Abstract
Enzymatic oxidations of thiophenes, including thiophene-containing drugs, are important for biodesulfurization of crude oil and drug metabolism of mono- and poly-cyclic thiophenes. Thiophene oxidative dearomatization pathways involve reactive metabolites, whose detection is important in the pharmaceutical industry, and are catalyzed by monooxygenase (sulfoxidation, epoxidation) and dioxygenase (sulfoxidation, dihydroxylation) enzymes. Sulfoxide and epoxide metabolites of thiophene substrates are often unstable, and, while cis-dihydrodiol metabolites are more stable, significant challenges are presented by both types of metabolite. Prediction of the structure, relative and absolute configuration, and enantiopurity of chiral metabolites obtained from thiophene enzymatic oxidation depends on the substrate, type of oxygenase selected, and molecular docking results. The racemization and dimerization of sulfoxides, cis/trans epimerization of dihydrodiol metabolites, and aromatization of epoxides are all factors associated with the mono- and di-oxygenase-catalyzed metabolism of thiophenes and thiophene-containing drugs and their applications in chemoenzymatic synthesis and medicine.
Highlights
The link between aromaticity and resulting molecular stability is well established, enzymes have a remarkable capacity for dearomatization of many stable and recalcitrant arene and heteroarene substrates
The most convincing indirect evidence for thiophene epoxide intermediates being formed by CYP450-catalyzed oxidation of thiophenes comes from the formation of transhydroxysulfide adducts (Scheme 11)
A major emphasis of this review has been on the complementary nature of monooxygenase and dioxygenase enzyme activities, in the context of oxidative dearomatization of mono- and poly-cyclic thiophenes
Summary
The link between aromaticity and resulting molecular stability is well established, enzymes have a remarkable capacity for dearomatization of many stable and recalcitrant arene and heteroarene substrates. Attempted chemical approaches to the oxidative dearomatization reactions of carbocyclic arenes, shown in Scheme 1a, often result in further oxidation, or rearomatization of the initial products Due to their instability, relatively few arene oxide metabolites B have been isolated from monooxygenase (MO)-catalyzed epoxidations of substituted benzene substrates A. Studies of the bacterial metabolism of thiaarenes showed that dioxygenase-catalyzed cis-dihydroxylation of carbocyclic and heterocyclic rings could yield chiral cis-dihydrodiols as transient metabolites. Isolation of these intermediates was possible when using P. putida mutant strains (or E. coli recombinant strains), ex-. ColipFDTG141) yielded only a phenyl ring cis-dihydrodiol 8g, while an alternative strain (E. coli-pF352V) gave thienyl ring cis:trans dihydrodiols (2g:4g) exclusively (Table 1) This shows the value of having different bacterial strains and dioxygenase enzymes available to produce preferred metabolites
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
