title: Arylamino Esters As P-Glycoprotein Modulators: SAR Studies to Establish Requirements for Potency and Selectivity.
abstract: A set of basic aryl-group-containing compounds was synthesized with the aim of developing potent and selective P-glycoprotein (P-gp) modulators that are able to reverse multidrug resistance (MDR). The natures of the spacer (dicyclohexylamine or dialkylamine) and the aryl moieties were modified to investigate selectivity and the mechanism of P-gp interaction. The inhibitory activities of the compounds toward P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), the most relevant ATP binding cassette (ABC) transporters for MDR, were evaluated. The mechanism of P-gp interaction for each compound was investigated with three biological assays: apparent permeability (Papp ) determination (B→A/A→B) in Caco-2 cell monolayers, ATP cell depletion, and inhibition of Calcein-AM transport in MDCK-MDR1 cells. These assays allowed us to estimate the selectivity of the compounds for the three efflux pumps and to identify the structural requirements that define the P-gp-interaction profile. All dicyclohexylamine derivatives were found to be P-gp substrates, whereas one dialkylamine derivative was shown to be a P-gp inhibitor. The good MRP1 activity of one cis/cis isomer highlighted this as a lead candidate for the development of MRP1 ligands.
authors.affiliation: Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (Italy). elisabetta.teodori@unifi.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Teodori
authors.affiliation: Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (Italy).
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.affiliation: Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (Italy).
authors.forename: Elisa
authors.initials: E
authors.lastname: Floriddia
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro" via Orabona 4, 70125, Bari (Italy).
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.affiliation: Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (Italy).
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.affiliation: Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (Italy).
authors.forename: Maria Novella
authors.initials: MN
authors.lastname: Romanelli
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro" via Orabona 4, 70125, Bari (Italy).
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro" via Orabona 4, 70125, Bari (Italy).
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003514:Cyclohexylamines / Q000737:chemistry; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004952:Esters; D005452:Fluoresceins / Q000737:chemistry; D006801:Humans; D007536:Isomerism; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D004952:Esters; D005452:Fluoresceins; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C116614:ABCG2 protein, human; C085925:calcein AM; C011769:dicyclohexylamine; C421109:multidrug resistance-associated protein 1
keywords: BCRP; MRP1; P-glycoprotein; inhibitors; multidrug resistance; substrates