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

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.

Automated summary

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.