Natural Products Targeting Clinically Relevant Enzymes

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.

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