One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases.

@article{Kiebist2015OnepotSO,
  title={One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases.},
  author={Jan Kiebist and Wolfgang Dr. Holla and Johannes Heidrich and Marzena Poraj-Kobielska and Martin Sandvoss and Reiner Simonis and Glenn Gr{\"o}be and Jens Atzrodt and Martin Hofrichter and Katrin Scheibner},
  journal={Bioorganic \& medicinal chemistry},
  year={2015},
  volume={23 15},
  pages={
          4324-32
        }
}
Unspecific peroxygenases (UPOs, EC 1.11.2.1) have proved to be stable oxygen-transferring biocatalysts for H2O2-dependent transformation of pharmaceuticals. We have applied UPOs in a drug development program and consider the enzymatic approach in parallel to a conventional chemical synthesis of the human metabolites of the bile acid reabsorption inhibitor SAR548304. Chemical preparation of N,N-di-desmethyl metabolite was realized by a seven-step synthesis starting from a late precursor of… 
21 Citations
Synthesis of cyclophosphamide metabolites by a peroxygenase from Marasmius rotula for toxicological studies on human cancer cells
TLDR
The high yield of 4-OH-CPAUPO and its biological activity demonstrate that UPOs can be efficiently used to produce CYP-specific drug metabolites for pharmacological assessment.
Selective synthesis of the human drug metabolite 5’-hydroxypropranolol by an evolved self-sufficient peroxygenase
Propranolol is a widely used beta-blocker that is metabolized by human liver P450 monooxygenases into equipotent hydroxylated human drug metabolites (HDMs). It is paramount for the pharmaceutical
Benchmarking of laboratory evolved unspecific peroxygenases for the synthesis of human drug metabolites
By mimicking the role of human liver P450 monooxygenases, fungal unspecific peroxygenases (UPOs) can perform a range of highly selective oxyfunctionalization reactions on pharmacological compounds,
A Peroxygenase from Chaetomium globosum Catalyzes the Selective Oxygenation of Testosterone
TLDR
A cell‐free approach to incorporate epoxy and hydroxyl functionalities directly into the bulky molecule testosterone by a novel unspecific peroxygenase (UPO) that is produced by the ascomycetous fungus Chaetomium globosum in a complex medium rich in carbon and nitrogen is investigated.
Biocatalytic Syntheses of Antiplatelet Metabolites of the Thienopyridines Clopidogrel and Prasugrel Using Fungal Peroxygenases
TLDR
UPOs can be effectively used for the selective synthesis of metabolites and late-state diversification of organic molecules, circumventing complex multistage chemical syntheses and providing sufficient material for structural elucidation, reference material, or cellular assays.
Fatty acid epoxidation byCollariella virescensperoxygenase and heme-channel variants
Enzyme-driven oxygenation reactions are in the spotlight for organic synthesis. In this regard, a heme-thiolate unspecific peroxygenase (UPO) from the fungus Chaetomium globosum has recently proven
Identification and Expression of New Unspecific Peroxygenases – Recent Advances, Challenges and Opportunities
TLDR
An overview of the state of the art in identification, expression, and screening approaches of fungal UPOs, challenges associated with current protein production and screening strategies, as well as potential solutions and opportunities are provided.
Fungal Peroxygenases: A Phylogenetically Old Superfamily of Heme Enzymes with Promiscuity for Oxygen Transfer Reactions
Fungal unspecific peroxygenases (UPOs, EC 1.11.2.1) form a superfamily of heme proteins and possess promiscuity for oxygen transfer reactions. The first UPO was discovered in the agaric fungus
Accessing Drug Metabolites via Transition-Metal Catalyzed C-H Oxidation: The Liver as Synthetic Inspiration.
TLDR
This Review highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end.
Synthesis of Indigo-Dyes from Indole Derivatives by Unspecific Peroxygenases and Their Application for In-Situ Dyeing
Tyrian purple (also known as royal or imperial purple) is the oldest known commercial pigment and still one of the most expensive dyes, often associated with the wardrobes of clergy and royalty. It
...
1
2
3
...

References

SHOWING 1-10 OF 55 REFERENCES
Preparation of human drug metabolites using fungal peroxygenases.
TLDR
The results indicate that fungal peroxygenases may be useful biocatalytic tools to prepare pharmacologically relevant drug metabolites.
Preparation of labeled human drug metabolites and drug-drug interaction-probes with fungal peroxygenases.
TLDR
This work shows that UPOs can be used in combination with hydrogen/deuterium exchange for an efficient one-step process for the preparation of 4'-OH-diclofenac-d6" and shows that the deuterium-labeling does not affect the kinetic parameters.
Oxidative Cleavage of Diverse Ethers by an Extracellular Fungal Peroxygenase*
TLDR
A hydrogen abstraction and oxygen rebound mechanism that oxidizes ethers to hemiacetals, which subsequently hydrolyze may have a role in the biodegradation of natural and anthropogenic low molecular weight ethers in soils and plant litter.
Enzymatic one-pot conversion of cyclohexane into cyclohexanone: Comparison of four fungal peroxygenases
Abstract Unspecific peroxygenases (UPO; EC 1.11.2.1) represent a group of secreted heme-thiolate proteins that are capable of catalyzing the mono-oxygenation of diverse organic compounds, using only
Selective hydroxylation of alkanes by an extracellular fungal peroxygenase
TLDR
Results point to a hydrogen abstraction and oxygen rebound mechanism for alkane hydroxylation and may have a role in the bioconversion of natural and anthropogenic alkane‐containing structures in soils, plant litter, and wood.
Synthesis of potential drug metabolites by a modified Udenfriend reaction
Abstract Several drugs (clozapine, chlorpromazine, imipramine, buspirone, diltiazem, and propranolol) were subjected to modified Udenfriend conditions (Fe 2+ /Mn 2+ /EDTA/ascorbic acid/O 2 ). From
The use of biocatalysis in the synthesis of labelled compounds
Since most biotransformations are highly chemo-, regio- and stereoselective, they offer many opportunities for the synthesis of compounds that are not easily attainable by classical organic
High-yield production of aromatic peroxygenase by the agaric fungus Marasmius rotula
TLDR
M. rotula APO was found to be highly stable in a pH range from 5 to 10 as well as in the presence of organic solvents such as methanol, acetonitrile and N,N-dimethylformamide and the peroxygenase showed neither brominating nor chlorinating activities.
Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity.
  • F. Guengerich
  • Chemistry, Medicine
    Chemical research in toxicology
  • 2001
TLDR
P450s also catalyze less generally discussed reactions including reduction, desaturation, ester cleavage, ring expansion, ring formation, aldehyde scission, dehydration, ipso attack, coupling reactions, rearrangement of fatty acid and prostaglandin hydroperoxides, and phospholipase activity.
Mechanisms of cytochrome P450 substrate oxidation: MiniReview
  • F. Guengerich
  • Chemistry, Medicine
    Journal of biochemical and molecular toxicology
  • 2007
TLDR
A general chemical mechanism can be used to rationalize most of the oxidations and involves a perfenyl intermediate and odd‐electron chemistry, i.e. abstraction of a hydrogen atom or electron followed by oxygen rebound and sometimes rearrangement.
...
1
2
3
4
5
...