Abstract
The enantiomers of aromatic 4-dibenzocyclooctynol (DIBO), used for radiolabeling and subsequent conjugation of biomolecules to form radioligands for positron emission tomography (PET), were separated by kinetic resolution using lipase A from Candida antarctica (CAL-A). In optimized conditions, (R)-DIBO [(R)-1, ee 95%] and its acetylated (S)-ester [(S)-2, ee 96%] were isolated. In silico docking results explained the ability of CAL-A to differentiate the enantiomers of DIBO and to accommodate various acyl donors. Anhydrous MgCl2 was used for binding water from the reaction medium and, thus, for obtaining higher conversion by preventing hydrolysis of the product (S)-2 into the starting material. Since the presence of hydrated MgCl2·6H2O also allowed high conversion or effect on enantioselectivity, Mg2+ ion was suspected to interact with the enzyme. Binding site predictions indicated at least two sites of interest; one in the lid domain at the bottom of the acyl binding pocket and another at the interface of the hydrolase and flap domains, just above the active site.
Highlights
Positron emission tomography (PET) imaging provides a method for observing metabolic processes and biological macromolecules in living organisms and, an opportunity to diagnose various human diseases
To accommodate an acyl donor, CAL-A has a narrow and hydrophobic acyl binding pocket extending into its lid domain, while the active site itself is covered by a flap that moves away during interfacial activation to expose the binding pocket
We introduce a novel biocatalytic approach to separate the enantiomers of a highly strained and bulky molecular species, DIBO, the enantiomers of which have been difficult to isolate or synthesize with asymmetric catalysts
Summary
Positron emission tomography (PET) imaging provides a method for observing metabolic processes and biological macromolecules in living organisms and, an opportunity to diagnose various human diseases. 11,12-Didehydro-5,6-dihydrodibenzo[a,e]cyclooctyn-5-ol (DIBO, Scheme 1), most commonly called. We investigated the ability of lipases and especially CAL-A to separate the enantiomers of DIBO using detailed enzyme-substrate interaction analysis through in silico docking. Racemic DIBO has previously been used as a component of an antibody-based imaging agent that targets a biomarker of pancreatic cancer, CA19.9 [4]. Selection of enzyme andefficacy solvent: 18 hydrolases, mostly lipases in the typically improve safety and [5].Altogether, DIBO, poses a challenge for any(listed asymmetric. Among the few known enzymes acting on this type of substrates, lipase A from ( CAL-A), reaction high enantiomeric ratio (E) of. 49% conversion in Candida antarcticaprovided (CAL-A) the is known to with accept bulky secondary alcohols [6,7]. Candida antarctica antarctica (CAL-A)-catalyzed kinetic resolution of 4-dibenzocyclooctynol
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