Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis☆
Graphical abstract
The design, synthesis, and biochemical evaluation of mechanism-based OSB-CoA synthetase inhibitors is reported.
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Acknowledgments
We thank Dr. George Sukenick, Hui Liu, Hui Fang, and Sylvi Rusli (MSKCC Analytical Core Facility) for expert mass spectral analyses. D.S.T. is an Alfred P. Sloan Research Fellow. Financial support from the NIH (R01 AI068038 to D.S.T.; R01 AI044639 and R21 AI058785 to P.J.T.), NYSTAR Watson Investigator Program (D.S.T.), William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, and MSKCC Experimental Therapeutics Center is gratefully acknowledged.
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2019, Annual Reports in Medicinal ChemistryCitation Excerpt :A small set of sulfamates, sulfamides and vinyl sulfonamides (e.g., 54–57) was prepared as mimics of 53 and evaluated in a coupled enzyme assay (E.coli MenE and M.tb MenB), using the production of the MenB product, 1,4-dihydroxy-2-napthoyl-CoA as readout. The vinyl sulfonamide ketone 56 was the most effective MenE inhibitor in this assay (IC50 5.7 μM), six- to sevenfold better than 54 and 55, whereas its terminal alkene counterpart 57 was inactive.58 Unlabelled Image
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Dedicated to Professor Benjamin F. Cravatt, in honor of his outstanding contributions to chemical biology and his receipt of the 2008 Tetrahedron Young Investigator Award.
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These authors contributed equally to this work.