1314642-40-4Relevant academic research and scientific papers
Discovery of potent and selective inhibitors of human platelet-type 12-lipoxygenase
Kenyon, Victor,Rai, Ganesha,Jadhav, Ajit,Schultz, Lena,Armstrong, Michelle,Jameson, J. Brian,Perry, Steven,Joshi, Netra,Bougie, James M.,Leister, William,Taylor-Fishwick, David A.,Nadler, Jerry L.,Holinstat, Michael,Simeonov, Anton,Maloney, David J.,Holman, Theodore R.
, p. 5485 - 5497 (2011)
We report the discovery of novel small molecule inhibitors of platelet-type 12-human lipoxygenase, which display nanomolar activity against the purified enzyme, using a quantitative high-throughput screen (qHTS) on a library of 153607 compounds. These compounds also exhibit excellent specificity, >50-fold selectivity vs the paralogues, 5-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity vs ovine cyclooxygenase-1 and human cyclooxygenase-2. Kinetic experiments indicate this chemotype is a noncompetitive inhibitor that does not reduce the active site iron. Moreover, chiral HPLC separation of two of the racemic lead molecules revealed a strong preference for the (-)-enantiomers (IC50 of 0.43 ± 0.04 and 0.38 ± 0.05 μM) compared to the (+)-enantiomers (IC50 of >25 μM for both), indicating a fine degree of selectivity in the active site due to chiral geometry. In addition, these compounds demonstrate efficacy in cellular models, which underscores their relevance to disease modification.
Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases
Thinnes,Tumber,Yapp,Scozzafava,Yeh,Chan,Tran,Hsu,Tarhonskaya,Walport,Wilkins,Martinez,Müller,Pugh,Ratcliffe,Brennan,Kawamura,Schofield
supporting information, p. 15458 - 15461 (2015/10/20)
There is interest in developing potent, selective, and cell-permeable inhibitors of human ferrous iron and 2-oxoglutarate (2OG) oxygenases for use in functional and target validation studies. The 3-component Betti reaction enables efficient one-step C-7 functionalisation of modified 8-hydroxyquinolines (8HQs) to produce cell-active inhibitors of KDM4 histone demethylases and other 2OG oxygenases; the work exemplifies how a template-based metallo-enzyme inhibitor approach can be used to give biologically active compounds.
