PMID: 11334560May 4, 2001Paper

Design, synthesis, and proposed active site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen

Journal of Medicinal Chemistry
R M AdlingtonG J Pritchard

Abstract

A homology derived molecular model of prostate specific antigen (PSA) was created and refined. The active site region was investigated for specific interacting functionality and a binding model postulated for the novel 2-azetidinone acyl enzyme inhibitor 1 (IC(50) = 8.98 +/- 0.90 microM) which was used as a lead compound in this study. A single low energy conformation structure II (Figure 2) was adopted as most likely to represent binding after minimization and dynamics calculations. Systematic analysis of the binding importance of all three side chains appended to the 2-azetidinone was conducted by the synthesis of several analogues. A proposed salt bridge to Lys-145 with 4 (IC(50) = 5.84 +/- 0.92 microM) gave improved inhibition, but generally the binding of the N-1 side chain in a specific secondary aromatic binding site did not tolerate much structural alteration. A hydrophobic interaction of the C-4 side chain afforded inhibitor 6 (IC(50) = 1.43 +/- 0.19 microM), and polar functionality could also be added in a proposed interaction with Gln-166 in 5 (IC(50) = 1.34 +/- 0.05 microM). Reversal of the C-4 ester connectivity furnished inhibitors 7 (IC(50) = 1.59 +/- 0.15 microM), 11 (IC(50) = 3.08 +/- 0.41 microM), and 13 (IC(5...Continue Reading

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Citations

Nov 5, 2002·Bioorganic & Medicinal Chemistry·Stéphane GérardJacqueline Marchand-Brynaert
May 6, 2009·Journal of the American Chemical Society·David M ChenowethPeter B Dervan
Sep 9, 2011·Journal of Medicinal Chemistry·Marion FeledziakJacqueline Marchand-Brynaert
Apr 28, 2011·The Journal of Antibiotics·Gianfranco De PascaleGerard D Wright
May 27, 2008·The Prostate·Hannu KoistinenUlf-Håkan Stenman
Mar 12, 2011·The Prostate·Simon A WilliamsSamuel R Denmeade
Jul 23, 2003·Analytical Biochemistry·Petr KuzmicJames W Janc
Feb 28, 2014·Expert Opinion on Therapeutic Targets·Konstantinos MavridisAndreas Scorilas
Jul 10, 2010·Biochimie·Peter GoettigHans Brandstetter
Mar 5, 2016·Expert Opinion on Therapeutic Targets·Margaritis Avgeris, Andreas Scorilas
Jun 14, 2017·Medicinal Research Reviews·Nicolas MasurierVincent Lisowski
Feb 23, 2008·Bioorganic & Medicinal Chemistry Letters·Wei WangPeter T W Cheng
Oct 30, 2019·Cancer Metastasis Reviews·Afshin MoradiJyotsna Batra
Jun 13, 2020·Biology of Reproduction·Prashanth Anamthathmakula, Wipawee Winuthayanon
Sep 30, 2008·Journal of Enzyme Inhibition and Medicinal Chemistry·Mary J MeeganDavid G Lloyd
Feb 2, 2012·Organic & Biomolecular Chemistry·Gitanjeli PrasadNathan A Schnarr
Jun 6, 2014·ACS Medicinal Chemistry Letters·Albert M DeBerardinisM Kyle Hadden
Jan 20, 2018·Journal of Medicinal Chemistry·Eric J MillerDennis C Liotta
Dec 12, 2002·Chemical Reviews·James C PowersKaren Ellis James

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