title: Ionic immobilization, diversification, and release: application to the generation of a library of methionine aminopeptidase inhibitors.
abstract: Development of an ionic immobilization, diversification, and release method for the generation of methionine aminopeptidase inhibitors is reported. This method involves the immobilization of 5-bromofuran-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid onto PS-BEMP, followed by Suzuki reaction on a resin-bound intermediate and subsequent release to provide products in moderate yields and excellent purities. Compound potencies were evaluated on the Co(II), Mn(II), Ni(II), and Fe(II) forms of Escherichia coli MetAP1. The furoic-acid analogs were found to be Mn(II) selective with IC 50 values in the low micromolar range. Qualitative SAR analysis, supplemented by molecular modeling studies, provides valuable information on structural elements responsible for potency and selectivity.
authors.affiliation: Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, USA.
authors.forename: Punitha
authors.initials: P
authors.lastname: Vedantham
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Guerra
authors.forename: Frank
authors.initials: F
authors.lastname: Schoenen
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Parul J
authors.initials: PJ
authors.lastname: Gor
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Wang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neuenswander
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Lushington
authors.forename: Lester A
authors.initials: LA
authors.lastname: Mitscher
authors.forename: Qi-Zhuang
authors.initials: QZ
authors.lastname: Ye
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hanson
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D004926:Escherichia coli / Q000201:enzymology; D013058:Mass Spectrometry; D063208:Methionyl Aminopeptidases; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet
chemical_list: D011480:Protease Inhibitors; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases