New Tide of Natural Product Chemistry

Introduction
Contents
Part I Exploring Novel Bioactive Natural Products and Uncovering Life Phenomena with Natural Products
1 Synthetic Biology-Based Natural Product Discovery
1.1 Introduction
1.2 Diterpenoid Pyrones (DDPs) with a Decalin Skeleton Produced by Filamentous Fungi
1.3 Reconstruction of Natural DDP Biosynthetic Pathways and Discovery of Naturally Programmed DDPs
1.4 Discovery of DDPs not Programmed in Nature by Redesign of the DDP Biosynthetic Pathways
1.5 Evaluation of Biological Activities of the DDPs
1.6 Conclusion
References
2 Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Inhibitors Isolated from Subtropical Marine Cyanobacteria in Japan
2.1 Introduction
2.2 Iezoside
2.3 Kurahyne
2.4 Biselyngbyasides and Their Aglycons, Biselyngbyolides
2.5 Possible Ecological Role of SERCA Inhibitors Produced by Marine Cyanobacteria
2.6 Conclusion
References
3 Marine Natural Products Targeting Tumor Microenvironment
3.1 Introduction
3.2 Screening of Hypoxia-Selective Growth Inhibitors
3.2.1 Bioactivity and Action Mechanism of Furospinosulin-1
3.2.2 Synthesis and Evaluation of Affinity Probe of Furospinosulin-1
3.2.3 Target Identification of Furospinosulin-1
3.2.4 Structure Confirmation of Dictyoceratins-A and -C by Total Synthesis
3.2.5 SAR and Target Identification of Dictyoceratin-C
3.3 Search for Selective Growth Inhibitors Under Glucose-Starved Condition
3.3.1 Structure Elucidation of Biakamides A-D by NMR and Total Synthesis
3.3.2 Bioactivity and SAR of Biakamides
3.4 Conclusion
References
4 Chemical Biology Studies on Aplyronine A, A PPI-Inducing Antitumor Macrolide from Sea Hare
4.1 Introduction
4.2 Biochemical Evaluations of ApA
4.3 Binding Mode of Actin–ApA–Tubulin HTC Revealed by MD Simulation
4.4 Synthesis and Biological Activities of ApA Analogs
4.5 Molecular Modeling Studies of ApA and Its Side-Chain Analogs
4.6 Development of Versatile Actin-Affinity Tags Designed from the ApA Side-Chain Part
4.7 Conclusion
References
5 Chemical Synthesis and Immunological Functions of Bacterial Lipid A for Vaccine Adjuvant Development and Bacterial-Host Chemical Ecology Research
5.1 Introduction
5.2 Bacterial Glycolipid Lipid A, an Innate Immune Stimulator
5.3 Practical Synthetic and Semi-Synthetic Lipid A Adjuvants
5.4 Lipid A Adjuvant Development Based on Bacterial-Host Chemical Ecology
5.4.1 Lipid A Mediates Bacterial-Host Chemical Ecology
5.4.2 Parasitic Bacterial Lipid A
5.4.3 Symbiotic Bacterial Lipid A
5.4.4 Lipid A in Fermented Foods as Adjuvants
5.5 Conclusion
References
Part II Uncovering Biosynthesis of Natural Products
6 Dissecting Biosynthesis of Natural Products Toward Drug Discovery
6.1 Introduction
6.2 Aspirochlorine Biosynthesis
6.3 Fumagillin Biosynthesis
6.4 Pseurotin/Synerazol Biosynthesis
6.5 Closing Remarks
References
7 A New Trend in Biosynthetic Studies of Natural Products: The Bridge Between the Amino Acid Sequence Data and the Chemical Structure
7.1 Introduction
7.2 Fungal Polyketide Synthases
7.2.1 Classification of Fungal Polyketide Synthases
7.2.2 General Polyketide Chain Elongation Mechanism
7.3 Phylogenetic Analysis of Hybrid-PKSs to Predict the Chemical Space of Hybrid-PKs
7.4 Focused Functional Analysis of HR-PKSs Using the Aspergillus Oryzae Expression System
7.5 Unified Stereochemical Rule of Fungal PKSs
7.5.1 Stereochemical Course to Synthesize the Backbone Structure of Polyhydroxy PKs Classified into PMA Clades
7.5.2 Proposal of a Unified Stereochemical Rule
7.6 Conclusion and Perspectives
References
8 Biosynthesis of β-Amino Acid-Containing Macrolactam Polyketides
8.1 Introduction
8.2 3-Aminoisobutyric Acid Unit-Containing Macrolactams Such as Vicenistatin
8.2.1 Chemical Structures and Biological Activities of 3-Aminoisobutyric Acid Unit-Containing Macrolactams
8.2.2 Vicenistatin Biosynthesis
8.2.3 Structural Analysis of Vicenistatin Biosynthetic Enzymes
8.2.4 Production of Vicenistatin Derivative
8.3 β-Alanine Unit-Containing Macrolactams Such as Fluvirucin B2
8.3.1 Chemical Structures and Biological Activities of Fluvirucins
8.3.2 Fluvirucin Biosynthesis
8.4 3-Aminobutyric Acid Unit-Containing Macrolactams Such as Incednine
8.4.1 Chemical Structures and Biological Activities of 3-Aminobutyric Acid Unit-Containing Macrolactams
8.4.2 Incednine Biosynthesis
8.4.3 Structural Analysis of Incednine Biosynthetic Enzymes
8.4.4 Production of Incednine Derivatives
8.5 β-Phenylalanine Unit-Containing Macrolactams Such as Hitachimycin
8.5.1 Chemical Structures and Biological Activities of β-Phenylalanine Unit-Containing Macrolactams
8.5.2 Hitachimycin Biosynthesis
8.5.3 Structural Analysis of HitB
8.5.4 Production of Hitachimycin Derivatives
8.6 3-Aminofatty Acid Unit-Containing Macrolactams Such as Cremimycin
8.6.1 Chemical Structures and Biological Activities of 3-Aminofatty Acid Unit-Containing Macrolactams
8.6.2 Cremimycin Biosynthesis
8.6.3 Structural Analysis of CmiS6
8.7 Conclusions and Future Perspectives
References
Part III Total Synthesis of Complex Natural Products by Innovative Strategies
9 Synthetic Approach Toward Structural Elucidation of Marine Natural Product Symbiodinolide
9.1 Introduction
9.2 Synthesis and Absolute Configuration of the C1′–C25′ Fragment
9.3 Synthesis and Relative Configuration of the C1–C13 Fragment
9.4 Synthesis and Absolute Configuration of the C14–C24 Fragment
9.5 Synthesis and Absolute Configuration of the C23–C34 Fragment
9.6 Synthesis and Absolute Configuration of the C33–C42 Fragment
9.7 Synthesis and Relative Configuration of the C79–C104 Fragment
9.7.1 Synthesis of the Proposed C79–C104 Fragment
9.7.2 Strategy for the Stereostructural Elucidation
9.7.3 Synthesis and Relative Configuration of the C79–C97 Fragment
9.7.4 Synthesis and Relative Configuration of the C94–C104 Fragment
9.7.5 Stereochemical Revision of the C79–C104 Fragment
9.8 Conclusion
References
10 Collective Synthesis of Monoterpenoid Indole Alkaloids Using Bioinspired Strategies
10.1 Introduction
10.2 Biosynthesis of Monoterpenoid Indole Alkaloids
10.3 Asymmetric Total Synthesis of Secologanin
10.4 Development of Diastereoselective Pictet–Spengler Reaction, and Total Synthesis of Strictosidine
10.5 Bioinspired Total Syntheses of Strictosamide, Neonaucleoside A, and Cymoside
10.6 Synthetic Strategies for Monoterpenoid Indole Alkaloids Produced in the Early Stages of Biosynthesis, and Synthesis of Secologanin Aglycone Silyl Ether
10.7 Bioinspired Transformations to Nacycline, Cathenamine, and Tetrahydroalstonine from Strictosidine Aglycone
10.8 Bioinspired Transformations to Corynantheine-Type Indole Alkaloids
10.9 Bioinspired Transformations to Akagerine-Related Indole Alkaloids
10.10 Bioinspired Transformations to Naucleaoral-Related Indole Alkaloids
10.11 Conclusion
References
11 Total Syntheses of Bioactive Oxacyclic Natural Products
11.1 Introduction
11.2 Lysidicin A
11.3 Amphirionin-4
11.4 Anthecularin
11.5 Celafolins B-1, B-2, B-3
11.6 Conclusion
References
12 Total Syntheses of Densely Oxygenated Natural Products by Radical-Based Decarbonylative Convergent Assembly
12.1 Introduction
12.2 Design of Radical-Based Convergent Strategies for the Synthesis of Highly Oxygenated Natural Products
12.3 Total Synthesis of Manzacidin A
12.4 Unified Total Synthesis of Polyoxins
12.5 Total Synthesis of Hikizimycin
12.6 Summary and Perspective
References
13 Nucleophilic Addition to Amides Toward Efficient Total Synthesis of Complex Alkaloids
13.1 Nucleophilic Addition to Amides
13.2 Total Synthesis of Gephyrotoxin
13.2.1 Gephyrotoxin
13.2.2 Chemoselective Reductive Nucleophilic Addition to N-Methoxyamides
13.2.3 Total Synthesis of Gephyrotoxin
13.3 Unified Total Synthesis of Stemoamide-Type Alkaloids
13.3.1 Stemoamide-Type Alkaloids and Their Synthetic Plan
13.3.2 Iridium-Catalyzed Reductive Nucleophilic Addition to Tertiary Amides
13.3.3 Unified Total Synthesis of Stemoamide-Type Alkaloids
13.4 Conclusions
References
14 Equilibrium-Controlled Stereoselective Sequential Cyclizations Enabled Concise Total Synthesis of Complex Indole Alkaloid, Tronocarpine
14.1 Introduction
14.2 Tronocarpine
14.3 First Total Synthesis of (+)-Tronocarpine by Hans and Coworkers
14.4 Synthetic Design for the Construction of the Azabicyclo[3.3.1]nonane Core by Equilibrium-Controlled Stereoselective Tandem Cyclization
14.5 Concise Total Synthesis of (Rac)-Tronocarpine
14.6 Attempts to Obtain an Optical Tronocarpine
14.7 Conclusion and Perspective
References
Part IV New Approach for Drug Discovery Using Natural Products
15 High-Throughput Searches for Natural Products as Aggregation Modulators of Amyloidogenic Proteins
15.1 Aggregation of Amyloidogenic Proteins and Neurodegeneration
15.2 Fluorescent Probes of Amyloid Aggregates
15.3 HTS of Natural Products That Modulate Amyloid Aggregation
15.4 Searching for Natural Products That Delay the Nucleation Phase and Promote the Elongation Phase of Aβ Aggregation
15.5 Differential Activity Searching for Aβ Aggregation Inhibitors Using LC–MS Combined with Principal Component Analysis (PCA)
15.6 Inhibitory Mechanism of Aβ Aggregation by Natural Products
15.7 Conclusions and Future Perspectives
References
16 Discovery of Natural Product Analogues with Altered Activities by a High-Throughput Strategy
16.1 Introduction
16.2 Lysocin E
16.3 Strategy Design for Discovering More Potent Analogues of Lysocin E
16.4 Construction of a Lysocin E-Based Library
16.5 Discovery of Lysocin E Analogues Showing Enhanced Antibacterial Activity
16.6 Gramicidin A
16.7 Strategy Design for Discovering Gramicidin A Analogues with Altered Activity Profiles
16.8 Construction of the Gramicidin A-Based Library
16.9 Discovery of Gramicidin A Analogues That Exhibit Altered Activities
16.10 Conclusion
References
17 Development of Novel Ligands That Modulate Innate-Like T Cells
17.1 Introduction
17.2 Development of Novel NKT Cell Modulators
17.2.1 Background of NKT Cells
17.2.2 Ligand Design of Amide-Containing α-GalCer Analogues
17.2.3 Synthesis of α-GalCer Analogues
17.2.4 Evaluation of α-GalCer Analogues
17.2.5 MD Simulation of Complexes with mCD1d and α-GalCer Analogues
17.2.6 Design of Th2 Selective Ligands
17.2.7 Summary of the Development of Novel NKT Cell Modulators
17.3 SAR Studies of MAIT Cell Modulators
17.3.1 Background of MAIT Cells
17.3.2 Concept of SAR Studies
17.3.3 Synthesis of 5-OP-RU Analogues
17.3.4 Evaluation of 5-OP-RU Analogues
17.3.5 Binding Mode Analysis of 5-OP-RU Analogues
17.3.6 Summary of SAR Studies on 5-OP-RU Analogues
17.4 Conclusion
References