Structure and stereochemistry of cis-dihydro diol and phenol metabolites of bicyclic azaarenes from Pseudomonas putida UV4

Abstract

Biotransformation of quinoline, isoquinoline, quinoxaline and quinazoline using growing cultures of Pseudomonas putida UV4 yielded cis-dihydro diols from the oxidation of the carbocyclic aromatic ring. Aromatic hydroxylation was observed in both carbocyclic and heterocyclic rings. Ring cleavage of the quinoline skeleton to yield anthranilic acid, and cis-diol formation (with alkene bond reduction) to yield cis-5,6,7,8-tetrahydroquinazoline-5.6-diol from quinazoline were observed. The cis-dihydro diol metabolites of quinoline (5,6and 7,8-) and quinoxaline (5,6-) were found to be optically pure, while metabolism of isoquinoline gave one homochiral (5,6-) and one racemic (7.8-) cis-dihydro diol product. The absolute configurations of the cis-dihydro diol metabolites have been determined using ' H N M R analyses, stereochemical correlations and X-ray crystallography methods.Azaarenes (e.g. quinoline 1 and isoquinoline 2) are widely distributed throughout the global environment, mainly as a result of partial combustion of plant material and fossil fuels. 'Quinoline I, the most abundant of the azaarenes in the environment, is both carcinogenic and mutagenic. The latter effects probably result from the derived metabolites of quinoline 1. Known and potential metabolites of quinoline l 2 and isoquinoline 23 have recently been synthesised as part of a Paper 2/06567C

Regioselectivity and Enantioselectivity of Naphthalene Dioxygenase during Arene cis -Dihydroxylation: Control by Phenylalanine 352 in the α Subunit

“…1. 1-Bromo-2-iodobenzene (2.0 g, 7.07 mmol [compound 1]) was oxidized by P. putida UV4 using the standard procedure (7,8), to yield the major cis-diol, To a solution of the (ϩ)-cis-diol (compound 2; 0.12 g, 0.38 mmol) in methanol (8 ml) was added sodium acetate trihydrate (0.105 g), quinoline (75 l), and 3% Pd/C (0.016 g). The reaction mixture was stirred in an atmosphere of hydrogen at ambient temperature.…”

Efficient Pathway for the Preparation of Aryl(isoquinoline)iodonium(III) Salts and Synthesis of Radiofluorinated Isoquinolines

“…[13] For instance, the natural product berberine shows therapeutic potential in treatment of cancer and diabetes, [14] and aspergillitine, isolated from Aspergillus versicolor in marine sponge, exhibited antibacterial activity against Bacillus subtilis . [15] Fluorine incorporation into isoquinoline has been proven to reduce in vivo metabolism, [16] particularly as a bioisostere of hydrogen to block oxidation at C-4 (the major metabolism), and thus serves as a valuable fluorine-containing component in pharmaceutical design, [17] for example Glanatec ® . [17d] For the purpose of molecular imaging by PET, 18 F-isotopologues of fluoroisoquinoline would provide a unique and non-invasive way to track in vivo behavior of labeled drug candidates and their interactions with biological targets.…”

Laboratory Evolution of Toluene Dioxygenase To Accept 4-Picoline as a Substrate

“…N-Heterocyclic compounds are useful for the synthesis of biologically active compounds; recent reports describe the regioand/or stereo-controlled biooxidation of N-heterocycles (20,26). Bicyclic compounds such as quinolines and benzofurans are accepted by TDO, with oxygen insertion occurring primarily in the carbocylic rings (3)(4)(5).…”