Pharmaceutical Biocatalysis: Chemoenzymatic Synthesis of Active Pharmaceutical Ingredients

 

Description:

This volume provides an insight into the future strategies for commercial biocatalysis with a focus on sustainable technologies, together with chemoenzymatic and biotechnological approaches to synthesize various types of approved and new active pharmaceutical ingredients (APIs) via proven and latest synthetic routes using single-step biocatalytic or enzyme cascade reactions. Many of these drugs act as enzyme inhibitors, as discussed in a chapter with a variety of examples. The targeted enzymes are involved in diseases such as different cancers, metastatic and infectious diseases, osteoporosis, and cardiovascular disorders. The biocatalysts employed for API synthesis include hydrolytic enzymes, alcohol dehydrogenases, laccases, imine reductases, reductive aminases, peroxygenases, cytochrome P450 enzymes, polyketide synthases, transaminases, and halogenases. Many of them have been improved with respect to their properties by engineering methods. The book discusses the syntheses of drugs, including alkaloids and antibiotics, non-ribosomal peptides, antimalarial and antidiabetic drugs, prenylated xanthones, antioxidants, and many important (chiral) intermediates required for the synthesis of pharmaceuticals.

 

Table of Contents:

 

1. Future Strategies for Commercial Biocatalysis

1.1 Introduction

1.2 Cascades

1.2.1 Cell-Free Enzyme Cascades

1.2.2 Chemoenzymatic Cascades

1.3 Micro- and Nanoscale Process Design Considerations

1.3.1 Nanoscale Compartmentalisation

1.3.2 Microfluidic Reactors

1.4 Conclusion

2. Synthetic Approaches to Inhibitors of Isoprenoid Biosynthesis

2.1 Introduction

2.2 Bisphosphonates

2.2.1 Direct Method: Reaction of Carboxylic Derivatives with Phosphorous Reagents

2.2.2 Indirect Method: Reaction of Acylphosphonates with Dialkyl Phosphites

2.2.3 Michael Addition to Tetraethyl Vinylidenebisphosphonate

2.2.4 Alkylation of Tetralkylbisphosphonate

2.2.5 Other Methods

2.3 Non-Bisphosphonate Derivative

2.4 Concluding Remarks

3. Using a Recombinant Metagenomic Lipase for Enantiomeric Separation of Pharmaceutically Important Drug Intermediates

3.1 Introduction

3.2 The Metagenomic Approach

3.3 Lipases as Biocatalysts

3.4 Use of Lipases in Drug Synthesis

3.5 Results

3.5.1 Metagenomic DNA Isolation and Purification

3.5.2 Cloning of Lipase (LipR1) Gene from Soil Sample

3.5.3 Expression and Purification of the LipR1 Protein

3.5.4 Effect of Temperature

3.5.5 Effect of pH

3.5.6 Thermostability Studies

3.5.7 Effect of Different Additives on Lipase Activity

3.5.8 Substrate Specificity

3.5.9 Kinetic Study of the Purified Lipase

3.5.10 Application of This Lipase for Transesterification Reactions

3.6 Use of Ionic Liquids

3.6.1 Reaction with 1-INDANOL

3.6.2 Reaction with (RS)-3-Benzyloxy-1,2-propanediol

3.6.3 Reaction with (RS)-α-Methyl-4 Pyridine Methanol

3.6.4 Reaction with (RS)-α-(Trifluoromethyl) Benzyl Alcohol

3.6.5 Reaction with 1-(1-Naphthyl) Ethanol

3.7 Summary

4. Biotechnological Production of Prenylated Xanthones for Pharmaceutical Use

4.1 Introduction

4.2 Biosynthesis of the Core Structure

4.3 Enzymatic Prenylation of Xanthone Scaffolds in Nature

4.4 Limitations of Chemical Synthesis

4.5 Biotechnological Approaches for in vitro Production of Xanthones

4.5.1 In vitro Cultures

4.5.2 Cascade Biocatalysis: Learning from Nature

4.6 Pharmacological Potential: Effect of Pharmacophores on Cytotoxic Activity of Xanthones

4.6.1 Bioactivities of Chiral Derivatives of Xanthones

4.7 Conclusions

5. Chemoenzymatic Approaches towards (S)-Duloxetine

5.1 Introduction

5.2 Chemoenzymatic Approaches towards (S)-Duloxetine

5.3 Stereoselective Resolution Mediated Synthetic Approaches towards (S)-Duloxetine

5.3.1 Synthesis of (S)-Duloxetine via Immobilized/Mobilized Lipases

5.3.2 Modified Synthesis of (S)-Duloxetine through Dynamic Kinetic Resolution (DKR)

5.4 Stereoselective Reduction Mediated Synthetic Approaches towards (S)-Duloxetine

5.4.1 Synthesis of (S)-Duloxetine via Candida viswanathii

5.4.2 Synthesis of (S)-Duloxetine through Candida pseudotropicalis

5.4.3 Application of Rhodotorula glutinis to Synthesize (S)-Duloxetine

5.4.4 Saccharomyces cerevisiae-Based Synthetic Approach for (S)-Duloxetine

5.4.5 (S)-Duloxetine Synthesis via Candida tropicalis

5.4.6 Synthesis of (S)-Duloxetine by Recombinant Aromatoleum aromaticum

5.4.7 Construction of (S)-Duloxetine Entity via Recombinant Exiguobacterium sp. F42

5.4.8 Synthesis of (S)-Duloxetine through Recombinant Chryseobacterium sp. CA49

5.4.9 (S)-Duloxetine Synthesis via Recombinant Rhodosporidium toruloides

5.4.10 Application of Recombinant Candida albicans to Synthesize (S)-Duloxetine

5.5 Enantioselective Hydrocyanation Mediated Approaches towards (S)-Duloxetine

5.5.1 Synthesis of (S)-Duloxetine via Prunus armeniaca

5.6 Conclusion

6. Synthesis of Antioxidants via Biocatalysis

6.1 Introduction

6.2 What Are Antioxidants?

6.3 Mechanism of Action

6.4 Free-Radical Sources and Implications

6.5 Antioxidants from Biocatalysis

6.5.1 Pure Enzyme Technology

6.5.2 Whole-Cell Biotransformation

6.6 Conclusion

7. Biocatalysts: The Different Classes and Applications for Synthesis of APIs

7.1 Introduction

7.2 Classification of Biocatalysts

7.3 Biocatalysts: Some General Properties

7.4 Enzymes: Mechanisms and Applications

7.4.1 Biocatalysts for Redox Reactions: Mechanisms

7.4.1.1 Applications

7.4.2 Transaminases: Mechanism and Applications

7.4.3 Hydrolases: Mechanism and Applications

7.4.4 Lyases: Aldolases—Mechanism

7.4.4.1 Application in drug design

7.4.5 Hydroxinitrile Lyases

7.5 Conclusion

8. Laccase-Mediated Synthesis of Novel Antibiotics and Amino Acid Derivatives

8.1 Introduction

8.2 Laccases as Mediator for Organic Synthesis

8.3 Enzymatic Transformation of Antibiotics

8.3.1 Phenolic Oxidative Homodimerization

8.3.2 Phenolic Oxidative Heterodimerization

8.3.3 Oxidation Followed by Nuclear Amination

8.3.3.1 para-Dihydroxy aromatic acids and their derivatives aminated by amino-β-lactams

8.3.3.2 ortho-Dihydroxy aromatic acids and their derivatives aminated by amino-β-lactams

8.3.3.3 meta-Dihydroxy aromatics and their reactivity

8.3.3.4 Catechols aminated by amino-β-lactams

8.3.3.5 Alkyl-para-hydroquinones aminated by amino-β-lactams

8.3.3.6 Dihydroxylated aromatics aminated by corollosporines

8.3.3.7 Dihydroxylated aromatics aminated by morpholines

8.3.3.8 Synthesis of mitomycin-like derivatives

8.3.4 Oxidation Followed by Nuclear Thiolation

8.3.4.1 Catechols thiolated by heterocyclic thiols

8.3.4.2 1,4-Naphthohydroquinones thiolated by aryl thiols

8.4 Derivatization of Amino Acids

8.5 Conclusions

9. Hydrolytic Enzymes for the Synthesis of Pharmaceuticals

9.1 Introduction

9.2 Enzymatic Hydrolytic Reactions for the Synthesis of Pharmaceuticals

9.2.1 Hydrolysis of Esters and Amino Esters

9.2.2 Hydrolysis of Amides

9.2.3 Hydrolysis of Epoxides and Nitriles

9.3 Design of Synthetic Transformations over Hydrolysis Processes for the Production of Pharmaceuticals

9.3.1 Esterification of Carboxylic Acids and Acylation of Alcohols and Diols

9.3.2 Acylation Reactions of Amines

9.3.3 Alkoxycarbonylation Reactions

9.4 Conclusions

10. Ene-Reductases in Pharmaceutical Chemistry

10.1 Introduction

10.2 Ene-Reductases: Classification, Substrate Scope, and Reaction Mechanism

10.3 Biocatalytic Applications

10.3.1 Enzyme Engineering

10.3.2 Hydride Sources

10.3.3 Multienzyme Reactions

10.4 Industrial Use of Ene-Reductases

10.4.1 Ene-Reductase Use in the Synthesis of Drugs

10.4.1.1 Profens (2-arylpropanoic acids)

10.4.1.2 Baclofen (β-(4-chlorophenyl)-γ-aminobutyric acid)

10.4.1.3 Pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid)

10.4.1.4 Phosphonates

10.4.1.5 Latanoprost

10.4.2 Ene-Reductase Use in the Synthesis of Building Blocks

10.5 Conclusion

11. Biocatalyzed Synthesis of Antidiabetic Drugs

11.1 Introduction

11.2 Insulin and Insulin Analogues

11.3 Amylin Analogues

11.4 Sensitizers

11.4.1 PPAR-α Agonists

11.4.2 Thiazolidinediones (TZDS, Glitazones)

11.4.3 Glitazars

11.5 Insulin Secretagogues

11.6 G Protein-Coupled Receptors Agonists

11.6.1 Incretin Mimetics

11.6.2 GPR119 Agonists

11.7 Enzyme Inhibitors

11.7.1 Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

11.7.1.1 Sitagliptin

11.7.1.2 Saxagliptin

11.7.1.3 Alogliptin, linagliptin, and trelagliptin

11.7.1.4 Teneligliptin and gosogliptin

11.7.1.5 Other DPP4 inhibitors

11.7.2 11β-Hydroxysteroid Dehydrogenase type 1 (11β-HSD1) Inhibitors

11.7.3 α-Glucosidase Inhibitors

11.7.3.1 Iminosugars

11.7.3.2 Carbasugars

11.8 Glycosurics

11.9 Conclusions

12. Glucose-Sensitive Drug Delivery Systems Based on Phenylboronic Acid for Diabetes Treatment

12.1 Introduction

12.2 PBA-Mediated LbL Assembles

12.3 PBA-Regulated Micelles and Vesicles

12.4 PBA-Functionalized Gels

12.5 Conclusion

13. Synthesis of Important Chiral Building Blocks for Pharmaceuticals Using Lactobacillus and Rhodococcus Alcohol Dehydrogenases

13.1 Introduction

13.2 Requirements for Lactobacillus and Rhodococcus ADHs as Versatile Enzymes for the Synthesis of Enantiopure Alcohols

13.3 Alcohols as Chiral Building Blocks Synthesized by Lactobacillus and Rhodococcus ADHs

13.4 Synthesis of Enantiomerically Pure Alcohols with Lactobacillus and Rhodococcus ADHs in Preparative Scale with 1-Phenylethanol as Example

13.5 ADHs from Lactobacillus and Rhodococcus Species in Biocatalytic Cascades

13.6 Searching for New ADHs or Engineering of Well-Known ADHs for Novel Drug Candidates

13.7 Summary

14. Asymmetric Reduction of C=N Bonds by Imine Reductases and Reductive Aminases

14.1 Introduction

14.1.1 Why Are IREDs Important Tools for Biocatalysis

14.1.2 Most Acyclic Imines Have a Low Stability in Aqueous Solutions—Reductive Aminases (RedAm) Solve This Problem

14.1.3 Focus of This Book Chapter

14.2 Imine Reductions Observed in Nature

14.2.1 Imine Reductions of Substrates Bearing a Carboxylate Function

14.2.2 Imine Reductions of Substrates Lacking a Carboxylate Function

14.2.2.1 Alkaloid biosynthesis: IREDs installing an α-chiral amine moiety

14.2.2.2 Alkaloid biosynthesis: IREDs installing a β-chiral amine moiety

14.2.3 Reductive Aminations Observed in Nature

14.3 Imine Reductases Explored for Biocatalytical Imine Reduction

14.3.1 IREDs Belonging to the Hydroxyisobutyrate Dehydrogenases Subfamily

14.3.2 Imine Reduction with Enzymes Belonging to Other Families or Created by Protein Engineering

14.3.3 Scope of Biocatalytic Imine Reduction

14.3.4 Scope of Biocatalytic Reductive Amination: IREDs Require a Large Excess of the Amine Nucleophiles

14.3.5 Reductive Aminases Allow Usage of Near-Stoichiometric Amounts of Amine Nucleophiles for Selected Substrate Combinations

14.3.6 Towards the Synthesis of β-Chiral Amines by Dynamic Kinetic Resolution (DKR) of Aldehydes

14.4 IREDs and RedAms Employed in Cascade Reactions

14.5 Mechanistic Basis of IREDs and RedAms

14.5.1 Structural Features of IREDs Important for Imine Reduction

14.5.2 Mechanistic Differences between Imine Reduction and Reductive Amination

14.6 Conclusive Remarks

15. Cipargamin: Biocatalysis in the Discovery and Development of an Antimalarial Drug

15.1 Introduction

15.1.1 Biocatalysis at Novartis

15.1.2 Malaria and Drug Development

15.2 Biocatalysis in Synthesis of a Drug Candidate

15.3 Biocatalysis in the Synthesis of Metabolites of Cipargamin (KAE609)

15.3.1 Biocatalytic Synthesis of M23

15.4 Biocatalysis in the Synthesis of Cipargamin during Drug Development

15.4.1 Design of a New Route

15.4.2 Biocatalysis Using Kinetic Resolutions

15.4.3 Biocatalysis as a Tool for Asymmetric Synthesis of Chiral Amines

15.4.3.1 Ketone synthesis

15.4.3.2 Transaminase approach

15.4.3.3 Route comparison

15.5 Conclusion

16. Halogenases with Potential Applications for the Synthesis of Halogenated Pharmaceuticals

16.1 Introduction

16.2 Halogenation Mechanisms

16.2.1 Electrophilic Mechanism: Haloperoxidases

16.1.1.1 Heme-iron halogenases

16.1.1.2 Vanadium-dependent alogenases

16.1.1.3 Flavin-dependent halogenases

16.2.2 Radical Mechanism

16.2.3 Nucleophilic Mechanism

16.3 Biosynthesis of Halogenated Pharmaceuticals

16.3.1 Halogenated Pharmaceutical with Antitumor Activity

16.3.2 Halogenated Pharmaceutical with Antibiotic Activity

16.3.3 Halogenated Pharmaceutical with Antifungal Activity

16.4 Perspective

17. Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450

17.1 Introduction

17.2 Cytochromes P450: General Features

17.2.1 Nomenclature and Classification

17.2.2 Catalytic Cycle of Cytochromes P450

17.3 Cytochromes P450 as Biocatalysts

17.3.1 Importance of Cytochromes P450 in Biocatalysis

17.3.2 Natural Products as a Source of Cytochromes P450 Substrates

17.4 Pharmaceutical Biocatalysis by Cytochromes P450

17.4.1 Synthesis of Statins

17.4.2 Synthesis of Active Steroids

17.4.3 Synthesis of Anticancer Drugs

17.4.4 Synthesis of Antibiotics, Antifungal, and Antiprotozoal Agents

17.4.5 Synthesis of New Natural Product–Inspired Drugs

17.4.5.1 Hydroxy fatty acids

17.4.5.2 Phytopharmaceuticals

17.5 Conclusions and Future Perspectives

18. Oxyfunctionalization of Pharmaceuticals by Fungal Peroxygenases

18.1 Introduction

18.2 Unspecific Peroxygenases

18.2.1 Properties and Occurrence of Unspecific Peroxygenases

18.2.2 Catalyzed Reactions and Reaction Mechanism

18.3 Oxyfunctionalization of Pharmaceuticals

18.3.1 Oxidation of Aliphatics

18.3.2 Oxidation of Aromatics and Olefins

18.3.3 Oxidations Resulting in Cleavage Reactions

18.4 Conclusion and Outlook

19. Biocatalytic Synthesis of Chiral 1,2,3,4-Tetrahydroquinolines

19.1 Introduction

19.2 Enantiomeric Synthesis of 1,2,3,4-Tetrahydroquinoline-4-ols

19.3 Enantiomeric Synthesis of 1,2,3,4-Tetrahydroquinolines

19.4 Conclusion

20. New Strategies to Discover Non-Ribosomal Peptides as a Source of Antibiotics Molecules

20.1 Introduction

20.2 Molecular Mechanism of Antibiotic Resistance

20.3 Nonribosomal Peptides as a Source of New Antibiotics

20.4 Genome Mining Strategies to Find NRPs

20.5 Conclusion

21. Enzyme Kinetics and Drugs as Enzyme Inhibitors

21.1 Introduction

21.2 Enzyme Kinetics

21.2.1 Michaelis–Menten Equation and the Determination of KM and Vmax

21.2.2 Inhibition of Enzymes

21.2.2.1 Competitive inhibition

21.2.2.2 Non-competitive inhibition

21.2.2.3 Uncompetitive inhibition

21.2.2.4 Allosteric modulation

21.2.2.5 Covalent (reversible)inhibition: Pros and cons

21.2.2.6 Ki-/IC50-values and the residence-time model

21.2.3 Enzyme Inhibitors and Activators as Drugs

21.2.3.1 New treatment options for cardiac insufficiency

21.2.3.2 The aldose reductase inhibitor fidarestat enforces chemotherapy

21.2.3.3 Lipid-lowering agents

21.2.3.4 Strategies to combat cancer

21.3 Concluding Remarks

Index

 

An aparitie	8 Jan. 2020
Autor	Peter Grunwald
Dimensiuni	15.49 x 4.06 x 23.11 cm
Editura	CRC Press
Format	Hardcover
ISBN	9789814800808
Limba	Engleza
Nr pag	862