title: N,N-bis(cyclohexanol)amine aryl esters: a new class of highly potent transporter-dependent multidrug resistance inhibitors.
abstract: A new series of Pgp-dependent MDR inhibitors having a N,N-bis(cyclohexanol)amine scaffold was designed on the basis of the frozen analogue approach. The scaffold chosen gives origin to different geometrical isomers. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells in the pirarubicin uptake assay. The most interesting compounds (isomers of 3) were studied further evaluating their action on the ATPase activity present in rat small intestine membrane vesicles and doxorubicin cytotoxicity potentiation on K562 cells. The latter assay was performed also on the isomers of 4. The four isomers of each set present different behavior in each of these tests. Compound 3d shows the most promising properties as it was able to completely reverse Pgp-dependent pirarubicin extrusion at low nanomolar concentration, inhibited ATPase activity at 5 x 10(-9) and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 36.4 at 3 microM concentration.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita di Firenze, via U. Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Martelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Alderighi
authors.forename: Marcella
authors.initials: M
authors.lastname: Coronnello
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Le Bozec
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Neri
authors.forename: Maria Novella
authors.initials: MN
authors.lastname: Romanelli
authors.forename: Milena
authors.initials: M
authors.lastname: Salerno
authors.forename: Serena
authors.initials: S
authors.lastname: Scapecchi
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
authors.forename: Giampietro
authors.initials: G
authors.lastname: Sgaragli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Teodori
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003511:Cyclohexanols / Q000138:chemical synthesis* / Q000494:pharmacology; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003511:Cyclohexanols; D003514:Cyclohexylamines; D004317:Doxorubicin; C027260:pirarubicin