title: Structure-activity relationships studies in a series of N,N-bis(alkanol)amine aryl esters as P-glycoprotein (Pgp) dependent multidrug resistance (MDR) inhibitors.
abstract: As a continuation of a previous research, a series of N,N-bis(alkanol)amine aryl esters, as Pgp-dependent MDR inhibitors, was designed and synthesized. The aromatic ester portions are suitably modulated, and new aryl rings (Ar(1) and Ar(2)) were combined with trans-3-(3,4,5-trimethoxyphenyl)vinyl, 3,4,5-trimethoxybenzyl and anthracene moieties that were present in the most potent previously studied compounds. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Selected compounds (5, 6, 8, 9, and 21) were further studied, evaluating their action on doxorubicin cytotoxicity potentiation on K562 cells; they significantly enhanced doxorubicin cytotoxicity on K562/DOX cells, confirming the results obtained with pirarubicin. Compound 9 shows the most promising properties as it was able to nearly completely reverse Pgp-dependent pirarubicin extrusion at nanomolar doses and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 19.1 at 3 microM dose.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione Sintesi e Studio di Eterocicli Bioattivi (HeteroBioLab), Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Martelli
authors.forename: Marcella
authors.initials: M
authors.lastname: Coronnello
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Orlandi
authors.forename: Serena
authors.initials: S
authors.lastname: Scapecchi
authors.forename: Maria
authors.initials: M
authors.lastname: Novella Romanelli
authors.forename: Milena
authors.initials: M
authors.lastname: Salerno
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Teodori
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004952:Esters; D006801:Humans; D020014:K562 Cells; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000588:Amines; D000970:Antineoplastic Agents; D004952:Esters; D004317:Doxorubicin; C027260:pirarubicin