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Concepts and Case Studies in Chemical Biology


Concepts and Case Studies in Chemical Biology


2. Aufl.

von: Herbert Waldmann, Petra Janning

74,99 €

Verlag: Wiley-VCH
Format: PDF
Veröffentl.: 26.06.2014
ISBN/EAN: 9783527675982
Sprache: englisch
Anzahl Seiten: 464

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Beschreibungen

Retaining the proven didactic concept of the successful "Chemical Biology - Learning through Case Studies", this sequel features 27 new case studies, reflecting the rapid growth in this interdisciplinary topic over the past few years.<br> Edited by two of the world's leading researchers in the field, this textbook introduces students and researchers to the modern approaches in chemical biology, as well as important results, and the techniques and methods applied. Each chapter presents a different biological problem taken from everyday lab work, elucidated by an international team of renowned scientists.<br> With its broad coverage, this is a valuable source of information for students, graduate students, and researchers working on the borderline between chemistry, biology, and biochemistry.<br>
<p>List of Contributors xvii</p> <p>Introduction and Preface xxv</p> <p>Abbreviations xxix</p> <p><b>1 Real-Time and Continuous Sensors of Protein Kinase Activity Utilizing Chelation-Enhanced Fluorescence 1<br /> </b><i>Laura B. Peterson and Barbara Imperiali</i></p> <p>1.1 Introduction 1</p> <p>1.2 The Biological Problem 1</p> <p>1.3 The Chemical Approach 3</p> <p>1.3.1 Chelation-Enhanced Fluorescence 3</p> <p>1.3.2 β-Turn-Focused Kinase Activity Sensors 7</p> <p>1.3.3 Recognition-Domain-Focused Kinase Activity Sensors 7</p> <p>1.3.4 Chimeric Kinase Activity Sensors 10</p> <p>1.4 Chemical Biological Research/Evaluation 12</p> <p>1.4.1 Kinetic Parameters 12</p> <p>1.4.2 Assessing Kinase Selectivity 12</p> <p>1.4.3 Kinase Profiling in Cell Lysates and Tissue Homogenates 14</p> <p>1.5 Conclusions 14</p> <p>References 15</p> <p><b>2 FLiK and FLiP: Direct Binding Assays for the Identification of Stabilizers of Inactive Kinase and Phosphatase Conformations 17<br /> </b><i>Daniel Rauh and Jeffrey R. Simard</i></p> <p>2.1 Introduction – The Biological Problem 17</p> <p>2.1.1 Kinase Inhibitors – Stabilizing Inactive Enzyme Conformations 17</p> <p>2.1.2 Monitoring Conformational Changes upon Ligand Binding 19</p> <p>2.2 The Chemical Approach 20</p> <p>2.3 Chemical Biological Research/Evaluation 23</p> <p>2.3.1 Finding the Unexpected 25</p> <p>2.3.2 Targeting Protein Interfaces – iFLiK 26</p> <p>2.3.3 Screening Akt 27</p> <p>2.3.4 Targeting Phosphatases – FLiP 29</p> <p>2.3.5 Lessons Learned from High-Throughput Screens 31</p> <p>2.4 Conclusions 34</p> <p>References 35</p> <p><b>3 Strategies for Designing Specific Protein Tyrosine Phosphatase Inhibitors and Their Intracellular Activation 37<br /> </b><i>Birgit Hoeger and Maja Köhn</i></p> <p>3.1 Introduction – The Biological Problem 37</p> <p>3.1.1 Chemical Inhibition of Protein Tyrosine Phosphatase Activity 37</p> <p>3.1.2 PTP1B as Inhibitor Target 40</p> <p>3.2 The Chemical Approach 41</p> <p>3.2.1 The Concept of Bivalent Ligands – Development of a Specific PTP1B Inhibitor 41</p> <p>3.2.2 Cell Permeability and Intracellular Activation of a Self-Silenced Inhibitor 43</p> <p>3.2.3 A Prodrug Strategy to Gain Cell Permeability 44</p> <p>3.3 Chemical Biological Research/Evaluation 45</p> <p>3.3.1 An Affinity-Based ELISA Assay to Identify Potent Binders 45</p> <p>3.3.2 Evaluation of Cell Permeability and Cellular Activity by Monitoring Insulin Receptor Signaling 47</p> <p>3.4 Conclusions 47</p> <p>References 48</p> <p><b>4 Design and Application of Chemical Probes for Protein Serine/Threonine Phosphatase Activation 51<br /> </b><i>Yansong Wang and Maja Köhn</i></p> <p>4.1 Introduction 51</p> <p>4.2 The Biological Problem 52</p> <p>4.3 The Chemical Approach 54</p> <p>4.4 Chemical Biological Research/Evaluation 57</p> <p>4.4.1 Selectivity of PDPs toward PP1 over PP2A and PP2B 57</p> <p>4.4.2 Studying the Functions of PP1 in Mitosis with PDPs 58</p> <p>4.4.3 Studying the Functions of PP1 in Ca 2+ Signaling with PDPs 59</p> <p>4.5 Conclusion 60</p> <p>References 60</p> <p><b>5 Autophagy: Assays and Small-Molecule Modulators 63<br /> </b><i>Gemma Triola</i></p> <p>5.1 Introduction 63</p> <p>5.2 The Biological Problem 65</p> <p>5.2.1 Assays 66</p> <p>5.2.2 Small-Molecule Modulators of Autophagy 67</p> <p>5.3 The Chemical Approach 68</p> <p>5.3.1 Assays 68</p> <p>5.4 Chemical Biological Evaluation 71</p> <p>5.5 Conclusion 80</p> <p>References 80</p> <p><b>6 Elucidation of Protein Function by Chemical Modification 83<br /> </b><i>Yaowen Wu and Lei Zhao</i></p> <p>6.1 Introduction 83</p> <p>6.2 The Biological Problem 84</p> <p>6.2.1 Small GTPases 84</p> <p>6.2.2 Autophagy 85</p> <p>6.3 The Chemical Approach 88</p> <p>6.3.1 Expressed Protein Ligation and Click Ligation 88</p> <p>6.3.2 Site-Specific Modification of Proteins 90</p> <p>6.3.3 Semisynthesis of Lipidated LC3 Protein 94</p> <p>6.4 Biological Research/Evaluation 97</p> <p>6.4.1 Thermodynamic Basis of Rab Membrane Targeting 97</p> <p>6.4.2 Monitoring Protein Unfolding and Refolding Using a Dual-Labeled Protein 99</p> <p>6.4.3 Semisynthetic Lipidated LC3 Protein Mediates Membrane Fusion 101</p> <p>6.5 Conclusion 103</p> <p>References 103</p> <p><b>7 Inhibition of Oncogenic K-Ras Signaling by Targeting K-Ras–PDEδ Interaction 105</b><br /><i>Gemma Triola</i></p> <p>7.1 Introduction 105</p> <p>7.2 The Biological Problem 105</p> <p>7.3 The Chemical Approach 108</p> <p>7.3.1 Chemical Synthesis of Proteins 108</p> <p>7.3.2 Synthesis of Lipidated Ras Peptides 109</p> <p>7.3.3 Synthesis of K-Ras4B Protein 110</p> <p>7.4 Chemical Biological Evaluation 113</p> <p>7.5 Conclusions 120</p> <p>References 121</p> <p><b>8 Development of Acyl Protein Thioesterase 1 (APT1) Inhibitor Palmostatin B That Revert Unregulated H/N-Ras Signaling 123<br /> </b><i>Frank J. Dekker, Nachiket Vartak, and Christian Hedberg</i></p> <p>8.1 Introduction 123</p> <p>8.2 TheBiologicalProblem–TheRoleofAPT1inRasSignaling 123</p> <p>8.3 The Chemical Approach 125</p> <p>8.3.1 The Challenge to Make Small-Molecule Modulators of Protein Function 125</p> <p>8.3.2 Bioinformatics – Target Clustering 126</p> <p>8.3.3 Compound Collection Synthesis 126</p> <p>8.3.4 In vitro Enzyme Inhibition Studies 129</p> <p>8.3.5 Mechanistic Investigation on APT1 Inhibition 129</p> <p>8.4 Chemical Biological Research/Evaluation 130</p> <p>8.4.1 In vivo Enzyme Inhibition Studies 130</p> <p>8.4.2 Palmostatins Inhibit Depalmitoylation of Ras GTPases 132</p> <p>8.4.3 Palmostatins Disturb the Localization of Ras GTPases 134</p> <p>8.4.4 Palmostatins Inhibit Downstream Signaling of Ras GTPases 135</p> <p>8.5 Conclusions 136</p> <p>References 138</p> <p><b>9 Functional Analysis of Host–Pathogen Posttranslational Modification Crosstalk of Rab Proteins 141<br /> </b><i>Christian Hedberg, Roger S. Goody, and Aymelt Itzen</i></p> <p>9.1 Introduction 141</p> <p>9.2 The Biological Problem 141</p> <p>9.2.1 Posttranslational Modifications 141</p> <p>9.2.2 Adenylylation of Small GTPases 142</p> <p>9.3 The Chemical Approach 143</p> <p>9.3.1 Preparative Adenylylation of Rab 1 144</p> <p>9.3.2 Identification of the Site of Adenylylation 145</p> <p>9.3.3 Synthesis of Site-Specifically Adenylylated Peptides 146</p> <p>9.3.4 Generation and Application of α-AMP-Tyr/Ser/ Thr-Antibodies 146</p> <p>9.3.5 Detection of Adenylylation by MS Techniques 150</p> <p>9.4 Chemical Biological Research/Evaluation 150</p> <p>9.4.1 Functional Consequences of Adenylylation 151</p> <p>9.4.2 Detection of Adenylylated Proteins in Mammalian Cell Lysates 152</p> <p>9.5 Conclusions 152</p> <p>References 153</p> <p><b>10 Chemical Biology Approach to Suppression of Statin-Induced Muscle Toxicity 155<br /> </b><i>Bridget K. Wagner</i></p> <p>10.1 Introduction 155</p> <p>10.2 The Biological Problem 155</p> <p>10.3 The Chemical Approach 157</p> <p>10.3.1 Generation of a Compendium of Mitochondrial Activity 157</p> <p>10.4 Chemical Biology Research/Evaluation 158</p> <p>10.4.1 Chemical Epistasis Analysis 158</p> <p>10.4.2 High-Throughput Screening 160</p> <p>10.5 Conclusion 161</p> <p>References 162</p> <p><b>11 A Target Identification System Based on MorphoBase, ChemProteoBase, and Photo-Cross-Linking Beads 163<br /> </b><i>Hiroyuki Osada, Makoto Muroi, Yasumitsu Kondoh, and Yushi Futamura</i></p> <p>11.1 Introduction 163</p> <p>11.2 The Biological Problem 163</p> <p>11.3 Chemical Approaches 165</p> <p>11.3.1 MorphoBase 165</p> <p>11.3.2 ChemProteoBase 166</p> <p>11.3.3 Photo-Cross-Linking Beads 169</p> <p>11.4 Chemical Biological Research/Evaluation 171</p> <p>11.4.1 Npd6689/npd8617/npd 8969 171</p> <p>11.4.2 Bns- 22 172</p> <p>11.4.3 Methyl-Gerferin 173</p> <p>11.4.4 Xanthohumol 173</p> <p>11.5 Conclusion 174</p> <p>References 174</p> <p><b>12 Activity-Based Proteasome Profiling in Medicinal Chemistry and Chemical Biology 177<br /> </b><i>Gerjan de Bruin, Nan Li, Guillem Paniagua, Lianne Willems, Bo-Tao Xin, Martijn Verdoes, Paul Geurink, Wouter van der Linden, Mario van der Stelt, Gijs van der Marel, Herman Overkleeft, and Bogdan Florea</i></p> <p>12.1 Introduction 177</p> <p>12.2 The Biological Problem 177</p> <p>12.3 The Chemical Approach 179</p> <p>12.3.1 Comparative and Competitive Activity-Based Proteasome Profiling 181</p> <p>12.3.2 Two-Step Activity-Based Proteasome Profiling 183</p> <p>12.4 Biological Research/Evaluation 186</p> <p>12.4.1 Identification of Proteasome Active Sites 187</p> <p>12.5 Conclusions 188</p> <p>References 189</p> <p><b>13 Rational Design of Activity-Based Retaining β-Exoglucosidase Probes 191<br /> </b><i>Kah-Yee Li, Wouter Kallemeijn, Jianbing Jiang, Marthe Walvoort, Lianne Willems, Thomas Beenakker, Hans van den Elst, Gijs van der Marel, Jeroen Codée, Hans Aerts, Bogdan Florea, Rolf Boot, Martin Witte, and Herman Overkleeft</i></p> <p>13.1 Introduction 191</p> <p>13.2 The Biological Problem 191</p> <p>13.3 The Chemical Approach 192</p> <p>13.3.1 Development of a Human Acid Glucosylceramidase Activity-Based Probe 195</p> <p>13.3.2 Cyclophellitol Aziridine Is a Broad-Spectrum Activity-Based Retaining β-Exoglucosidase Probe 198</p> <p>13.4 Biological Research/Evaluation 201</p> <p>13.4.1 In situ Monitoring of Active-Site-Directed GBA Chemical/Pharmacological Chaperones 201</p> <p>13.4.2 Mapping of Human Retaining β-Glucosidase Active Site Residues 203</p> <p>13.5 Conclusions 203</p> <p>References 205</p> <p><b>14 Modulation of ClpP Protease Activity: from Antibiotics to Antivirulence 207<br /> </b><i>Malte Gersch and Stephan A. Sieber</i></p> <p>14.1 Introduction 207</p> <p>14.2 The Biological Problem 207</p> <p>14.3 The Chemical Approach 209</p> <p>14.4 The Discovery of a Novel Antibiotic Mechanism 210</p> <p>14.4.1 Target Identification 210</p> <p>14.4.2 Target Validation 214</p> <p>14.4.3 Mechanism of Action 214</p> <p>14.5 The Antivirulence Approach 215</p> <p>14.6 Conclusions 219</p> <p>References 219</p> <p><b>15 Affinity-Based Isolation of Molecular Targets of Clinically Used Drugs 221<br /> </b><i>Shin-ichi Sato and Motonari Uesugi</i></p> <p>15.1 Introduction – The Biological/Medicinal Problem 221</p> <p>15.2 The Chemical Approach 221</p> <p>15.3 Chemical Biological Research 225</p> <p>15.3.1 Lessons from Isolation of FK506-Binding Protein (FKBP) Using Fk 506 225</p> <p>15.3.2 Lessons from Isolation of Cereblon (CRBN) Using Thalidomide 226</p> <p>15.3.3 Lessons from Isolation of Glyoxalase 1 (GLO1) Using Indomethacin 227</p> <p>15.4 Conclusion 228</p> <p>References 228</p> <p><b>16 Identification of the Targets of Natural-Product-Inspired Mitotic Inhibitors 231<br /> </b><i>Kamal Kumar and Slava Ziegler</i></p> <p>16.1 Introduction 231</p> <p>16.2 The Biological Problem 231</p> <p>16.2.1 Mitosis and Modulation of Mitosis by Small Molecules 231</p> <p>16.2.2 Phenotypic Screening 234</p> <p>16.2.3 Target Identification and Confirmation 236</p> <p>16.3 The Chemical Approach 236</p> <p>16.3.1 Design and Synthesis of Natural-Product-Inspired Compound Collections 236</p> <p>16.4 Chemical Biological Evaluation 239</p> <p>16.4.1 Phenotypic Screen for Mitotic Inhibitors 239</p> <p>16.4.2 Identification of the Target Protein(s) of Centrocountin 1 241</p> <p>16.4.3 Confirmation of the Target Candidates 243</p> <p>16.5 Conclusion 246</p> <p>References 247</p> <p><b>17 Finding a Needle in a Haystack. Identification of Tankyrase, a Novel Therapeutic Target of the Wnt Pathway Using Chemical Genetics 249<br /> </b><i>Atwood K. Cheung and Feng Cong</i></p> <p>17.1 Introduction 249</p> <p>17.2 The Biological Problem 250</p> <p>17.2.1 Modulating the Wnt Signaling Pathway for Cancer Therapeutics 250</p> <p>17.3 The Chemical Approach 251</p> <p>17.3.1 Screening Approach 251</p> <p>17.3.2 Chemical Proteomics Target Identification 251</p> <p>17.3.3 Target Validation 254</p> <p>17.4 Chemical Biological Research/Evaluation 254</p> <p>17.4.1 Identification of XAV939 as a Wnt Pathway Inhibitor 254</p> <p>17.4.2 XAV939 Regulates Axin Protein Levels by Inhibiting Tankyrases 256</p> <p>17.4.3 Validation of Tankyrase as the Target for XAV 939 257</p> <p>17.4.4 XAV939 Inhibits TNKS-Mediated Ubiquitination and PARsylation of Axin 258</p> <p>17.4.5 TNKS Inhibitor Blocks the Growth of Colon Cancer Cells 258</p> <p>17.4.6 Crystal Structure of XAV939 and TNKS 1 259</p> <p>17.5 Conclusion 260</p> <p>References 261</p> <p><b>18 The Identification of the Molecular Receptor of the Plant Hormone Abscisic Acid 265<br /> </b><i>Julian Oeljeklaus and Markus Kaiser</i></p> <p>18.1 Introduction 265</p> <p>18.2 The Biological Problem 267</p> <p>18.3 The Chemical Genetics Approach 268</p> <p>18.3.1 Identification of a Synthetic ABA-Agonist Using a Chemical Genetics Screen 268</p> <p>18.3.2 Target Gene Identification of Pyrabactin 270</p> <p>18.4 The Chemical Biology Approach 273</p> <p>18.4.1 Elucidation of the Functional ABA-Receptor Complex 273</p> <p>18.4.2 Validation and Further Structural Studies on the ABA–Receptor Mechanism 279</p> <p>18.5 Conclusion 282</p> <p>References 283</p> <p><b>19 Chemical Biology in Plants: Finding New Connections between Pathways Using the Small Molecule Sortin 1 285<br /> </b><i>Chunhua Zhang, Glenn R. Hicks, and Natasha V. Raikhel</i></p> <p>19.1 Introduction 285</p> <p>19.2 The Biological Problem 285</p> <p>19.3 The Chemical Approach 286</p> <p>19.3.1 Chemical Library Screening 286</p> <p>19.3.2 Identification of Pathway(s) that are Targeted by Sortin 1 287</p> <p>19.3.3 Sortin1-Hypersensitive Mutants Link Vacuolar Trafficking to Flavonoids Metabolism 289</p> <p>19.3.4 Sortin1 Resembles the Effects of Buthionine Sulfoximine (bso) 290</p> <p>19.3.5 Substructures Required for Sortin1 Bioactivity 290</p> <p>19.4 Biological Research/Evaluation 292</p> <p>19.4.1 Chemicals That Disrupt Yeast Vacuolar Trafficking also Target Plant Vacuolar Trafficking Pathway 292</p> <p>19.4.2 Sortin1 Disrupts Vacuolar Trafficking of both Proteins and Flavonoids 292</p> <p>19.4.3 Mechanism of Sortin1 Action 293</p> <p>19.5 Conclusion 293</p> <p>Acknowledgment 293</p> <p>References 294</p> <p><b>20 Selective Targeting of Protein Interactions Mediated by BET Bromodomains 295<br /> </b><i>Susanne Müller, Hannah Lingard, and Stefan Knapp</i></p> <p>20.1 Introduction 295</p> <p>20.2 The Biological Problem 295</p> <p>20.2.1 Druggability of the BET Acetyl-Lysine-Binding Pocket 297</p> <p>20.3 The Chemical Approach 298</p> <p>20.3.1 Development of High-Throughput Assays 298</p> <p>20.3.2 Secondary Screening Assays 300</p> <p>20.3.3 Cellular Testing 300</p> <p>20.3.4 Discovery of Acetyl-Lysine Competitive Inhibitors 300</p> <p>20.3.4.1 Acetyl-Lysine Mimetic Fragments Crystallized with Bromodomains 300</p> <p>20.3.4.2 Discovery of Benzo- and Thienodiazepines 302</p> <p>20.3.4.3 Other BET Inhibitors 302</p> <p>20.4 Chemical/Biological Investigations 305</p> <p>20.5 Conclusion 305</p> <p>References 306</p> <p><b>21 The Impact of Distant Polypharmacology in the Chemical Biology of PARPs 309<br /> </b><i>Albert A. Antolín and Jordi Mestres</i></p> <p>21.1 Introduction 309</p> <p>21.2 The Biological Problem 309</p> <p>21.2.1 Studying the Function of Proteins Using Chemical Probes with Unknown Polypharmacology 309</p> <p>21.2.2 Development of Poly(ADP-Ribose)Polymerase-1 (PARP-1) Chemical Probes and Follow-on Drugs 311</p> <p>21.2.3 Unexpected Differential Effects between PARP Inhibitors 312</p> <p>21.3 The Chemical Approach 312</p> <p>21.3.1 Molecular Informatics 312</p> <p>21.3.2 In silico Target Profiling 313</p> <p>21.4 Chemical Biological Research/Evaluation 315</p> <p>21.4.1 In silico Identification and In Vitro Confirmation of Novel Targets for Pj 34 315</p> <p>21.4.2 Implications for the Use of PJ34 and Follow-on Drugs 316</p> <p>21.5 Conclusions 319</p> <p>References 320</p> <p><b>22 Splicing Inhibitors: From Small Molecule to RNA Metabolism 323<br /> </b><i>Tilman Schneider-Poetsch and Minoru Yoshida</i></p> <p>22.1 Introduction 323</p> <p>22.2 The Biological Problem 323</p> <p>22.2.1 Splicing 323</p> <p>22.2.2 Alternative Splicing 325</p> <p>22.2.3 mRNA Processing 326</p> <p>22.3 The Chemical Approach 326</p> <p>22.3.1 The First Splicing Inhibitors 326</p> <p>22.3.2 Inhibition 328</p> <p>22.4 Chemical Biological Research/Evaluation 331</p> <p>22.4.1 Cellular Effect 331</p> <p>22.4.2 Clinical Utility 331</p> <p>22.5 Conclusion 333</p> <p>References 333</p> <p><b>23 Photochemical Control of Gene Function in Zebrafish Embryos with Light-Activated Morpholinos 337<br /> </b><i>Qingyang Liu and Alexander Deiters</i></p> <p>23.1 Introduction 337</p> <p>23.2 The Biological Problem 337</p> <p>23.3 The Chemical Approach 340</p> <p>23.3.1 Hairpin-Caged MO 340</p> <p>23.3.2 Sense-Caged MO 342</p> <p>23.3.3 Nucleobase-Caged MO 344</p> <p>23.3.4 Cyclic-Caged MO 345</p> <p>23.4 Chemical Biological Research/Evaluation 347</p> <p>23.5 Conclusion 349</p> <p>Acknowledgment 349</p> <p>References 349</p> <p><b>24 Life Cell Imaging of mRNA Using PNA FIT Probes 351<br /> </b><i>Andrea Knoll, Susann Kummer, Felix Hövelmann, Andreas Herrmann, and Oliver Seitz</i></p> <p>24.1 Introduction 351</p> <p>24.2 The Biological Problem 351</p> <p>24.2.1 Selection of Biological Targets 352</p> <p>24.3 The Chemical Approach 352</p> <p>24.3.1 Design and Synthesis of PNA FIT Probes 352</p> <p>24.4 Chemical Biological Research/Validation 355</p> <p>24.4.1 Probe Validation by Fluorescence Measurement 355</p> <p>24.4.2 Quantitation of Viral mRNA by qPCR 356</p> <p>24.4.3 Imaging of Viral mRNA in Living Cells 358</p> <p>24.5 Conclusion 361</p> <p>References 362</p> <p><b>25 Targeting the Transcriptional Hub β-Catenin Using Stapled Peptides 365<br /> </b><i>Tom N. Grossmann and Gregory L. Verdine</i></p> <p>25.1 Introduction 365</p> <p>25.2 The Biological Problem 365</p> <p>25.2.1 Canonical Wnt Signaling 366</p> <p>25.2.2 Oncogenic Activation of Wnt Signaling 366</p> <p>25.3 The Chemical Approach: Hydrocarbon Peptide Stapling 368</p> <p>25.4 The Biological Approach: Phage-Display-Based Optimization 371</p> <p>25.5 Biochemical and Biological Evaluation 375</p> <p>25.6 Conclusions 376</p> <p>References 377</p> <p><b>26 Diversity-Oriented Synthesis: Developing New Chemical Tools to Probe and Modulate Biological Systems 379<br /> </b><i>Warren R. J. D. Galloway, David Wilcke, Feilin Nie, Kathy Hadje-Georgiou, Luca Laraia, and David R. Spring</i></p> <p>26.1 Introduction 379</p> <p>26.2 The Biological Problem 379</p> <p>26.2.1 How to Discover New Chemical Modulators of Biological Function? 379</p> <p>26.2.2 Sources of Small Molecules for Screening 380</p> <p>26.2.2.1 Natural Products 380</p> <p>26.2.2.2 Chemical Synthesis and the Need for Structural Diversity 380</p> <p>26.3 The Chemical Approach 382</p> <p>26.3.1 Diversity-Oriented Synthesis 382</p> <p>26.3.1.1 DOS and Scaffold Diversity 382</p> <p>26.4 Chemical Biology Research 384</p> <p>26.4.1 DOS as a Tool for Identifying New Modulators of Mitosis 384</p> <p>26.4.1.1 DOS Library Synthesis 384</p> <p>26.4.1.2 Biological Studies: Phenotypic Screening for Antimitotic Effects 384</p> <p>26.4.1.3 Biological Studies: Target Identification 385</p> <p>26.5 Conclusion 388</p> <p>References 388</p> <p><b>27 Scaffold Diversity Synthesis with Branching Cascades Strategy 391<br /> </b><i>Kamal Kumar</i></p> <p>27.1 Introduction 391</p> <p>27.2 The Biological/Pharmacological Problem: Discovering Small Bioactive Molecules 391</p> <p>27.3 The Chemical Approach: Scaffold Diversity 395</p> <p>27.3.1 Beyond the Biased Exploration of Chemical Space 395</p> <p>27.3.2 Scaffold Diversity Synthesis 397</p> <p>27.4 Chemical/Biological Evaluation – Branching Cascades Strategy in Scaffold Diversity Synthesis 399</p> <p>27.5 Conclusions 409</p> <p>References 410</p> <p>Index 415</p>
Herbert Waldmann obtained his PhD in organic chemistry from the University of Mainz, Germany, in 1985 working with Professor H. Kunz, after which he completed a postdoctoral appointment with Professor G. Whitesides at Harvard University (USA). He was appointed as Professor of Organic Chemistry at the University of Bonn (1991), full Professor of Organic Chemistry at the University of Karlsruhe (1993), and Director at the Max-Planck-Institute of Molecular Physiology Dortmund and Professor of Organic Chemistry at the University of Dortmund, Germany, in 1999. He has received numerous awards, e.g. the Otto-Bayer-Award (2001), the Max Bergmann Medal (2003), and recently the Emil-Fischer-Prize (2012). His research interests lie in bioactive compound development, target identification, and the chemical biology of Ras proteins. <br> <br> Petra Janning studied chemistry at the University of Munster, Germany, and did her PhD thesis at the Institute for Analytical Sciences in Dortmund, Germany in 1995. After different positions where she worked in the area of analytical chemistry and on the borderline between chemistry and biology she joined the Max-Planck-Institute of Molecular Physiology, Dortmund, in the department of Professor H. Waldmann, where she is currently working. She is responsible for the Bioorganic Practical Course and the analytics in the department. She focused her work on mass spectrometry based methods in proteome research in particular in target protein identification of small molecules. <br>
Retaining the proven didactic concept of the successful "Chemical Biology - Learning through Case Studies", this sequel features 27 new case studies, reflecting the rapid growth in this interdisciplinary topic over the past few years.<br> Edited by two of the world's leading researchers in the field, this textbook introduces students and researchers to the modern approaches in chemical biology, as well as important results, and the techniques and methods applied. Each chapter presents a different biological problem taken from everyday lab work, elucidated by an international team of renowned scientists.<br> With its broad coverage, this is a valuable source of information for students, graduate students, and researchers working on the borderline between chemistry, biology, and biochemistry.<br>

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