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E-book: Pharmaceutical Biocatalysis: Chemoenzymatic Synthesis of Active Pharmaceutical Ingredients

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  • Pub. Date: 07-Nov-2019
  • Publisher: Pan Stanford Publishing Pte Ltd
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  • ISBN-13: 9781000707571
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Pharmaceutical Biocatalysis: Chemoenzymatic Synthesis of Active Pharmaceutical IngredientsLarger Image
  • Format: EPUB+DRM
  • Pub. Date: 07-Nov-2019
  • Publisher: Pan Stanford Publishing Pte Ltd
  • Language: eng
  • ISBN-13: 9781000707571
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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.

Preface xix
1 Future Strategies for Commercial Biocatalysis
1(30)
Robert E. Speight
Karen T. Robins
1.1 Introduction
1(3)
1.2 Cascades
4(15)
1.2.1 Cell-Free Enzyme Cascades
4(7)
1.2.2 Chemoenzymatic Cascades
11(8)
1.3 Micro- and Nanoscale Process Design Considerations
19(7)
1.3.1 Nanoscale Compartmentalisation
20(3)
1.3.2 Microfluidic Reactors
23(3)
1.4 Conclusion
26(5)
2 Synthetic Approaches to Inhibitors of Isoprenoid Biosynthesis
31(46)
Pedro Merino
Loredana Maiuolo
Ignacio Delso
Vincenzo Algieri
Antonio De Nino
Tomas Tejero
2.1 Introduction
31(5)
2.2 Bisphosphonates
36(20)
2.2.1 Direct Method: Reaction of Carboxylic Derivatives with Phosphorous Reagents
36(7)
2.2.2 Indirect Method: Reaction of Acylphosphonates with Dialkyl Phosphites
43(5)
2.2.3 Michael Addition to Tetraethyl Vinylidenebisphosphonate
48(4)
2.2.4 Alkylation of Tetralkylbisphosphonate
52(3)
2.2.5 Other Methods
55(1)
2.3 Non-Bisphosphonate Derivative
56(12)
2.4 Concluding Remarks
68(9)
3 Using a Recombinant Metagenomic Lipase for Enantiomeric Separation of Pharmaceutically Important Drug Intermediates
77(26)
Rakesh Kumar
Uttam Chand Banerjee
Jagdeep Kaur
3.1 Introduction
77(1)
3.2 The Metagenomic Approach
78(1)
3.3 Lipases as Biocatalysts
78(1)
3.4 Use of Lipases in Drug Synthesis
79(1)
3.5 Results
80(14)
3.5.1 Metagenomic DNA Isolation and Purification
80(1)
3.5.2 Cloning of Lipase (LipRl) Gene from Soil Sample
80(1)
3.5.3 Expression and Purification of the LipRl Protein
80(1)
3.5.4 Effect of Temperature
81(2)
3.5.5 Effect of pH
83(1)
3.5.6 Thermostability Studies
83(1)
3.5.7 Effect of Different Additives on Lipase Activity
83(3)
3.5.8 Substrate Specificity
86(1)
3.5.9 Kinetic Study of the Purified Lipase
87(1)
3.5.10 Application of This Lipase for Transesterification Reactions
87(7)
3.6 Use of Ionic Liquids
94(4)
3.6.1 Reaction with 1-INDANOL
95(1)
3.6.2 Reaction with (RS)-3-Benzyloxy-l, 2-propanediol
96(1)
3.6.3 Reaction with (RS)-a-Methyl-4 Pyridine Methanol
96(1)
3.6.4 Reaction with (RS)-a-(Trifluoromethyl) Benzyl Alcohol
97(1)
3.6.5 Reaction with l-(l-Naphthyl) Ethanol
98(1)
3.7 Summary
98(5)
4 Biotechnological Production of Prenylated Xanthones for Pharmaceutical Use
103(40)
Mariam Gaid
Poonam Singh
Islam El-Awaad
Mohamed Nagia
Ludger Beerhues
4.1 Introduction
103(4)
4.2 Biosynthesis of the Core Structure
107(3)
4.3 Enzymatic Prenylation of Xanthone Scaffolds in Nature
110(3)
4.4 Limitations of Chemical Synthesis
113(3)
4.5 Biotechnological Approaches for in vitro Production of Xanthones
116(9)
4.5.1 In vitro Cultures
116(5)
4.5.2 Cascade Biocatalysis: Learning from Nature
121(4)
4.6 Pharmacological Potential: Effect of Pharmacophores on Cytotoxic Activity of Xanthones
125(9)
4.6.1 Bioactivities of Chiral Derivatives of Xanthones
131(3)
4.7 Conclusions
134(9)
5 Chemoenzymatic Approaches towards (S)-Duloxetine
143(28)
Danish Shahzad
Muhammad Faisal
Aamer Saeed
5.1 Introduction
143(4)
5.2 Chemoenzymatic Approaches towards (Sj-Duloxetine
147(1)
5.3 Stereoselective Resolution Mediated Synthetic Approaches towards (S)-Duloxetine
148(8)
5.3.1 Synthesis of (Sj-Duloxetine via Immobilized/Mobilized Lipases
148(6)
5.3.2 Modified Synthesis of (S)-Duloxetine through Dynamic Kinetic Resolution (DKR)
154(2)
5.4 Stereoselective Reduction Mediated Synthetic Approaches towards (5]-Duloxetine
156(9)
5.4.1 Synthesis of (S)-Duloxetine via Candida viswanathii
156(1)
5.4.2 Synthesis of (S)-Duloxetine through Candida pseudotropicalis
157(1)
5.4.3 Application of Rhodotorula glutinis to Synthesize (S)-Duloxetine
158(1)
5.4.4 Saccharomyces cerevisiae-Based Synthetic Approach for (S)-Duloxetine
159(1)
5.4.5 (S)-Duloxetine Synthesis via Candida tropicalis
160(1)
5.4.6 Synthesis of (S)-Duloxetine by Recombinant Aromatoleum aromaticum
161(1)
5.4.7 Construction of (S)-Duloxetine Entity via Recombinant Exiguobacterium sp. F42
161(1)
5.4.8 Synthesis of (S)-Duloxetine through Recombinant Chryseobacterium sp. CA49
162(1)
5.4.9 (S)-Duloxetine Synthesis via Recombinant Rhodosporidium toruloides
163(1)
5.4.10 Application of Recombinant Candida albicans to Synthesize (S)-Duloxetine
164(1)
5.5 Enantioselective Hydrocyanation Mediated Approaches towards (S)-Duloxetine
165(1)
5.5.1 Synthesis of (S)-Duloxetine via Prunus armeniaca
165(1)
5.6 Conclusion
166(5)
6 Synthesis of Antioxidants via Biocatalysis
171(18)
Salman Zafar
6.1 Introduction
171(1)
6.2 What Are Antioxidants?
172(1)
6.3 Mechanism of Action
172(1)
6.4 Free-Radical Sources and Implications
173(3)
6.5 Antioxidants from Biocatalysis
176(8)
6.5.1 Pure Enzyme Technology
176(3)
6.5.2 Whole-Cell Biotransformation
179(5)
6.6 Conclusion
184(5)
7 Biocatalysts: The Different Classes and Applications for Synthesis of APIs
189(30)
Peter Grunwald
7.1 Introduction
189(1)
7.2 Classification of Biocatalysts
189(3)
7.3 Biocatalysts: Some General Properties
192(2)
7.4 Enzymes: Mechanisms and Applications
194(19)
7.4.1 Biocatalysts for Redox Reactions: Mechanisms
194(1)
7.4.1.1 Applications
195(6)
7.4.2 Transaminases: Mechanism and Applications
201(2)
7.4.3 Hydrolases: Mechanism and Applications
203(3)
7.4.4 Lyases: Aldolases--Mechanism
206(2)
7.4.4.1 Application in drug design
208(3)
7.4.5 Hydroxinitrile Lyases
211(2)
7.5 Conclusion
213(6)
8 Laccase-Mediated Synthesis of Novel Antibiotics and Amino Acid Derivatives
219(50)
Annett Mikolasch
8.1 Introduction
219(1)
8.2 Laccases as Mediator for Organic Synthesis
220(12)
8.3 Enzymatic Transformation of Antibiotics
232(26)
8.3.1 Phenolic Oxidative Homodimerization
232(2)
8.3.2 Phenolic Oxidative Heterodimerization
234(1)
8.3.3 Oxidation Followed by Nuclear Amination
235(1)
8.3.3.1 para-Dihydroxy aromatic acids and their derivatives aminated by amino-6-lactams
235(8)
8.3.3.2 ort/io-Dihydroxy aromatic acids and their derivatives aminated by amino-8-lactams
243(3)
8.3.3.3 meta-Dihydroxy aromatics and their reactivity
246(1)
8.3.3.4 Catechols aminated by amino-6-lactams
247(2)
8.3.3.5 Alkyl-para-hydroquinones aminated by amino-6-lactams
249(3)
8.3.3.6 Dihydroxylated aromatics aminated by corollosporines
252(2)
8.3.3.7 Dihydroxylated aromatics aminated by morpholines
254(1)
8.3.3.8 Synthesis of mitomycin-like derivatives
255(1)
8.3.4 Oxidation Followed by Nuclear Thiolation
256(1)
8.3.4.1 Catechols thiolated by heterocyclic thiols
256(1)
8.3.4.2 1, 4-Naphthohydroquinones thiolated by aryl thiols
256(2)
8.4 Derivatization of Amino Acids
258(5)
8.5 Conclusions
263(6)
9 Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
269(42)
Sergio Gonzdlez-Granda
Vicente Gotor-Ferndndez
9.1 Introduction
269(2)
9.2 Enzymatic Hydrolytic Reactions for the Synthesis of Pharmaceuticals
271(14)
9.2.1 Hydrolysis of Esters and Amino Esters
271(9)
9.2.2 Hydrolysis of Amides
280(3)
9.2.3 Hydrolysis of Epoxides and Nitriles
283(2)
9.3 Design of Synthetic Transformations over Hydrolysis Processes for the Production of Pharmaceuticals
285(20)
9.3.1 Esterification of Carboxylic Acids and Acylation of Alcohols and Diols
286(13)
9.3.2 Acylation Reactions of Amines
299(3)
9.3.3 Alkoxycarbonylation Reactions
302(3)
9.4 Conclusions
305(6)
10 Ene-Reductases in Pharmaceutical Chemistry
311(38)
Katrin Hecht
Rebecca Butter
10.1 Introduction
311(1)
10.2 Ene-Reductases: Classification, Substrate Scope, and Reaction Mechanism
312(5)
10.3 Biocatalytic Applications
317(8)
10.3.1 Enzyme Engineering
318(2)
10.3.2 Hydride Sources
320(3)
10.3.3 Multienzyme Reactions
323(2)
10.4 Industrial Use of Ene-Reductases
325(15)
10.4.1 Ene-Reductase Use in the Synthesis of Drugs
326(1)
10.4.1.1 Profens (2-arylpropanoic acids)
326(2)
10.4.1.2 Baclofen (B-(4-chlorophenyl)-Y-aminobutyric acid)
328(2)
10.4.1.3 Pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid)
330(1)
10.4.1.4 Phosphonates
331(1)
10.4.1.5 Latanoprost
332(2)
10.4.2 Ene-Reductase Use in the Synthesis of Building Blocks
334(6)
10.5 Conclusion
340(9)
11 Biocatalyzed Synthesis of Antidiabetic Drugs
349(88)
Andres R. Alcantara
11.1 Introduction
349(3)
11.2 Insulin and Insulin Analogues
352(9)
11.3 Amylin Analogues
361(2)
11.4 Sensitizers
363(11)
11.4.1 PPAR-a Agonists
365(2)
11.4.2 Thiazolidinediones (TZDS, Glitazones)
367(2)
11.4.3 Glitazars
369(5)
11.5 Insulin Secretagogues
374(1)
11.6 G Protein-Coupled Receptors Agonists
374(6)
11.6.1 Incretin Mimetics
375(3)
11.6.2 GPR119 Agonists
378(2)
11.7 Enzyme Inhibitors
380(35)
11.7.1 Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
380(1)
11.7.1.1 Sitagliptin
381(3)
11.7.1.2 Saxagliptin
384(2)
11.7.1.3 Alogliptin, linagliptin, and trelagliptin
386(2)
11.7.1.4 Teneligliptin and gosogliptin
388(2)
11.7.1.5 Other DPP4 inhibitors
390(3)
11.7.2 HB-Hydroxysteroid Dehydrogenase type 1 (11β-HSD1) Inhibitors
393(4)
11.7.3 a-Glucosidase Inhibitors
397(1)
11.7.3.1 Iminosugars
397(14)
11.7.3.2 Carbasugars
411(4)
11.8 Glycosurics
415(3)
11.9 Conclusions
418(19)
12 Glucose-Sensitive Drug Delivery Systems Based on Phenylboronic Acid for Diabetes Treatment
437(24)
Li Zhao
Bozhong Lin
Liyan Wang
Guangqing Gai
Jianxun Ding
12.1 Introduction
437(3)
12.2 PBA-Mediated LbL Assembles
440(4)
12.3 PBA-Regulated Micelles and Vesicles
444(6)
12.4 PBA-Functionalized Gels
450(5)
12.5 Conclusion
455(6)
13 Synthesis of Important Chiral Building Blocks for Pharmaceuticals Using Lactobacillus and Rhodococcus Alcohol Dehydrogenases
461(50)
Marion Rauter
Simon Krebs
Gotthard Kunze
13.1 Introduction
461(3)
13.2 Requirements for Lactobacillus and Rhodococcus ADHs as Versatile Enzymes for the Synthesis of Enantiopure Alcohols
464(8)
13.3 Alcohols as Chiral Building Blocks Synthesized by Lactobacillus and Rhodococcus ADHs
472(13)
13.4 Synthesis of Enantiomerically Pure Alcohols with Lactobacillus and Rhodococcus ADHs in Preparative Scale with 1-Phenylethanol as Example
485(6)
13.5 ADHs from Lactobacillus and Rhodococcus Species in Biocatalytic Cascades
491(6)
13.6 Searching for New ADHs or Engineering of Weil-Known ADHs for Novel Drug Candidates
497(5)
13.7 Summary
502(9)
14 Asymmetric Reduction of C=N Bonds by Imine Reductases and Reductive Aminases
511(48)
Matthias Hdhne
Philipp Matzel
Martin Gand
14.1 Introduction
511(6)
14.1.1 Why Are IREDs Important Tools for Biocatalysis
513(2)
14.1.2 Most Acyclic Imines Have a Low Stability in Aqueous Solutions--Reductive Aminases (RedAm) Solve This Problem
515(1)
14.1.3 Focus of This Book
Chapter
516(1)
14.2 Imine Reductions Observed in Nature
517(14)
14.2.1 Imine Reductions of Substrates Bearing a Carboxylate Function
518(1)
14.2.2 Imine Reductions of Substrates Lacking a Carboxylate Function
518(10)
14.2.2.1 Alkaloid biosynthesis: IREDs installing an a-chiral amine moiety
528(1)
14.2.2.2 Alkaloid biosynthesis: IREDs installing a y3-chiral amine moiety
529(1)
14.2.3 Reductive Aminations Observed in Nature
530(1)
14.3 Imine Reductases Explored for Biocatalytical Imine Reduction
531(13)
14.3.1 IREDs Belonging to the Hydroxyisobutyrate Dehydrogenases Subfamily
531(2)
14.3.2 Imine Reduction with Enzymes Belonging to Other Families or Created by Protein Engineering
533(1)
14.3.3 Scope of Biocatalytic Imine Reduction
534(4)
14.3.4 Scope of Biocatalytic Reductive Amination: IREDs Require a Large Excess of the Amine Nucleophiles
538(4)
14.3.5 Reductive Aminases Allow Usage of Near-Stoichiometric Amounts of Amine Nucleophiles for Selected Substrate Combinations
542(1)
14.3.6 Towards the Synthesis of β-Chiral Amines by Dynamic Kinetic Resolution (DKR) of Aldehydes
543(1)
14.4 IREDs and RedAms Employed in Cascade Reactions
544(3)
14.5 Mechanistic Basis of IREDs and RedAms
547(6)
14.5.1 Structural Features of IREDs Important for Imine Reduction
547(3)
14.5.2 Mechanistic Differences between Imine Reduction and Reductive Amination
550(3)
14.6 Conclusive Remarks
553(6)
15 Cipargamin: Biocatalysis in the Discovery and Development of an Antimalarial Drug
559(20)
Thomas Ruch
Elina Siirola
Radka Snajdrova
15.1 Introduction
559(3)
15.1.1 Biocatalysis at Novartis
559(2)
15.1.2 Malaria and Drug Development
561(1)
15.2 Biocatalysis in Synthesis of a Drug Candidate
562(3)
15.3 Biocatalysis in the Synthesis of Metabolites of Cipargamin (KAE609)
565(2)
15.3.1 Biocatalytic Synthesis of M23
566(1)
15.4 Biocatalysis in the Synthesis of Cipargamin during Drug Development
567(8)
15.4.1 Design of a New Route
567(1)
15.4.2 Biocatalysis Using Kinetic Resolutions
568(1)
15.4.3 Biocatalysis as a Tool for Asymmetric Synthesis of Chiral Amines
569(1)
15.4.3.1 Ketone synthesis
570(1)
15.4.3.2 Transaminase approach
571(2)
15.4.3.3 Route comparison
573(2)
15.5 Conclusion
575(4)
16 Halogenases with Potential Applications for the Synthesis of Halogenated Pharmaceuticals
579(24)
Georgette Rebollar-Pe'rez
Cynthia Romero-Guido
Antonino Baez
Eduardo Torres
16.1 Introduction
579(2)
16.2 Halogenation Mechanisms
581(3)
16.2.1 Electrophilic Mechanism: Haloperoxidases
581(1)
16.1.1.1 Heme-iron halogenases
581(1)
16.1.1.2 Vanadium-dependent alogenases
582(1)
16.1.1.3 Flavin-dependent halogenases
583(1)
16.2.2 Radical Mechanism
584(1)
16.2.3 Nucleophilic Mechanism
584(1)
16.3 Biosynthesis of Halogenated Pharmaceuticals
584(13)
16.3.1 Halogenated Pharmaceutical with Antitumor Activity
593(3)
16.3.2 Halogenated Pharmaceutical with Antibiotic Activity
596(1)
16.3.3 Halogenated Pharmaceutical with Antifungal Activity
597(1)
16.4 Perspective
597(6)
17 Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
603(40)
Giovanna Di Nardo
Gianfranco Gilardi
17.1 Introduction
603(1)
17.2 Cytochromes P450: General Features
604(6)
17.2.1 Nomenclature and Classification
607(1)
17.2.2 Catalytic Cycle of Cytochromes P450
608(2)
17.3 Cytochromes P450 as Biocatalysts
610(3)
17.3.1 Importance of Cytochromes P450 in Biocatalysis
610(2)
17.3.2 Natural Products as a Source of Cytochromes P450 Substrates
612(1)
17.4 Pharmaceutical Biocatalysis by Cytochromes P450
613(18)
17.4.1 Synthesis of Statins
613(2)
17.4.2 Synthesis of Active Steroids
615(4)
17.4.3 Synthesis of Anticancer Drugs
619(3)
17.4.4 Synthesis of Antibiotics, Antifungal, and Antiprotozoal Agents
622(4)
17.4.5 Synthesis of New Natural Product-Inspired Drugs
626(1)
17.4.5.1 Hydroxy fatty acids
626(1)
17.4.5.2 Phytopharmaceuticals
627(4)
17.5 Conclusions and Future Perspectives
631(12)
18 Oxyfunctionalization of Pharmaceuticals by Fungal Peroxygenases
643(38)
Jan Kiebist
Martin Hofrichter
Ralf Zuhse
Katrin Scheibner
18.1 Introduction
643(2)
18.2 Unspecific Peroxygenases
645(11)
18.2.1 Properties and Occurrence of Unspecific Peroxygenases
647(6)
18.2.2 Catalyzed Reactions and Reaction Mechanism
653(3)
18.3 Oxyfunctionalization of Pharmaceuticals
656(17)
18.3.1 Oxidation of Aliphatics
656(8)
18.3.2 Oxidation of Aromatics and Olefins
664(5)
18.3.3 Oxidations Resulting in Cleavage Reactions
669(4)
18.4 Conclusion and Outlook
673(8)
19 Biocatalytic Synthesis of Chiral 1, 2, 3, 4-Tetrahydroquinolines
681(20)
Yongzheng Chen
Liu Song
Zhongqiang Wang
19.1 Introduction
681(2)
19.2 Enantiomeric Synthesis of 1, 2, 3, 4-Tetrahydroquinoline-4-ols
683(6)
19.3 Enantiomeric Synthesis of 1, 2, 3, 4-Tetrahydroquinolines
689(7)
19.4 Conclusion
696(5)
20 New Strategies to Discover Non-Ribosomal Peptides as a Source of Antibiotics Molecules
701(20)
Mario Alberto Martinez-Nunez
Zuemy Rodriguez-Escamilla
Victor Ldpezy Ldpez
20.1 Introduction
701(2)
20.2 Molecular Mechanism of Antibiotic Resistance
703(6)
20.3 Nonribosomal Peptides as a Source of New Antibiotics
709(2)
20.4 Genome Mining Strategies to Find NRPs
711(4)
20.5 Conclusion
715(6)
21 Enzyme Kinetics and Drugs as Enzyme Inhibitors
721(86)
Peter Grunwald
21.1 Introduction
721(1)
21.2 Enzyme Kinetics
722(42)
21.2.1 Michaelis-Menten Equation and the Determination of KM and Vmax
722(3)
21.2.2 Inhibition of Enzymes
725(1)
21.2.2.1 Competitive inhibition
726(1)
21.2.2.2 Non-competitive inhibition
727(1)
21.2.2.3 Uncompetitive inhibition
728(2)
21.2.2.4 Allosteric modulation
730(1)
21.2.2.5 Covalent (reversible) inhibition: Pros and cons
731(4)
21.2.2.6 K1/IC50-values and the residence-time model
735(2)
21.2.3 Enzyme Inhibitors and Activators as Drugs
737(1)
21.2.3.1 New treatment options for cardiac insufficiency
737(1)
21.2.3.2 The aldose reductase inhibitor fidarestat enforces chemotherapy
738(3)
21.2.3.3 Lipid-lowering agents
741(10)
21.2.3.4 Strategies to combat cancer
751(13)
21.3 Concluding Remarks
764(43)
Index 807
Peter Grunwald
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