title: Synthesis of Transition-State Inhibitors of Chorismate Utilizing Enzymes from Bromobenzene cis-1,2-Dihydrodiol.
abstract: In order to survive in a mammalian host, Mycobacterium tuberculosis (Mtb) produces aryl-capped siderophores known as the mycobactins for iron acquisition. Salicylic acid is a key building block of the mycobactin core and is synthesized by the bifunctional enzyme MbtI, which converts chorismate into isochorismate via a SN2″ reaction followed by further transformation into salicylate through a [3,3]-sigmatropic rearrangement. MbtI belongs to a family of chorismate-utilizing enzymes (CUEs) that have conserved topology and active site residues. The transition-state inhibitor 1 described by Bartlett, Kozlowski, and co-workers is the most potent reported inhibitor to date of CUEs. Herein, we disclose a concise asymmetric synthesis and the accompanying biochemical characterization of 1 along with three closely related analogues beginning from bromobenzene cis-1S,2S-dihydrodiol produced through microbial oxidation that features a series of regio- and stereoselective transformations for introduction of the C-4 hydroxy and C-6 amino substituents. The flexible synthesis enables late-stage introduction of the carboxy group and other bioisosteres at the C-1 position as well as installation of the enol-pyruvate side chain at the C-5 position.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , 152 Luoyu Road, Wuhan, Hubei 430079, People's Republic of China.
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , 308 Harvard Street Southeast, 8-174 WDH, Minneapolis, Minnesota 55455, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , 308 Harvard Street Southeast, 8-174 WDH, Minneapolis, Minnesota 55455, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Fiers
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , 152 Luoyu Road, Wuhan, Hubei 430079, People's Republic of China.
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Sun
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , 152 Luoyu Road, Wuhan, Hubei 430079, People's Republic of China.
authors.forename: Jun
authors.identifier: 0000-0002-2097-5054
authors.initials: J
authors.lastname: Guo
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , 152 Luoyu Road, Wuhan, Hubei 430079, People's Republic of China.
authors.forename: Zheng
authors.identifier: 0000-0002-3696-339X
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , 308 Harvard Street Southeast, 8-174 WDH, Minneapolis, Minnesota 55455, United States.
authors.forename: Courtney C
authors.identifier: 0000-0001-9261-594X
authors.initials: CC
authors.lastname: Aldrich
mesh_terms: D001969:Bromobenzenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053138:Cyclohexenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008190:Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D001969:Bromobenzenes; D053138:Cyclohexenes; D004791:Enzyme Inhibitors; C041284:3-bromo-3,5-cyclohexadiene-1,2-diol; D008190:Lyases; C022620:salicylate synthetase