title: Design, synthesis and biological profile of new inhibitors of multidrug resistance associated proteins carrying a polycyclic scaffold.
abstract: Following the identification of a novel polycyclic scaffold, leading to the previously reported potent P-gp modulator 1, a small series of easily affordable derivatives bearing a properly selected nitrogen-containing but-2-ynyl side chain was now synthesized and tested to evaluate the MDR reverting activity on two different experimental models. All compounds proved not to be cytotoxic when tested alone and more potent chemosensitizers than the reference verapamil. Some of them showed remarkable effects in combination with doxorubicin, being able to induce apoptotic cell death due to their reverting activity. In particular, 2a and 2c could be regarded as non-toxic new potential chemosensitizers, being able to interfere with different ABC proteins. Moreover, the intrinsic cytotoxicity of compound 1 could broaden its employment as MDR modulator. These results also seem to confirm the polycyclic core of these compounds as a potential new pharmacophoric carrier in medicinal chemistry.
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro, 6, 40126 Bologna, Italy. Electronic address: alessandra.bisi@unibo.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro, 6, 40126 Bologna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gobbi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via S. Donato, 19/2, 40127 Bologna, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Merolle
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via S. Donato, 19/2, 40127 Bologna, Italy; National Institute of Biostructures and Biosystems, Via delle Medaglie D'oro, 305, 00136 Roma, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Farruggia
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro, 6, 40126 Bologna, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro, 6, 40126 Bologna, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
authors.affiliation: Institute of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnar
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via S. Donato, 19/2, 40127 Bologna, Italy.
authors.forename: Emil
authors.initials: E
authors.lastname: Malucelli
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via S. Donato, 19/2, 40127 Bologna, Italy.
authors.forename: Concettina
authors.initials: C
authors.lastname: Cappadone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011083:Polycyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011083:Polycyclic Compounds
keywords: Anticancer; Chemosensitizers; Drug design; MDR modulators; MDR-1; P-glycoprotein