title: Solid phase synthesis of tariquidar-related modulators of ABC transporters preferring breast cancer resistance protein (ABCG2).
abstract: Aiming at structural optimization of potent and selective ABCG2 inhibitors, such as UR-ME22-1, from our laboratory, an efficient solid phase synthesis was developed to get convenient access to this class of compounds. 7-Carboxyisatoic anhydride was attached to Wang resin to give resin bound 2-aminoterephthalic acid. Acylation with quinoline-2- or -6-carbonyl chlorides, coupling with tetrahydroisoquinolinylethylphenylamine derivatives, cleavage of the carboxylic acids from solid support and treatment with trimethylsilydiazomethane gave the corresponding methyl esters. Among these esters highly potent and selective ABCG2 modulators were identified (inhibition of ABCB1 and ABCG2 determined in the calcein-AM and the Hoechst 33342 microplate assay, respectively). Interestingly, compounds bearing triethyleneglycol ether groups at the tetrahydroisoquinoline moiety (UR-COP77, UR-COP78) were comparable to UR-ME22-1 in potency but considerably more efficient (max inhibition 83% and 88% vs 60%, rel. to fumitremorgin c, 100%) These results support the hypothesis that solubility of the new ABCG2 modulators and of the reference compounds tariquidar and elacridar in aqueous media is the efficacy-limiting factor.
authors.affiliation: Departamento de Química, Universidad Nacional de Colombia, Bogotá DC, Colombia.
authors.forename: Cristian Ochoa
authors.initials: CO
authors.lastname: Puentes
authors.forename: Peter
authors.initials: P
authors.lastname: Höcherl
authors.forename: Matthias
authors.initials: M
authors.lastname: Kühnle
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bauer
authors.forename: Kira
authors.initials: K
authors.lastname: Bürger
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Burkhard
authors.initials: B
authors.lastname: König
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D021381:Protein Transport / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011804:Quinolines; C402343:tariquidar