title: N-alkanol-N-cyclohexanol amine aryl esters: Multidrug resistance (MDR) reversing agents with high potency and efficacy.
abstract: In a continuing search for potent P-gp-dependent multidrug-resistant (MDR) reversers we synthesized and studied a new series of N-alkanol-N-cyclohexanol amine aryl esters characterized by the presence of two linkers with different flexibility: a polymethylene chain of variable length and a cyclohexylic scaffold, that gave origin to two geometrical isomers (cis and trans). The reversal activity of the new compounds was evaluated on the K562/DOX cell line by three tests: pirarubicin uptake modulation, doxorubicin cytotoxicity enhancement (reversal fold, RF) and inhibition of P-gp-mediated rhodamine-123 (Rhd 123) efflux tests. The chemical stability of their ester function was evaluated in the experimental conditions utilized (phosphate buffer solution (PBS), bovine serum and in the presence of K562/DOX cells) and in human plasma. The new series of molecules showed very interesting MDR reversing properties; in particular compound 5b (ELF26B), characterized by trans stereochemistry and a 5-methylene chain, presented the best pharmacological profile and is stable in each tested medium. Compound 5b could be an interesting lead for the development of new potent and efficacious P-gp-dependent MDR modulators.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy. Electronic address: elisabetta.teodori@unifi.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Teodori
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Coronnello
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Floriddia
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolucci
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Maria Novella
authors.initials: MN
authors.lastname: Romanelli
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Diego
authors.initials: D
authors.lastname: Santo Domingo Porqueras
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Milena
authors.initials: M
authors.lastname: Salerno
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000588:Amines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D003511:Cyclohexanols / Q000737:chemistry* / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004355:Drug Stability; D004952:Esters / Q000737:chemistry*; D006801:Humans; D020014:K562 Cells; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000588:Amines; D000970:Antineoplastic Agents; D003511:Cyclohexanols; D004952:Esters; D020112:Rhodamine 123; D004317:Doxorubicin; C027260:pirarubicin
keywords: Chemosensitizers; Doxorubicin-resistant human erythroleukemia K562 cells (K562/DOX); MDR reversers; N-alkanol-N-cyclohexanol amine aryl esters; P-gp modulators; Pirarubicin uptake