Studies towards the synthesis of methionine aminopeptidase inhibitors: diversification utilizing a ROMP-derived coupling reagent.
Efforts to synthesize potential methionine aminopeptidase inhibitors is described. Preliminary SAR and docking studies served as a guide to design the compound libraries. "Chromatography-free" synthesis of various heterocyclic amides was realized by using a high-load, soluble coupling reagent derived via ring-opening metathesis polymerization (ROMP). Subsequent microwave-assisted Suzuki reactions with ortho-substituted arylboronic acids, followed by chromatographic purification afforded a 55-member library in high yields and purities. While the biological testing was not satisfactory, concurrent X-ray crystallography studies revealed key structural features essential for inhibition of methionine aminopeptidase, which directed fruitful results reported in the accompanying manuscript. In addition, in silico Lipinksi profiles and ADME properties of the library are also reported.
Vedantham
Punitha
P
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, USA.
Zhang
Mianji
M
Gor
Parul J
PJ
Huang
Min
M
Georg
Gunda I
GI
Lushington
Gerald H
GH
Mitscher
Lester A
LA
Ye
Qi-Zhuang
QZ
Hanson
Paul R
PR
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology; D007202:Indicators and Reagents / Q000737:chemistry*; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D007202:Indicators and Reagents; D011480:Protease Inhibitors; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases