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Natural Products Targeting Clinically Relevant Enzymes

ISBN: 978-3-527-34205-1
352 pages
December 2017
Natural Products Targeting Clinically Relevant Enzymes (3527342052) cover image

Description

The past decade has seen the reappearance of natural products as a valuable source of potent therapeutics. Here, experts on bioactive natural products cover the full spectrum of clinically relevant enzymes that are known to be targeted by natural products. Key enzymes include acetylcholine esterase, angiotensin-I-converting enzyme, cyclooxygenase, dihydrofolate reductase, phospholipase A2, respiratory complexes, and many more.
By connecting the diversity of medicinal natural product sources with their potential clinical applications, this volume serves as a companion for the medicinal chemist looking for innovative small molecule compounds as well as for pharmacologist interested in the clinical effects and mode of action of herbal and traditional medicines.
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Table of Contents

Lists of Contributors xiii

1 Natural Products as Enzyme Inhibitors 1
David M. Pereira, Catarina Andrade, Patricia Valentao, and Paula B. Andrade

1.1 Why Are Natural Products Good Enzyme Inhibitors? 1

1.2 Drawbacks of Natural Products 4

1.3 The Future of Natural Products Drug Discovery 5

1.3.1 New Sources and New Production Methods 5

1.3.2 New Strategies for Delivery 9

1.3.3 New Targets?/Drug Repurposing 12

1.4 Conclusion 13

References 13

2 Molecular Targets of Clinically Relevant Natural Products from Filamentous Marine Cyanobacteria 19
Lik T. Tan

2.1 Introduction 19

2.2 Histone Deacetylase Inhibitors 20

2.2.1 Largazole 20

2.2.2 Santacruzamate A 22

2.3 Proteasome Inhibitors 23

2.3.1 Carmaphycins 23

2.4 Protease Enzymes 24

2.4.1 Serine Protease Inhibitors 24

2.4.2 Falcipain Inhibitors 27

2.4.2.1 Gallinamide A 27

2.4.3 Cathepsin Inhibitors 28

2.4.4 β -Secretase 1 (BACE1) Inhibitors 30

2.4.4.1 Tasiamide B 30

2.5 Protein Kinase C Modulators 30

2.5.1 Aplysiatoxins 30

2.6 Interference of the Actin and Microtubule Filaments 31

2.6.1 Dolastatins 10/15 31

2.6.2 Bisebromoamide 32

2.7 Sec61 Protein Translocation Channel Inhibitors 32

2.7.1 Apratoxin A 32

2.8 Prohibitin Inhibitors 34

2.8.1 Aurilide 34

2.9 Sodium Channels Modulators 35

2.10 Conclusions 35

References 36

3 Natural Angiotensin Converting Enzyme (ACE) Inhibitors with Antihypertensive Properties 45
Maria Margalef, Francisca I. Bravo, Anna Arola-Arnal, and Begona Muguerza

3.1 Introduction 45

3.2 Mechanisms of Blood Pressure Regulation 46

3.2.1 Renin–Angiotensin–Aldosterone System 46

3.3 The Treatment of Hypertension 47

3.3.1 Angiotensin Converting Enzyme Inhibitors 47

3.4 Natural Products as Angiotensin Converting Enzyme Inhibitors 50

3.4.1 Polyphenols 50

3.4.2 Protein Derived Peptides 55

3.5 Conclusions 58

References 58

4 Phospholipase A2 Inhibitors of Marine Origin 69
Tania Silva, David M. Pereira, Patricia Valentao, and Paula B. Andrade

4.1 Relevance of Marine Organisms 69

4.2 Inflammation 69

4.2.1 Phospholipase A2 70

4.3 Marine Molecules as PLA2 Inhibitors 72

4.3.1 Sponge ]Derived Metabolites 72

4.3.2 Metabolites from Other Organisms 83

4.4 Conclusion 86

References 86

5 β-Secretase (BACE1) Inhibitors from Natural Products 93
Wei -Shuo Fang, Deyang Sun, Shuang Yang, and Na Guo

5.1Introduction 93

5.2 Flavonoids 94

5.2.1 Flavones, Flavonols and Flavone Glycosides 95

5.2.2 Dihydroflavonoids 96

5.2.3 Biflavonoids 98

5.2.4 Chalcones 100

5.2.5 Isoflavonoids 102

5.2.6 Catechins 102

5.2.7 Xanthones 104

5.3 Chromones 104

5.4 Phenolic Acids and Tannins 105

5.4.1 Phenol Acids 105

5.4.2 Tannins 106

5.4.3 Simple Phenol Derivatives and Polyphenols 107

5.5 Stilbenes and Derivatives 110

5.6 Coumarins 112

5.7 Benzoquinones and Anthraquinones 114

5.8 Alkaloids 116

5.9 Terpenes 118

5.10 Lignans 120

5.11 Fatty Acid 121

5.12 Saccharides, Peptides and Amino Acid Derivatives 121

5.13 BACE1 Inhibitory Active Extracts of Natural Products 122

5.14 Bioassays for the Discovery of BACE1 Inhibitors 124

5.15 Prospective 124

5.16 Acknowledgements 125

References 125

6 Hypoglycaemic Effects of Plants Food Constituents via Inhibition of Carbohydrate-Hydrolysing Enzymes: From Chemistry to Future Applications 135
Monica R. Loizzo, Marco Bonesi, Seyed M. Nabavi, Eduardo Sobarzo ]Sanchez, Luca Rastrelli, and Rosa Tundis

6.1 Introduction 135

6.2 α-Amylase 136

6.3 α-Glucosidase 137

6.4 Hypoglycaemic Natural Compounds 137

6.4.1 Flavonoids 139

6.4.2 Phenolic Acids 141

6.4.3 Terpenoids 142

6.4.4 Alkaloids 147

6.4.5 Tannins 150

6.4.5.1 Ellagitannins 150

6.4.6 Miscellaneous 152

6.5 Conclusions and Future Perspective 152

Abbreviations 153

References 153

7 Natural Products Targeting Clinically Relevant Enzymes of Eicosanoid Biosynthesis Implicated in Inflammation and Cancer 163
Gorla V. Reddy, Nagendra S. Yarla, Shobha Ediga, Dinesh K. Tiwari, Naresh Kumar, Sandhya Singh, Vasundhra Bhandari, Anupam Bishayee, Chintalapally V. Rao, and Pallu Reddanna

7.1 Introduction 163

7.2 Eicosanoid Biosynthetic Pathways 164

7.2.1 Phospholipases 165

7.2.2 Cyclooxygenases 166

7.2.3 Lipoxygenases 166

7.2.4 Cytochrome P450 (CYP) ]dependent Monooxygenases 166

7.3 Eicosanoid Biosynthetic Pathways in Inflammation and Cancer 167

7.3.1 Role of PLA2s in Inflammation and Cancer 167

7.3.2 Role of COXs in Inflammation and Cancer 168

7.3.3 Role of LOXs in Inflammation and Cancer 169

7.3.4 Role of CYP ]dependent Monooxygenases in Inflammation and Cancer 170

7.4 Natural Products as Anti-inflammatory Agents 170

7.4.1 Natural Products from Plant Origin 170

7.4.1.1 Baicalein 170

7.4.1.2 Berberine 171

7.4.1.3 Chebulagic Acid 172

7.4.1.4 Curcumin 172

7.4.1.5 Ellagic Acid 173

7.4.1.6 Epigallocatechin ]3 ]Gallate 174

7.4.1.7 Eugenol 174

7.4.1.8 Fisetin 174

7.4.1.9 Gallic Acid 175

7.4.1.10 Genistein 175

7.4.1.11 Guggulsterone 176

7.4.1.12 Piperine 176

7.4.1.13 Quercetin 177

7.4.1.14 Resveratrol 178

7.4.1.15 Silibinin 178

7.4.1.16 Terpenoids 179

7.4.1.17 Triptolids 180

7.4.1.18 Ursolic Acid (UA) 181

7.4.2 Natural Products from Marine Origin 182

7.4.2.1 Axinelline A 182

7.4.2.2 Scalaradial 182

7.4.2.3 Tetrapetalone 183

7.4.3 Natural Products from Microorganisms 183

7.4.3.1 C ]Phycocyanin 183

7.4.3.2 Kojic Acid 184

7.4.3.3 Lobaric Acid 185

7.5 Conclusions and Future Directions 185

References 186

8 Anti-HIV Natural Products 209
Tzi B. Ng, Jack H. Wong, Chi F. Cheung, Charlene C. W. Ng, Tak F. Tse, and Helen Chan

8.1 Introduction 209

8.2 Ribosome-Inactivating Proteins 209

8.3 Reverse Transcriptase Inhibitors 210

8.3.1 Antifungal Proteins 210

8.3.2 Defensins and Defensin ]Like Anti ]Fungal Peptides 210

8.3.3 Cathelicidins 210

8.3.4 Whey Proteins 211

8.3.5 Proteases and Protease Inhibitors 211

8.3.6 Lectins 211

8.3.7 Laccases and Ribonucleases 212

8.3.8 Polysaccharides and Polysaccharopeptides 212

8.3.9 Other HIV ]Reverse Transcriptase Inhibitors 212

8.4 Inhibitors of HIV Reverse Transcriptase Associated RNase H 213

8.5 HIV-1 Protease Inhibitors 213

8.6 HIV-1 Integrase Inhibitors 214

8.7 Discussion 214

Acknowledgements 216

References 216

9 Natural Inhibitors of Mitochondrial Respiratory Chain: Therapeutic and Toxicological Implications 225
Fernando Pelaez, Nuria de Pedro, and Jose R. Tormo

9.1 Introduction: The Structure of the Electron Transport Chain 225

9.2 Natural Inhibitors of the Respiratory Chain 228

9.2.1 Complex I Inhibitors 228

9.2.1.1 Acetogenins from Annonaceae as Complex I Inhibitors 231

9.2.2 Complex II Inhibitors 233

9.2.3 Complex III Inhibitors 234

9.2.4 Complex IV Inhibitors 235

9.2.5 Complex V Inhibitors 237

9.3 Therapeutic, Agrochemical and Toxicological Implications 239

9.3.1 ETC Inhibitors as Fungicides 239

9.3.2 ETC Inhibitors as Insecticides, Acaricides, and Anthelmintic Agents 240

9.3.3 ETC Inhibitors with Activity Against Protozoan Parasites 241

9.3.4 Diabetes and ETC Inhibition 241

9.3.5 ETC Inhibition as a Therapeutic Strategy in Cancer 242

9.3.5.1 Mechanistic Insights on the Anti ]Tumour Properties of ETC Inhibitors 244

9.3.6 Toxicological Implications of ETC Inhibition 245

9.3.6.1 Neurotoxicity and ETC Inhibition 245

9.3.6.2 Other Toxicity Aspects of ETC Inhibition 246

9.4Conclusions 247

References 247

10 Targeting Enzymatic Pathways with Marine-Derived Clinical Agents 255
Renato B. Pereira, Ramesh Dasari, Florence Lefranc, Alexander Kornienko, Robert Kiss, and Nelson G. M. Gomes

10.1 Marine Environment as an Established Source of Drug Candidates 255

10.2 Enzyme-Targeting Derived Effects of Marine-Derived Approved Drugs 256

10.3 Marine-Derived Agents in Clinical Development Targeting Relevant Enzymatic Pathways 261

10.4 Concluding Remarks 264

Acknowledgements 265

References 265

11 Anti-Malarial Drug Discovery: New Enzyme Inhibitors 277
Raghu Raj and Vipan Kumar

11.1 Introduction 277

11.2 Falcipain (FP-2) Inhibitors 278

11.3 Purine Nucleoside Phosphorylase Inhibitors (PNP) 284

11.4 Dihydrofolate Reductase (DHFR) and Thymidylate Synthase (TS) Inhibitors 286

11.5 Hypoxanthine-Guanine-(Xanthine) Phosphoribosyltransferase Inhibitors 290

11.6 Conclusion 293

References 293

12 Natural Plant-Derived Acetylcholinesterase Inhibitors: Relevance for Alzheimer’s Disease 297
Nady Braidy, Anne Poljak, Tharusha Jayasena, and Perminder Sachdev

12.1 Introduction 297

12.2 Natural Acetylcholinesterase Inhibitors 299

12.2.1 Alkaloid Acetylcholinesterase Inhibitors 302

12.2.1.1 Rutaceae 302

12.2.1.2 Nelumbonaceae 303

12.2.1.3 Papaveraceae 303

12.2.1.4 Menispermaceae 303

12.2.1.5 Magnoliaceae 304

12.2.1.6 Apocynaceae 304

12.2.1.7 Amaryllidaceae 304

12.2.1.8 Lycopodiaceae 305

12.2.1.9 Buxaceae 305

12.2.1.10 Liliaceae 306

12.2.2 Non ]Alkaloid Acetylcholinesterase Inhibitors 306

12.2.2.1 Asparagaceae 306

12.2.2.2 Chenopodiaceae 306

12.2.2.3 Clusiaceae 307

12.2.2.4 Gentianaceae 307

12.2.2.5 Fabaceae 307

12.2.2.6 Lamiaceae 307

12.2.2.7 Moraceae 308

12.2.2.8 Iridaceae 308

12.2.2.9 Zygophyllaceae 308

12.2.2.10 Sterculiaceae 308

12.2.2.11 Combretaceae 309

12.2.2.12 Myristicaceae 309

12.2.2.13 Anacardiaceae 309

12.2.2.14 Nelumbonaceae 309

12.3 Conclusion 309

Acknowledgements 309

References 310

Index 319

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Author Information

PAULA B. ANDRADE is Associate Professor at the Faculty of Pharmacy of the University of Porto. As head of the Pharmacognosy lab, she also coordinates the natural products group of the REQUIMTE/LAQV, an institute active in Green Chemistry, and evaluates research projects for various international entities. Her research on bioactive substances originating from matrices of marine and terrestrial origin was published in more than 30 book chapters and more than 300 articles in international journals.

PATRICIA VALENTÃO obtained her PhD in Pharmaceutical Sciences at the University of Porto for work on pharmacognosy. She was appointed Assistant Professor at the Faculty of Pharmacy, University of Porto in 2007. Her research focuses on qualitative and quantitative metabolite profiling of terrestrial and marine natural matrices with the goal to reveal composition/activity relationships of these compounds in various clinically-relevant areas. Patricia Valentão is member of the REQUIMTE/LAQV Institute of Green Chemistry and editorial board member of the "EJournal of Chemistry". She (co)authored more than 30 book chapters and more than 250 articles in international journals.

DAVID M. PEREIRA obtained his PhD in Pharmaceutical Sciences at the University of Porto for work on phytochemistry and pharmacognosy. In 2014 he was appointed Assistant Professor at the Faculty of Pharmacy of the same university. David Pereira edited one book, contributed more than 20 book chapters and over 60 papers covering research areas of natural products, inflammation, drug discovery and analytical techniques. He also serves in the Editorial Board of several journals related to natural products and analytical techniques. He is appointed expert in the "Global Burden of Disease" program of the University of Washington, and reviewer/consultant in Biomedical Sciences for several European institutions.
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