title: Inhibition of P-glycoprotein-mediated Multidrug Resistance (MDR) by N,N-bis(cyclohexanol)amine aryl esters: further restriction of molecular flexibility maintains high potency and efficacy.
abstract: Conformational modulation of the aryl portion of a set of N,N-bis(cyclohexanol)amine aryl esters (1a-d) that are potent Pgp-dependent MDR inhibitors has been performed. Toward this end the trans-3-(3,4,5-trimethoxyphenyl)acrylic acid present in set 1 was substituted with 3-(3,4,5-trimethoxyphenyl)propanoic and 3-(3,4,5-trimethoxyphenyl)propiolic moieties to give sets 2 and 3, respectively. While the introduction of 3-(3,4,5-trimethoxyphenyl)propanoic moiety resulted in a definite drop in potency and efficacy, esterification with 3-(3,4,5-trimethoxyphenyl)propiolic acid gave four isomers (3a-d) that maintain high potency and possess optimal efficacy. These results are discussed in terms of conformational flexibility of the different sets of compounds.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Martelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.forename: Catherine
authors.initials: C
authors.lastname: Lambert
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Orlandi
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: 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* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003511:Cyclohexanols / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004952:Esters; D006801:Humans; D007536:Isomerism; D008968:Molecular Conformation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000588:Amines; D000970:Antineoplastic Agents; D003511:Cyclohexanols; D004952:Esters