
abstract: Ketonic indeno[1,2-b]indole-9,10-dione derivatives, initially designed as human casein kinase II (CK2) inhibitors, were recently shown to be converted into efficient inhibitors of drug efflux by the breast cancer resistance protein ABCG2 upon suited substitutions including a N (5)-phenethyl on C-ring and hydrophobic groups on D-ring. A series of ten phenolic and seven p-quinonic derivatives were synthesized and screened for inhibition of both CK2 and ABCG2 activities. The best phenolic inhibitors were about threefold more potent against ABCG2 than the corresponding ketonic derivatives, and showed low cytotoxicity. They were selective for ABCG2 over both P-glycoprotein and MRP1 (multidrug resistance protein 1), whereas the ketonic derivatives also interacted with MRP1, and they additionally displayed a lower interaction with CK2. Quite interestingly, they strongly stimulated ABCG2 ATPase activity, in contrast to ketonic derivatives, suggesting distinct binding sites. In contrast, the p-quinonic indenoindoles were cytotoxic and poor ABCG2 inhibitors, whereas a partial inhibition recovery could be reached upon hydrophobic substitutions on D-ring, similarly to the ketonic derivatives.
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR5086 CNRS/Lyon I University, IBCP, Lyon, France ; Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Gustavo Jabor
authors.initials: GJ
authors.lastname: Gozzi
authors.affiliation: Faculty of Pharmacy - ISPB, EA 4446 Biomolecules, Cancer and Chemoresistance, Health SFR of East Lyon CNRS UMS3453 - INSERM US7, University of Lyon, Lyon I University, Lyon Cedex 8, France.
authors.forename: Zouhair
authors.initials: Z
authors.lastname: Bouaziz
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR5086 CNRS/Lyon I University, IBCP, Lyon, France ; Department of Pharmaceutical Sciences, PGFAR, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR5086 CNRS/Lyon I University, IBCP, Lyon, France.
authors.forename: Nathalia
authors.initials: N
authors.lastname: Daflon-Yunes
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR5086 CNRS/Lyon I University, IBCP, Lyon, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Honorat
authors.affiliation: Faculty of Pharmacy - ISPB, EA 4446 Biomolecules, Cancer and Chemoresistance, Health SFR of East Lyon CNRS UMS3453 - INSERM US7, University of Lyon, Lyon I University, Lyon Cedex 8, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guragossian
authors.affiliation: Faculty of Pharmacy - ISPB, EA 4446 Biomolecules, Cancer and Chemoresistance, Health SFR of East Lyon CNRS UMS3453 - INSERM US7, University of Lyon, Lyon I University, Lyon Cedex 8, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Marminon
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR5086 CNRS/Lyon I University, IBCP, Lyon, France ; Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Glaucio
authors.initials: G
authors.lastname: Valdameri
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Bollacke
authors.affiliation: ARNA Laboratory, Pharmaceutical Sciences UFR, INSERM U869, University of Bordeaux, Bordeaux Cedex, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.affiliation: ISM - CNRS UMR 5255, University of Bordeaux Cedex, France.
authors.forename: Noël
authors.initials: N
authors.lastname: Pinaud
authors.affiliation: ICMCB CNRS-UPR 9048, University of Bordeaux, Pessac Cedex, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Marchivie
authors.affiliation: Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Cadena
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
authors.affiliation: Faculty of Pharmacy - ISPB, EA 4446 Biomolecules, Cancer and Chemoresistance, Health SFR of East Lyon CNRS UMS3453 - INSERM US7, University of Lyon, Lyon I University, Lyon Cedex 8, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR5086 CNRS/Lyon I University, IBCP, Lyon, France.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007192:Indenes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008942:Mitoxantrone / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010636:Phenols / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D047390:Casein Kinase II; D007192:Indenes; D007211:Indoles; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010636:Phenols; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1
keywords: ABCG2/BCRP; ATPase activity; cancer cells; indenoindole inhibitors; multidrug resistance; structure–activity relationships