4.7 Article

Toluene Dioxygenase-Catalyzed cis-Dihydroxylation of Quinolines: A Molecular Docking Study and Chemoenzymatic Synthesis of Quinoline Arene Oxides

Journal

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fbioe.2020.619175

Keywords

arene oxides; cis-dihydrodiols; dioxygenase; docking; biocatalysis

Funding

  1. BBSRC [81/ABC09451, BB/E013848/1]
  2. Leverhulme Trust
  3. European Social Fund
  4. Queen's University of Belfast
  5. Oxford Glycosciences, and the Overseas Research Studentship
  6. BBSRC [BB/E013848/1] Funding Source: UKRI

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The molecular docking studies of quinoline and 2-chloroquinoline substrates at the active site of toluene dioxygenase provided insights into novel edge-to-face interactions and explained the stereoselective cis-dihydroxylation of carbocyclic rings. The findings also supported the postulated cis-dihydroxylation of electron-deficient pyridyl rings, leading to the formation of hydroxyquinolines. The chemoenzymatic synthesis of enantiopure arene oxide and arene dioxide derivatives from 2-chloroquinoline cis-dihydrodiol metabolites demonstrated the potential implications for mammalian metabolism and carcinogenicity of quinoline.
Molecular docking studies of quinoline and 2-chloroquinoline substrates at the active site of toluene dioxygenase (TDO), were conducted using Autodock Vina, to identify novel edge-to-face interactions and to rationalize the observed stereoselective cis-dihydroxylation of carbocyclic rings and formation of isolable cis-dihydrodiol metabolites. These in silico docking results of quinoline and pyridine substrates, with TDO, also provided support for the postulated cis-dihydroxylation of electron-deficient pyridyl rings, to give transient cis-dihydrodiol intermediates and the derived hydroxyquinolines. 2-Chloroquinoline cis-dihydrodiol metabolites were used as precursors in the chemoenzymatic synthesis of enantiopure arene oxide and arene dioxide derivatives of quinoline, in the context of its possible mammalian metabolism and carcinogenicity.

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