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Using a Recombinant Metagenomic Lipase for Enantiomeric Separation of Pharmaceutically Important Drug Intermediates
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Rakesh Kumar, Uttam Chand Banerjee, Jagdeep Kaur
The mathematical equations for the evaluation of enantioselectivity based on the conversion (C) and enantiomeric excess of the product (eeP) and the substrate (eeS) are
New Biological Targets for the Treatment of Leishmaniasis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Fabrizio Carta, Andrea Angeli, Christian D.-T. Nielsen, Claudiu T. Supuran, Agostino Cilibrizzi
A further extension of stereocontrol is enantioselectivity. Enantioselectivity and the resultant 3D orientation in space are key in biological structures (see section 7) and are often at the forefront of any synthetic approach. Morken and co-workers have recently utilized a well-known boron reactivity (1,2 migration of boronates) coupled with a metal induced 1,2-metallate rearrangement to yield a conjunctive coupling partner via the union of two nucleophilic reagents (Figure 17) (Zhang et al. 2016). Morken’s enantioselective conjunctive cross coupling. THF = tetrahydrofuran; Tf = triflate; L = ligand.
Structure and function of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Masuda et al. (2005, 2006) have also investigated the role of Phe120 using a site-directed mutagenesis approach in a yeast expression system and bufuralol and bunitrolol enantiomers as chiral probe substrates. The wild-type enzyme showed enantioselectivity of R- ≫ S-bufuralol and the Phe120Ala mutant exhibited substrate enantioselectivity of R- ≤ S-enantiomer, whereas the product diastereoselectivity of (R-1″-OH-≪ S-1”-OH-bufuralol) is similar between the wild-type enzyme and the mutant. Kinetic analysis revealed that apparent Km values for the formation of the four kinds of 1’-OH-bufuralol are similar between the mutant and the wild type, but Vmax values for S-bufuralol 1′-hydroxylation by the mutant are ~7-fold higher than those by the wild type (Masuda et al. 2005). However, the Km and Vmax values for R-bufuralol 1’-hydroxylation are similar between the Phe120Ala mutant and wild-type enzyme. When bunitrolol enantiomers are used as substrates, the substitution of Phe120 by Ala in CYP2D6 did not change the substrate enantioselectivity but resulted in a remarkable increase in bunitrolol 4-hydroxylase activity and Km values as compared with the wild-type enzyme (Masuda et al. 2006). A homology modeling study indicated that the hydrophobic interaction of an aromatic moiety of the substrate with Phe120 played an important role in substrate binding.
Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
I. Caroline Vaaland, Óscar López, Adrián Puerta, Miguel X. Fernandes, José M. Padrón, José G. Fernández-Bolaños, Magne O. Sydnes, Emil Lindbäck
No obvious enantioselectivity of eeAChE and eqBuChE was observed for the three pairs of enantiomeric inhibitors included in this study. In addition, no preferential inhibitory activity trend was found for the enantiomers incorporating a DAB or LAB moiety. For instance, 9a is a ca. 4-fold more potent eeAChE inhibitor than its enantiomer 9b, whereas 10b is a ca. 4-fold more potent eeAChE inhibitor than its enantiomer 10a. For the enantiomeric pair 11a and 11b, we observed essentially equal eeAChE inhibitory activities. These observations indicate that the impact on the eeAChE inhibitory potency of our heterodimers by switching between a DAB and LAB moiety is small compared to the contribution from the tacrine ring.
Synthesis and carbonic anhydrase activating properties of a series of 2-amino-imidazolines structurally related to clonidine1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Niccolò Chiaramonte, Soumia Maach, Caterina Biliotti, Andrea Angeli, Gianluca Bartolucci, Laura Braconi, Silvia Dei, Elisabetta Teodori, Claudiu T. Supuran, Maria Novella Romanelli
The most potent compound was 10 (KA 0.9 µM), a benzyl derivative carrying a methyl group on both N1 and Nα atoms; this compound was 47 times more active than CLO. The removal of the exocyclic Nα-Me group decreased 4 times the activity (11, KA 3.7 µM), while the removal of the N1-methyl group was more detrimental: as a matter of fact, compounds 6 (KA 40.5 µM) and 2 (KA 45.5 µM) were about 40 times less potent than 10 (KA 0.9 µM). On the contrary, the degree of methylation did not substantially affect the potency of the phenylethyl and phenyl propyl derivatives, since compounds 3, 5, 7, 8 and 12 had KA values in the range 9.9–17.2 µM. Similarly, aromatic substitution on the benzyl moiety slightly decreased the potency without substantial modulation, the KA values of compounds 13–18 being 2–4 times higher than 11. Side-chain branching (compounds S-4 and R-4) improved the activity on this isoform, and a small enantioselectivity was observed: the R-enantiomer was twice more potent as the S-isomer. A benzyl moiety on the terminal amino group of 21 (KA 31.2 µM) increased the activity, as analogue 19 and its N1-methyl derivative 20 were about 3 times more potent than the parent compound.
Design, synthesis and characterization of enzyme-analogue-built polymer catalysts as artificial hydrolases
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Divya Mathew, Benny Thomas, Karakkattu Subrahmanian Devaky
In 1995, Ohkubo et al. reported the catalytic activities of a water-soluble polymer and a water-insoluble one, both of which were imprinted using phenyl 1-benzyloxycarbonylamino-3-methylpentyl phosphonate towards p-nitrophenyl N-(benzyloxycarbony1)-L-leucinate [55]. Both catalysts possessing L-histidyl group as a catalytic site were prepared by radical polymerization (Figure 18). The template and binding site in 1:1 molar ratio gave a high yield of hydrogen bonded complex. Catalytic activity and substrate selectivity for the hydrolysis of amino acid p-nitrophenyl ester were claimed. Enantioselectivity of the polymer catalyst was explained as due to the L-histidine residues in the polymer. Both the polymer catalysts exhibited higher catalytic activities than His monomer in the esterolysis of Z-L-Leu-PNP, but the order of relative catalytic activities was reported as, water soluble MIP ≫ water insoluble MIP > His monomer > blank.