Progress in the Chemistry of Organic Natural Products Vol. 94 (Progress in the Chemistry of Organic Natural Products, 94)

The three reviews cover the advances in the chemistry and biology of withanolides over the last 16 years, review the chemistry and biology of the rocaglamide-type derivatives and related compounds, with emphasis on their structural diversity, biosynthesis, pharmacological significance and total synthesis, and summarize the extensive chemistry and biology studies on a natural product, which have resulted in a novel therapy approved worldwide. Progress in the Chemistry of Organic Natural Products 3 Contents 5 Contributors 9 About the Authors 11 Chemistry and Biology of Rocaglamides (= Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae) 19 1 Introduction 20 2 Structural Classification of Rocaglamides and Related Compounds 23 2.1 Rocaglamide Derivatives 23 2.2 Aglain Derivatives 30 2.3 Aglaforbesin Derivatives 35 2.4 Forbagline Derivatives 36 3 Biosynthesis of Rocaglamides and Related Metabolites 38 4 Pharmacological Significance of Rocaglamides and Related Compounds 41 4.1 Insecticidal Activity 41 4.2 Anti-inflammatory Activity 44 4.3 Anticancer Activity 46 4.3.1 Antitumor Activities In Vivo in Mouse Tumor Models 46 4.3.2 Cytostatic Activity and Inhibition of Translation 46 4.3.3 Apoptosis Induction 49 5 Chemical Synthesis of Cyclopenta[b]benzofurans 52 5.1 First Approaches to the Synthesis of Rocaglamides 52 5.2 The First Total Synthesis of Rocaglamide 54 5.3 Syntheses of Rocaglamide and Related Natural Products 55 5.4 New Approaches to Rocaglamide and Related Natural Products 57 5.5 Syntheses of Silvestrol 62 5.6 Development of Rocaglates and Analogues as Therapeutic Agents 65 6 Concluding Remarks 69 References 69 Chemistry of the Immunomodulatory Macrolide Ascomycin and Related Analogues 77 1 Introduction 77 1.1 Ascomycin and Related Natural Products 78 1.2 Ascomycin Derivatives, a Novel Class of Anti-inflammatory Compounds 80 1.2.1 Pimecrolimus 81 1.2.1.1 Pharmacology In Vitro and In Vivo 81 1.2.1.2 Clinical Profile 84 1.3 Structural Features of Ascomycin 84 1.3.1 Structural Flexibility of Ascomycin 87 2 Synthesis Aspects 88 2.1 Synthesis of the Four Diastereomeric ``Furano-Ascomycins ́ ́ 88 2.2 Synthesis of 13C Labeled Ascomycin 90 2.3 Reactivity of the Binding Domain 93 2.3.1 Reactivity of Ascomycin and Tacrolimus Towards Diazomethane 93 2.3.2 Rearrangement Reactions in the Binding Domain 96 2.3.2.1 Benzilic Acid-Type Rearrangement Reactions 96 2.3.2.2 Rearrangement Reactions in Aprotic Media 96 2.3.3 Reduction, Deoxygenation, Imine- and Aminal-Formation in the Binding Domain 102 2.3.4 Modification in the Binding Domain Through Photochemistry 104 2.3.5 Cleavage Reactions Within the Binding Domain: Amino Acid Exchange 109 2.4 Modifications in the Effector and Cyclohexyl Domains 112 3 Summary 134 References 136 Withanolides and Related Steroids 145 1 Introduction 146 2 Withanolides in the Plant Kingdom 147 2.1 Solanaceous Genera Containing Withanolides 147 2.2 Non-Solanaceous Genera Containing Withanolides 150 3 Classification of Withanolides 150 3.1. Withanolides with a δ-Lactone or δ-Lactol Side Chain 150 3.2. Withanolides with a γ-Lactone Side Chain 152 4 Withanolides with an Unmodified Skeleton 153 4.1 The Withania Withanolides 153 4.1.1. 5β,6β-Epoxywithanolides and Related Compounds 153 4.1.2 5α -Hydroxy-6α,7α-Epoxywithanolides and Related Compounds 154 4.1.3. 1α,3bβ-Dihydroxy-∆5-Withanolides and Related Compounds 156 4.1.4 Other ∆5-Withanolides 157 4.1.5 Other Substitution Patterns 160 4.2 Other Withanolides with an Unmodified Skeleton 161 4.2.1 C-14, C-17, and C-20 Hydroxylated Withanolides and Related Compounds 161 4.2.2 C-18 Hydroxylated Withanolides 166 4.2.3 C-12 and C-21 Oxygenated Withanolides 167 4.2.4 Other Hydroxylated Withanolides 170 4.2.5 Cilistols and Related Withanolides 173 5 Withanolides with Modified Skeletons 175 5.1 Withanolides with Additional Rings Involving C-21 175 5.1.1 Withametelins and Sativolides 175 5.1.2 Acnistins 177 5.1.3 Withajardins 179 5.1.4 15,21-Cyclowithanolides (Norbornane Type) 180 5.2 Physalins and Withaphysalins 181 5.2.1 Normal Physalins 181 5.2.2 Neophysalins and Cyclophysalins 183 5.2.3 Revised Physalin Structures 183 5.2.4 Withaphysalins and Related Withanolides 184 5.3 Withanolides Containing an Aromatic Ring and Related Steroids 186 5.3.1 Aromatic Ring-D Withanolides and Related Steroids 186 5.3.2 Aromatic Ring-A Withanolides and 19-Hydroxywithanolides 189 5.4. Withanolides with a γ-Lactone Side Chain 190 5.4.1 Ixocarpalactones and Perulactones 190 5.4.2 Trechonolides 192 5.4.3 Spiranoid-γ-Lactones 196 5.4.4 Taccalonolides 197 5.5 18-Norwithanolides 199 5.5.1 Subtriflora-δ-Lactones and Related Withanolides 200 5.5.2 Subtriflora-γ-Lactones 200 5.5.3 Other 18-Norwithanolides 202 5.6 Spiranoid Withanolides at C-22 202 6 Chemical and Bio-transformations of Withanolides 203 6.1 Chemical Transformations 204 6.2 Photochemical Transformations 206 6.3 Biotransformations 207 7 Biological Activities of the Withanolides 210 7.1 Insecticidal Activities 211 7.1.1 Antifeedant and Growth Inhibition 212 7.1.2 Ecdysteroid Agonists and Antagonists 214 7.2 Phytotoxic Activities 214 7.3 Antiparasitic Activities 215 7.3.1 Trypanocidal Activity 215 7.3.2 Leishmanicidal Activity 216 7.4 Antimicrobial Activities 217 7.5 Anti-inflammatory and Glucocorticoid Related Activities 218 7.5.1 Anti-inflammatory Activity 218 7.5.2 Antistress Activity 220 7.5.3 Immunosuppressive and Immunomodulatory Activity 220 7.6 Cancer-Related Activities 221 7.6.1 Cytotoxicity 221 7.6.2 Cancer Chemopreventive Activity 223 7.6.3 Antiangiogenic Activity 224 7.6.4 Microtubule Stabilizing Activity 225 7.7 CNS-Related Activities 226 7.7.1 Synaptogenesis and Neuritic Outgrowth 226 7.7.2 Cholinesterase Inhibition 226 8 Chemotaxonomic Considerations 227 8.1 Tribe Physaleae 228 8.2 Tribes Hyoscyameae, Lycieae, and Solaneae 231 8.3 Tribe Datureae 231 8.4 Genera with Uncertain Positions in the Solanaceae Taxonomic System 231 References 234 Author Index 248 Subject Index 265 Front Matter....Pages i-xviii Chemistry and Biology of Rocaglamides (= Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae)....Pages 1-58 Chemistry of the Immunomodulatory Macrolide Ascomycin and Related Analogues....Pages 59-126 Withanolides and Related Steroids....Pages 127-229 Back Matter....Pages 231-253 Includes the three reviews that cover the advances in the chemistry and biology of withanolides, and review the chemistry and biology of the rocaglamide-type derivatives and related compounds, with emphasis on their structural diversity, biosynthesis, pharmacological significance and total synthesis.