title: Potent and fully noncompetitive peptidomimetic inhibitor of multidrug resistance P-glycoprotein.
abstract: N(α)-Boc-l-Asp(OBn)-l-Lys(Z)-OtBu (reversin 121, 1), an inhibitor of the P-gp ABC transporter, was used to conceive compounds inhibiting the drug efflux occurring through the Hoechst 33342 and daunorubicin transport sites of P-gp, respectively H and R sites. Replacement of the aspartyl residue by trans-4-hydroxy-l-proline (4(R)Hyp) gave compounds 11 and 15 characterized by half-maximal inhibitory concentrations (IC(50)) of 0.6 and 0.2 μM, which are 2- and 7-fold lower than that of the parent molecule. The difference in IC(50) between 11 and 15 rests on the carbonyl group of the peptidyl bond, reduced in 15. Those compounds are rather specific of P-gp, having no or limited activity on MRP1 and BCRP. 15 displayed no marked cytotoxicity up to 10-fold its IC(50). Importantly, 15 equally inhibited the Hoechst 33342 and daunorubicin effluxes through a typical noncompetitive inhibition mechanism, suggesting its binding to a site different from the H and R drug-transport sites.
authors: Laboratoire des Protéines de Résistance aux Agents Chimiothérapeutiques, Equipe Labellisée Ligue 2009, Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS, Université Lyon 1, IFR 128 BioSciences Gerland Lyon-Sud, F-69367 Lyon, France.
authors: Ophélie
authors: O
authors: Arnaud
authors: Ali
authors: A
authors: Koubeissi
authors: Laurent
authors: L
authors: Ettouati
authors: Raphaël
authors: R
authors: Terreux
authors: Ghina
authors: G
authors: Alamé
authors: Catherine
authors: C
authors: Grenot
authors: Charles
authors: C
authors: Dumontet
authors: Attilio
authors: A
authors: Di Pietro
authors: Joëlle
authors: J
authors: Paris
authors: Pierre
authors: P
authors: Falson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D045744:Cell Line, Tumor; D006224:Cricetinae; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008024:Ligands; D009842:Oligopeptides; C120260:reversin 121