Drug Discovery from NatureS. Grabley, R. Thiericke Springer Science & Business Media, 26 лист. 1998 р. - 347 стор. Drug discovery strategies for both pharmaceutical and agrochemical applications are at a stage of rapid development. More than 30 % of sales of drugs for human consumption worldwide are of plant origin. This unique book covers the present status and future potential of natural products in drug discovery. It provides the reader with recent information regarding the impact on drug discovery, development and strategies, technical and automation aspects, and methods based on biochemistry as well as molecular biology, highlighting compounds from natural sources. Special emphasis is placed on the various strategies to gain access to natural compounds and combinatorial approaches by making use of both synthetic and biological methods. Because the renewed interest in the use of natural sources in drug discovery is an important supplement to combinatorial and parallel synthesis approaches, this book is timely and will have a great scientific impact. |
Зміст
The Impact of Natural Products on Drug Discovery | 3 |
12 Historical Issues of Drugs from Nature | 5 |
122 Acetysalicylic Acid | 7 |
123 Antibiotics | 9 |
124 Further Developments | 10 |
13 New Drugs from Microorganisms | 11 |
133 Antihypercholesterolemic Drugs | 13 |
134 Antidiabetic Drugs | 16 |
968 Ripostatin | 163 |
969 Sorangiolid | 164 |
9611 Crocacin | 165 |
9612 Gephyronic Acid | 166 |
9614 Cittilin | 167 |
9615 Myxochromid | 168 |
97 Derivatives and Total Syntheses of Myxobacterial Compounds | 169 |
99 Not all Myxobacterial Species are Equally Good Producers | 171 |
Hormone Antagonists | 17 |
136 Anticancer Drugs | 18 |
14 New Drugs from Plants | 20 |
142 Anticancer Drugs | 22 |
143 Drugs for Various Applications | 25 |
15 The Marine Environment | 26 |
16 Perspectives | 31 |
References | 33 |
Recent Developments in Drug Discovery Technologies | 38 |
22 Potential Impact of Genomic Sciences | 39 |
222 Analytical Methods | 40 |
223 Applicational Aspects of Gene Function Analysis | 41 |
23 HighThroughput Screening Assays | 43 |
24 Sample Supply in HighThroughput Screening | 46 |
References | 47 |
Technical Aspects | 49 |
A Central Natural Product Pool New Approach in Drug Discovery Strategies | 51 |
32 Concept | 52 |
Proprietary Rights and Other Guidelines | 53 |
34 Incentives | 54 |
References | 55 |
Automation Strategies in Drug Discovery | 56 |
42 History | 57 |
43 Economic Aspects | 58 |
44 Sample Sourcing | 60 |
442 Natural Sources | 62 |
46 Screening Systems | 64 |
47 DataHandling | 68 |
48 Conclusion | 69 |
Synergistic Use of Combinatorial and Natural Product Chemistry | 72 |
52 Combinatorial Chemistry Short Summary | 73 |
521 Solid Phase Synthesis | 74 |
5212 Linkers | 75 |
523 Design of Libraries | 76 |
524 Product Quality | 77 |
53 Biopolymers | 78 |
533 Oligosaccharides | 80 |
534 Polyketides | 81 |
54 Natural Product Derivatives | 82 |
541 NonAlkaloid Natural Product Derivatives | 84 |
5412 Balanol | 85 |
542 Alkaloids | 87 |
5422 Spiroindolines | 88 |
5425 Quinolines | 89 |
5425 Isoqulnalines | 90 |
5427 Quinazolinediones | 91 |
553 Other Natural Products as Templates | 93 |
56 Future Potential | 101 |
Supercritical Fluid Extraction SFE Novel Strategies in the Processing of Biomaterials | 106 |
62 Properties of Supercritical Fluids SF | 107 |
63 Supercritical Carbon Dioxide SCCO | 108 |
64 Extraction of Polar and Ionic Compounds | 109 |
66 Potential and Applications of SFE for the Pharmaceutical Industry | 110 |
662 Extraction of Antibiotics | 111 |
67 Concluding Remarks | 112 |
Natural Products from Microbial Sources | 115 |
From Past to Present | 117 |
73 The 1960s and 1970s | 118 |
74 Secondary Metabolites as Pharmacological Agents and New Screening Approaches | 119 |
75 Biosynthetic Modifications of Structures and Outlook | 120 |
References | 121 |
CHAPTER 8 The Chemical Screening Approach | 124 |
83 PhysicoChemical Screening | 128 |
84 Chemical Screening | 130 |
842 New Metabolites | 132 |
85 Further Development | 139 |
86 Discussion | 141 |
862 Future Potential | 144 |
Myxobacteria as Producers of Secondary Metabolites | 149 |
92 Myxobacteria are Common but Unusual Soil Bacteria | 150 |
93 Many Interesting Substances have been Found in Myxobacteria | 154 |
94 Myxobacterial Compounds Belong to Quite Different Chemical Classes | 155 |
96 Examples of More Recently Discovered Myxobacterial Compounds | 156 |
962 Epothilon | 157 |
963 Chondramid | 159 |
965 Ratjadon | 160 |
966 Disorazol | 161 |
967 Chivosazol | 162 |
910 The Genetics of Myxobacterial Secondary Metabolism | 174 |
9103 Myxovirescin | 175 |
911 A Historical Note | 176 |
References | 177 |
Trends in Marine Biotechnology | 180 |
103 Isolation and Culturing of Marine Microorganisms | 181 |
104 Natural Product Chemistry and Biological Activity of Marine Microorganism Derived Secondary Metabolites | 182 |
105 The Future | 185 |
Biochemistry and Molecular Biology Based Methods | 189 |
Structure Modification via Biological Derivatization Methods | 191 |
112 Biological Derivatization Methods and History | 192 |
114 PrecursorDirected Biosynthesis | 194 |
115 NonEnymatic Biotransformation | 198 |
117 Enzyme inhibition | 199 |
118 Mutasynthesis | 200 |
119 Hybrid Natural Products by Genetic Engineering | 201 |
1110 Enzymatic Catalysis | 202 |
11102 Reconstitution of Biosynthetic Pathways In Vitro | 203 |
11103 Enzymatic Catalysis in Carbohydrate Synthesis | 204 |
1111 Conclusion | 206 |
References | 209 |
Molecular Biological Aspects of Antibiotic Biosynthesis | 215 |
122 Strategies for Cloning Antibiotic Biosynthesis Genes | 217 |
1222 Hybridization with Heterologous Probes | 218 |
1223 Cloning Biosynthetic Genes via Resistance Genes | 219 |
1224 Reverse Genetics | 220 |
1225 Cloning Based on Consensus Sequences | 221 |
1232 Altering the Regulation of Gene Transcription | 222 |
1233 Improving Product Spectrum | 223 |
1234 Reengineering Biosynthesis to Produce New Compounds | 225 |
124 Future Prospects and Limitations | 227 |
1241 Combinatorial Biosynthesis | 229 |
1243 Expression of Genes from Uncultivable Organisms | 230 |
Combinatorial Biosynthesis of Antibiotics | 233 |
1322 Basic Requirements for the Production of Hybrid Antibiotics | 236 |
133 Hybrid Antibiotics Produced by Combinatorial Biosynthesis | 237 |
1332 By Manipulation of Iterative Type II Polyketide Synthase Genes | 244 |
1333 By Manipulation of Genes for the Polyketide Tailoring Enzymes | 248 |
1334 By Manipulation of Oligopeptide Synthetase Genes | 251 |
References | 252 |
Aspects in Application | 255 |
Impact of Natural Products on Cell Biology LowMolecular Mass Effectors of Folding Helper Proteins | 257 |
142 PeptidylProlyl cistrans Isomerases | 259 |
1422 Prolyl Isomerizations as Slow Steps in Protein Folding | 260 |
1423 Classification and Properties of Peptidyl Prolyl cistrans Isomerases | 261 |
143 Natural Inhibitors of Peptidyl Prolyl cistrans Isomerases | 263 |
1432 FK506 | 268 |
1433 Rapamycin | 269 |
1434 Meridamycin Antascomicins Hymenistatin | 272 |
144 The Gain of Function Model of Immunosuppression | 275 |
145 Summary | 277 |
Novel Antibacterial Drugs from Microorganisms | 281 |
152 Directed Screens for New Antibiotics and SiteDirected New Antibacterials | 282 |
153 New NarrowSpectrum Antibiotics | 284 |
154 New Structural Variations of Antibacterial Lead Structures | 287 |
1542 Macrolides | 289 |
1543 Tetracyclines | 290 |
1545 Ansamycins | 291 |
155 Bacteriocins and Antibiotics | 292 |
1551 Polyethers | 293 |
157 Summary and Outlook | 296 |
New Antibiotics with Novel Mode of Action | 302 |
162 Antibiotics with Novel Mode of Action from Old Classes? | 303 |
163 Approaches that Target the Resistance Mechanism Itself | 305 |
164 New Antibacterial Targets | 306 |
165 Conclusion | 309 |
Synthetic Combinatorial Libraries A New Tool for Antimicrobial Agent Discovery | 311 |
1722 Peptide SCL Generation | 312 |
1723 Strategies for the Identification of Active Peptides from an SCL | 313 |
173 Antimicrobial Peptides Derived from SCLs | 315 |
175 Conclusions | 317 |
Strobilurins and Oudemansins | 320 |
183 Biological Activities Mode of Action | 322 |
184 Syntheses of Strobilurins and Oudemansins | 323 |
185 Structural Requirements for the Antifungal Activities | 329 |
332 | |
335 | |
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Загальні терміни та фрази
Acad Sci USA actinomycetes amino acids analogues Angew Chem anti antibacterial antifungal antimicrobial application approach assays avermectins bacteria binding Biochem Biol biological activities biosynthetic biosynthetic gene biosynthetic pathways Biotechnology cells CH₂ CH3 CH3 CH3 OH Chem Chem Soc chemical screening cloned combinatorial chemistry complex compounds culture cyclosporin derivatives drug discovery enzymes epóthilon epothilone erythromycin extraction FKBPS formation gene cluster genetic Grabley H₂C high-throughput screening Höfle G Hopwood Houghten RA hybrid antibiotics inhibition inhibitors isolated libraries Liebigs Ann Chem lovastatin macrolide marine metabolism microbial Microbiol microorganisms molecular molecules mutant myxobacteria Natl Acad Sci natural products NH₂ novel OCH3 OH CH3 OH OH OH Omura organisms oudemansin paclitaxel penicillin peptide pharmaceutical polyketide Proc Natl Acad protein rapamycin reaction receptor Reichenbach Robotics sample secondary metabolites sequence solid phase Sorangium cellulosum soraphen strains strategies Streptomyces strobilurin substrate target Tetrahedron Lett Thiericke tion yield Zähner H Zeeck ОН
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