title: SAR study on arylmethyloxyphenyl scaffold: looking for a P-gp nanomolar affinity.
abstract: Starting from the previously developed P-gp ligands 1a and 1b (EC₅₀ = 0.25 μM and 0.65 μM, respectively), new arylmethyloxyphenyl derivatives have been synthesized as P-gp modulators in order to investigate: (i) the effect of small electron-donor groups (OMe) (5-11), (ii) the effect of the replacement of methoxy groups with an electron-withdrawal substituent (Cl) on C-ring (13) (iii) the effect induced by the replacement of C-ring with heteroaromatic cycles such as thiophene and pyrimidine (13, 15, 16), (iv) the effect induced by molecular constriction on C ring (14, 17, 18) on P-gp modulating activity. The results demonstrated that P-gp inhibition potency is strongly correlated to the number of methoxy groups in the A-ring whereas the methoxylation of C-ring seems to poorly affect P-gp activity. The best result was found for compound 10 that displays a nanomolar affinity (EC₅₀ = 7.1 nM) towards P-gp pump and, in the meantime lacks of activity against MRP1 pump.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno,6 56126 Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Nesi
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via Orabona, 4, 70125 Bari, Italy. Electronic address: nicolaantonio.colabufo@uniba.it.
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
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: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno,6 56126 Pisa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno,6 56126 Pisa, Italy.
authors.forename: Annalina
authors.initials: A
authors.lastname: Lapucci
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno,6 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno,6 56126 Pisa, Italy. Electronic address: simona.rapposelli@farm.unipi.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents
keywords: Arylmethyloxyphenyl compounds; Cancer; Neurodegenerative diseases; P-gp ligands