title: New structure-activity relationship studies in a series of N,N-bis(cyclohexanol)amine aryl esters as potent reversers of P-glycoprotein-mediated multidrug resistance (MDR).
abstract: As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure-activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis). The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I](0.5)) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5a-d and 6d, showed excellent efficacy with a α(max) close to 1. Selected compounds (2d, 3a, 3b, 5a-d) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells. The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site. In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,(29) are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Orlandi
authors.forename: Marcella
authors.initials: M
authors.lastname: Coronnello
authors.forename: Cristina
authors.initials: C
authors.lastname: Bellucci
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.forename: Luca
authors.initials: L
authors.lastname: Guandalini
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.forename: Cecilia
authors.initials: C
authors.lastname: Martelli
authors.forename: Maria Novella
authors.initials: MN
authors.lastname: Romanelli
authors.forename: Serena
authors.initials: S
authors.lastname: Scapecchi
authors.forename: Milena
authors.initials: M
authors.lastname: Salerno
authors.forename: Hayette
authors.initials: H
authors.lastname: Menif
authors.forename: Ivan
authors.initials: I
authors.lastname: Bello
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* / Q000378:metabolism; D000588:Amines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003511:Cyclohexanols / Q000737:chemistry*; D004317:Doxorubicin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D004952:Esters; D006801:Humans; D007536:Isomerism; D020014:K562 Cells; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000588:Amines; D000970:Antineoplastic Agents; D003511:Cyclohexanols; D004952:Esters; D004317:Doxorubicin