title: Design and synthesis of an optimized positional scanning library of peptoids: identification of novel multidrug resistance reversal agents.
abstract: Herein is reported the optimized solid-phase synthesis of a library of 5,120 trimeric N-alkylglycines (peptoids) using the positional scanning format and the submonomer strategy. Diversity at the N-terminal position was generated from 20 commercially available primary amines, whereas 16 primary amines were employed for the middle and C-terminal positions of the trimers. Formation of undesirable side-products observed in a previous library synthesis (Humet, M. et al. J. Comb. Chem. 2003, 5, 597-605) was averted by restricting the use of primary amines functionalized with tertiary amino groups to the third amination step. Screening of the new library for the identification of chemosensitizers yielded two peptoids, compounds 1 and 2, with potent in vitro activity as multidrug resistance (MDR) reversal agents. The structures of the lead peptoids are consistent with a pharmacophore model generated from the interaction of various known inhibitors with the MDR-implicated transmembrane glycoprotein P-gp.
authors.affiliation: Department of Biological Organic Chemistry, I.I.Q.A.B. (C.S.I.C.), J. Girona, 18, E-08034 Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Masip
authors.forename: Nuria
authors.initials: N
authors.lastname: Cortés
authors.forename: Maria-José
authors.initials: MJ
authors.lastname: Abad
authors.forename: Marisa
authors.initials: M
authors.lastname: Guardiola
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Payá
authors.forename: José
authors.initials: J
authors.lastname: Ferragut
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
mesh_terms: D000478:Alkylation; D000588:Amines / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D018432:Drug Resistance, Multiple; D005998:Glycine / Q000737:chemistry; D007473:Ion Channels / Q000037:antagonists & inhibitors; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D034444:Peptoids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000588:Amines; D007473:Ion Channels; D034444:Peptoids; D005998:Glycine