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Review
. 2018 Oct 8;57(41):13406-13423.
doi: 10.1002/anie.201800678. Epub 2018 Sep 11.

Human Enzymes for Organic Synthesis

Margit Winkler  1   2 , Martina Geier  2 , Steven P Hanlon  3 , Bernd Nidetzky  2   4 , Anton Glieder  1
Affiliations
Review

Human Enzymes for Organic Synthesis

Margit Winkler et al. Angew Chem Int Ed Engl. .

Abstract

Human enzymes have been widely studied in various disciplines. The number of reactions taking place in the human body is vast, and so is the number of potential catalysts for synthesis. Herein, we focus on the application of human enzymes that catalyze chemical reactions in course of the metabolism of drugs and xenobiotics. Some of these reactions have been explored on the preparative scale. The major field of application of human enzymes is currently drug development, where they are applied for the synthesis of drug metabolites.

Keywords: biocatalysis; biotransformation; drug metabolites; human enzymes; pharmaceutical compounds.

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Figures

Scheme 1
Scheme 1
CYP2C9‐catalyzed hydroxylation of diclofenac (1).
Scheme 2
Scheme 2
AOX‐catalyzed oxidation of phenanthridine (3).
Scheme 3
Scheme 3
AOX‐catalyzed oxidation of Famciclovir (5).
Scheme 4
Scheme 4
Biooxidation of testosterone (7) and diazepam (10) catalyzed by human CYP3A4.
Scheme 5
Scheme 5
Metabolites of a mGlu5 receptor antagonist (14) generated by human CYP isoforms.
Scheme 6
Scheme 6
Biooxidation of the 4′‐methyl substituted pyrrolidinophenones 15 and 17 by human CYP2D6.
Scheme 7
Scheme 7
Ibuprofen 19 is metabolized by human CYP2C9 to 3‐hydroxyibuprofen (20) and 2‐hydroxyibuprofen (21).
Scheme 8
Scheme 8
Biooxidation of sagopilone (22) to its main metabolite by CYP2C19.
Scheme 9
Scheme 9
Selective 11β‐hydroxylation of 24 to cortisol (25) catalyzed by human CYP11B1.
Scheme 10
Scheme 10
Steroid hydroxylations catalyzed by human CYP21.
Scheme 11
Scheme 11
Hydroxylation at the C7‐position of 29 to epipodophyllotoxin (30) catalyzed by human CYP3A4.
Scheme 12
Scheme 12
Biotransformation of (−)‐camphor (31) by human CYP2A6.
Scheme 13
Scheme 13
CYP‐mediated de‐ethylations of active pharmaceutical ingredients.
Scheme 14
Scheme 14
N‐Dealkylations catalyzed by CYP3A4.
Scheme 15
Scheme 15
N‐Deethylation of amodiaquine (41) catalyzed by CYP2C8.
Scheme 16
Scheme 16
N‐Oxidation of 43 catalyzed by FMO3.
Scheme 17
Scheme 17
Chemo‐ and regioselective N1‐Oxidation of 45 catalyzed by FMO2*1.
Scheme 18
Scheme 18
UGDH‐catalyzed oxidation of primary sugar alcohol.
Scheme 19
Scheme 19
FMO5‐catalyzed oxygenation of aliphatic and cyclic carbonyl compounds.
Scheme 20
Scheme 20
Metabolic reactions on 50. CYP3A4 mediates epoxidation followed by intramolecular cyclization to 51. Reductive conversion of the hydroxamic acid to the respective amide is catalyzed by both CYP3A4 and CYP2D6.
Scheme 21
Scheme 21
AKR1C1‐catalyzed reduction of progesterone (53).
Scheme 22
Scheme 22
AKR1C1‐catalyzed reduction of dydrogesterone (55).
Scheme 23
Scheme 23
17β‐Hydroxysteroid dehydrogenase mediated reduction of 57 to testosterone (7).
Scheme 24
Scheme 24
AKR1B1‐catalyzed reduction of 3,4‐hexanedione (58).
Scheme 25
Scheme 25
AKR1B1‐catalyzed reduction of acetoin (61).
Scheme 26
Scheme 26
HLADH‐catalyzed disproportionation of rac‐2‐phenylpropanal (65).
Scheme 27
Scheme 27
Human sEH‐catalyzed kinetic resolution of racemic epoxide 68.
Scheme 28
Scheme 28
General scheme of glucuronidation reactions catalyzed by human UGTs.
Scheme 29
Scheme 29
COMT‐catalyzed O‐methylation of 3,4‐dihydroxybenzaldehyde (70).
Scheme 30
Scheme 30
Methylation reaction catalyzed by N‐methyltransferase enzymes.
Scheme 31
Scheme 31
NAT2‐catalyzed N‐acetylation of sulfamethazine (74).
Scheme 32
Scheme 32
GST‐catalyzed thiolysis of azathioprine (76).
Scheme 33
Scheme 33
SULT1A1‐catalyzed sulfatation of minoxidil (79).
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