List of Contributors ......................................... xiii
1 Natural Products as Enzyme Inhibitors ...................... 1
David M. Pereira, Catarina Andrade, Patricia Valentão,
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 Tong 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 Я-Secretase 1 (BACE1) Inhibitors ................... 30
2.4.4.1 Tasiamide B .................................... 30
2.5 Protein Kinase С 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
2.6.1 Sec61 Protein Translocation Channel Inhibitors ..... 32
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, Francisco I. Bravo, Anna Arola-Arnal,
and Begoha 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
Tânia С. Silva, David M. Pereira, Patricia Valentão, and
Paula В. 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
5.1 Introduction .............................................. 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 ............................... 705
5.4.1 Phenol Acids ...................................... 105
5.4.2 Tannins ........................................... 706
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 ВACE1 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-Sánchez, 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 .................................... 147
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,
Priyanka Voori Giri, 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 ..................................... 177
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) ............................. 187
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
Jack Ho Wong, Tzi Bun Ng, Chi Fai Cheung, Chit Tam,
Charlene C.W.Ng, Ryan Tse, Так Fu Tse, and Helen Chan
8.1 Introduction ............................................. 209
8.2 Ribosome-Inactivating Proteins ........................... 209
8.3 Reverse Transcriptase Inhibitors ......................... 270
8.3.1 Antifungal Proteins ............................... 270
8.3.2 Defensins and Defensin-Like Anti-Fungal Peptides .. 270
8.3.3 Cathelicidins ..................................... 270
8.3.4 Whey Proteins and Peptides ........................ 277
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 Peláez, Nuria de Pedro, and José 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
9.4 Conclusions .............................................. 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
Acknowledgements ......................................... 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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