Ionic immobilization, diversification, and release: application to the generation of a library of methionine aminopeptidase inhibitors.
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.
Vedantham
Punitha
P
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, USA.
Guerra
Jennifer M
JM
Schoenen
Frank
F
Huang
Min
M
Gor
Parul J
PJ
Georg
Gunda I
GI
Wang
Jenna L
JL
Neuenswander
Benjamin
B
Lushington
Gerald H
GH
Mitscher
Lester A
LA
Ye
Qi-Zhuang
QZ
Hanson
Paul R
PR
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
D011480:Protease Inhibitors; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases