Holdings: Combinatorial chemistry

Combinatorial chemistry: from theory to application

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Bibliographic Details
Format:	Book
Language:	English
Published:	Weinheim Wiley-VCH 2006
Edition:	2., rev. ed.
Series:	Methods and principles in medicinal chemistry 26
Subjects:	Chimie combinatoire - Technique Composés organiques - Synthèse Combinatorial Chemistry Techniques Combinatorial chemistry Kombinatorische Synthese
Online Access:	Inhaltsverzeichnis
Physical Description:	XXII, 672 S. Ill., graph. Darst.
ISBN:	3527306935

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adam_text	WILLI BANNWARTH, BERTHOLD HINZEN (EDS.) COMBINATORIAL CHEMISTRY FROM THEORY TO APPLICATION SECOND REVISED EDITION WILEY- VCH WILEY-VCH VERLAG GMBH & CO. KGAA SERIES EDITORS: PROF. DR. RAIMUND MANNHOLD BIOMEDICAL RESEARCH CENTER MOLECULAR DRUG RESEARCH GROUP HEINRICH-HEINE-UNIVERSITAET UNIVERSTAETSSTRASSE 1 40225 DUESSELDORF GERMANY RAIMUND.MANNHOLD@UNI-DUESSELDORF.DE PROF. DR. HUGO KUBINYI DONNERSBERGSTRASSE 9 67256 WEISENHEIM AM SAND GERMANY KUBINYI@T-ONLINE.DE PROF. DR. GERD FOLKERS COLLEGIUM HELVETICUM STW/ETH ZENTRUM 8092 ZUERICH SWITZERLAND FOLKERS @ COLLEGIUM. ETHZ.CH VOLUME EDITORS: PROF. DR. WILLI BANNWARTH INSTITUT FUER ORG. CHEMIE UND BIOCHEMIE UNIVERSITAET FREIBURG ALBERTSTRASSE 21 79104 FREIBURG GERMANY WILLI.BANNWARTH@ORGANIK.CHEMIE.UNI- FREIBURG.DE DR. BERTHOLD HINZEN BAYER AG POSTFACH 101709 42096 WUPPERTAL BERTHOLD.HINZEN@BAYERHEALTHCARE.COM THIS BOOK WAS CAREFULLY PRODUCED. NEVERTHE- LESS, AUTHORS, EDITORS AND PUBLISHER DO NOT WARRANT THE INFORMATION CONTAINED THEREIN TO BE FREE OF ERRORS. READERS ARE ADVISED TO KEEP IN MIND THAT STATEMENTS, DATA, ILLUSTRA- TIONS, PROCEDURAL DETAILS OR OTHER ITEMS MAY INADVERTENTLY BE INACCURATE. COVER ILLUSTRATION: LIBRARY OF CONGRESS CARD NO. APPLIED FBR. BRITISH LIBRARY CATALOGUING-IN-PUBLICATION DATA: A CATALOGUE RECORD FOR THIS BOOK IS AVAILABLE FROM THE BRITISH LIBRARY DIE DEUTSCHE BIBLIOTHEK - CIP CATALOGUING- IN-PUBLICATION-DATA: A CATALOGUE RECORD FOR THIS PUBLICATION IS AVAILABLE FROM DIE DEUTSCHE BIBLIOTHEK ISBN 3-527-30693-5 2006 WILEY-VCH VERLAG GMBH & CO. KGAA, WEINHEIM PRINTED ON ACID-FREE AND CHLORINE-FREE PAPER ALL RIGHTS RESERVED (INCLUDING THOSE OF TRANS- LATION INTO OTHER LANGUAGES). NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM - BY PHOTOPRINTING, MICROFILM, OR ANY OTHER MEANS - NOR TRANSMITTED OR TRANSLATED INTO A MACHINE LANGUAGE WITHOUT WRITTEN PERMIS- SION FROM THE PUBLISHERS. REGISTERED NAMES, TRADEMARKS, ETC. USED IN THIS BOOK, EVEN WHEN NOT SPECIFICALLY MARKED AS SUCH, ARE NOT TO BE CONSIDERED UNPROTECTED BY LAW. COVER: GRAFIK-DESIGN SCHULZ, FUSSGOENHEIM COMPOSITION: TYPOMEDIA GMBH, OSTFILDEM PRINTING: STRAUSS GMBH, MOERLENBACH BOOKBINDING: LITGES & DOPF BUCHBINDEREI GMBH, HEPPENHEIM PRINTED IN THE FEDERAL REPUBLIC OF GERMANY. TABLE OF CONTENTS 1 1.1 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.3 1.3.1 1.3.2 1.3.3 1.4 1.4.1 1.5 1.5.1 1.5.2 1.6 1.7 2 2.1 2.2 2.2.1 2.2.2 2.2.2.1 2.2.2.2 2.2.2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.3 2.2.3.1 2.2.3.2 PREFACE GENERAL INTRODUCTION LIST OF AUTHORS PURIFICATION PRINCIPLES IN HIGH-SPEED SOLUTION-PHASE SYNTHESIS STEFFEN WEINBRENNER AND C. CHRISTOPH TZSCHUCKE INTRODUCTION LIQUID-LIQUID EXTRACTION AQUEOUS WORK-UP PHASE-SEPARATION TECHNIQUES FLUOROUS BIPHASIC SYSTEMS IONIC LIQUIDS SOLID-PHASE EXTRACTION SILICA GEL AND ALUMINA FLUOROUS SILICA GEL ION EXCHANGE COVALENT SCAVENGERS SOLUTION SCAVENGERS POLYMER-ASSISTED SOLUTION-PHASE CHEMISTRY (PASP) SCAVENGER RESINS RESIN CAPTURE COMPLEX PURIFICATION STRATEGIES CONCLUSION AND OUTLOOK REFERENCES LINKERS FOR SOLID-PHASE ORGANIC SYNTHESIS (SPOS) AND COMBINATORIAL APPROACHES ON SOLID SUPPORTS WILLI BANNWARTH GENERAL LINKERS FOR FUNCTIONAL GROUPS LINKERS FOR CARBOXYL FUNCTIONS LINKERS FOR AMINO FUNCTIONS LINKERS BASED ON BENZYLOXYCARBONYL (Z) LINKER BASED ON TERT-BUTYLOXYCARBONYL (BOC) A URETHANE LINKER CLEAVABLE BY FLUORIDE IONS BENZYL-LINKED APPROACHES FOR SECONDARY AMINES LINKERS BASED ON ACETYLDIMEDONE TRITYL LINKER LINKERS FOR THE ATTACHMENT OF ALCOHOLS OR PHENOLS LINKER BASED ON THE TETRAHYDROPYRANYL (THP) GROUP SILYL LINKER FOR THE ATTACHMENT OF ALCOHOLS XV XVII XXI 1 1 2 2 6 6 9 10 10 11 14 19 19 21 21 24 26 29 29 33 33 34 34 36 36 40 41 42 44 46 50 50 53 2.2.3.3 2.2.3.4 2.2.3.5 2.2.4 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.3.8 2.3.9 2.3.10 2.3.11 2.4 2.4.1 2.4.2 2.4.3 2.5 2.6 2.7 3 3.1 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.2.7 3.2.8 3.2.9 3.2.10 3.2.11 3.2.12 MISCELLANEOUS LINKERS FOR ALCOHOLS SERINE-BASED LINKER FOR PHENOLS CARBOXY-FUNCTIONALIZED RESINS FOR THE ATTACHMENT OF PHENOLS ACETAL LINKER FOR THE PREPARATION OF ALDEHYDES TRACELESS LINKER SYSTEMS APPLICATION OF HOFMANN ELIMINATION IN LINKER DESIGN TRACELESS LINKERS BASED ON SILYL FUNCTIONALIZATION TRACELESS LINKERS BASED ON CC COUPLING STRATEGIES TRACELESS LINKERS BASED ON IR-COMPLEXATION TRACELESS LINKERS BASED ON OLEFIN METATHESIS TRACELESS SYNTHESIS USING POLYMER-BOUND TRIPHENYLPHOSPHINE DECARBOXYLATION-BASED TRACELESS LINKING TRACELESS LINKER BASED ON ARYL HYDRAZIDES TRIAZENE-BASED TRACELESS LINKER TRACELESS LINKER BASED ON SULFONES TRACELESS CONCEPT BASED ON CYCLOADDITION-CYCLOREVERSION PHOTOLABILE LINKER UNITS INTRODUCTION LINKERS BASED ON O -NITROBENZYL PHOTOCLEAVABLE LINKER BASED ON PIVALOYL GLYCOL SAFETY-CATCH LINKERS DUAL LINKERS AND ANALYTICAL CONSTRUCTS SUMMARY AND OUTLOOK REFERENCES CYCLATIVE CLEAVAGE: A VERSATILE CONCEPT IN SOLID-PHASE ORGANIC CHEMISTRY JOSEF PERNERSTORFER PRINCIPLES CARBON-HETEROATOM BOND FORMATION HYDANTOINS PYRAZOLONES 2-AMINOIMIDAZOLONES URAZOLES AND THIOURAZOLES OXAZOLIDINONES DIKETOPIPERAZINE DERIVATIVES 4,5-DIHYDRO-3(2 H )-PYRIDAZINONES DIHYDROPYRIDINES 5,6-DIHYDROPYRIMIDINE-2,4-DIONES 2,4-(1 H ,3 H )-QUINAZOLINEDIONES QUINAZOLIN-4(3 H )-ONES 4-HYDROXYQUINOLIN-2(1 H )-ONES 56 57 58 58 61 61 64 68 71 71 78 80 81 83 85 85 89 89 89 91 93 101 105 105 111 111 112 112 115 116 118 119 120 123 124 125 126 126 128 3.2.13 3.2.14 3.2.15 3.2.16 3.2.17 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.4 3.4.1 3.4.2 3.5 4 4.1 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.2.6.1 4.3 4.3.1 4.3.2 4.3.3 4.4 4.4.1 4.4.2 4.5 4.5.1 4.5.2 4.5.3 4.5.4 4.5.5 3,4-DIHYDROQUINOXALIN-2-ONES 1,4-BENZODIAZEPINE-2,5-DIONES OXACEPHAMS LACTONES TETRAHYDROFURANS FORMATION OF CC BONDS TETRAMIC ACIDS WITTIG-TYPE REACTIONS STILLE REACTIONS S -YLIDES RING-CLOSING METATHESIS MISCELLANEOUS FURANS PHENOLS SUMMARY REFERENCES CC BOND-FORMING REACTIONS WOLFGANG K.-D. BRILL AND GIANLUCA PAPEO GENERAL TRANSITION METAL-MEDIATED VINYLATIONS, ARYLATIONS, AND ALKYLATIONS THE SUZUKI COUPLING THE HECK REACTION THE SONOGASHIRA COUPLING THE STILLE COUPLING REMARKS ON PD-MEDIATED COUPLINGS ON A POLYMERIC SUPPORT EXPERIMENTAL APPROACH MATERIALS AND METHODS MISCELLANEOUS ARYL-ARYL COUPLINGS ULLMANN/WURZ COUPLING ON A POLYMERIC SUPPORT INTERMOLECULAR ALKYL-ALKYL COUPLING NEGISHI COUPLINGS ALKENE METATHESIS REACTIONS RING-CLOSING METATHESIS (RCM) REACTIONS CROSS-METATHESIS (CM) REACTIONS CYCLOADDITION REACTIONS ON A POLYMERIC SUPPORT C1 FRAGMENTS (ADDITIONS OF CARBENES TO ALKENES) ELECTRON-DEFICIENT C2 FRAGMENTS (CYCLOADDITIONS INVOLVING AZOMETHINES, NITRONES, NITRILE OXIDES, AND DIENES) ELECTRON-RICH C2 FRAGMENTS ([2 + 1], [2 + 2], [2 + 3], [2 + 4]-CYCLOADDITIONS, ADDITIONS WITH NITRILE IMINES, NITRILE OXIDES, AND CHALCONES) CX FRAGMENT ON SOLID SUPPORT CCX FRAGMENTS ON THE POLYMERIC SUPPORT 128 129 129 130 133 133 133 134 136 137 137 137 138 138 140 140 143 143 143 144 159 164 172 174 175 175 189 189 190 192 193 195 199 200 201 207 216 224 229 4.5.6 CXC FRAGMENT 233 4.5.7 CXY-FRAGMENT (NITRILE OXIDE ON SOLID PHASE) 235 4.5.8 CCCC FRAGMENTS ON SOLID PHASE 237 4.5.9 CCCX FRAGMENTS ON SOLID SUPPORT 252 4.5.10 CCXC FRAGMENT ON SOLID SUPPORT (GRIECO THREE-COMPONENT CONDENSATION) 254 4.5.11 CXXC FRAGMENT ON SOLID SUPPORT 255 4.5.12 CCX*X FRAGMENT ON SOLID SUPPORT ([4 + 1]-CYCLOADDITION) 257 4.5.13 CYCLOADDITIONS INVOLVING LARGER SUPPORT-BOUND FRAGMENTS: INTRAMOLECULAR 257 HETERO DIELS-ALDER 4.5.14 PAUSON-KHAND AND NICOLAS REACTION 260 4.5.15 C-NITROALKENE ADDITIONS 263 4.6 MULTICOMPONENT REACTIONS (MCRS) 263 4.6.1 UGI FOUR-COMPONENT REACTION 264 4.6.1.1 UGI REACTION WITH SOLID-SUPPORTED ISONITRILES 264 4.6.1.2 UGI REACTION WITH SOLID-SUPPORTED AMINES 267 4.6.1.3 UGI REACTION WITH SOLID-SUPPORTED CARBOXYLIC ACID 269 4.6.1.4 DERIVATIZATION OF BORONIC ACIDS 270 4.6.2 OTHER MCRS USING ISONITRILES 271 4.6.2.1 PETASIS (BORONO-MANNICH) CONDENSATION 271 4.6.2.2 IMIDAZO[1,2-?]PYRIDINES 272 4.6.2.3 BIGINELLI DIHYDROPYRIMIDINES SYNTHESIS 273 4.6.2.4 THIOPHENE SYNTHESIS 275 4.6.2.5 TETRAHYDROPYRIDONES 276 4.6.2.6 CYCLIZATION 278 4.6.2.7 CLEAVAGE 278 4.7 ELECTROPHILES BOUND TO THE POLYMERIC SUPPORT 278 4.7.1 REACTIONS WITH ORGANYLS OF ZN, MG, LI 278 4.7.1.1 REACTIONS INVOLVING GRIGNARD REAGENTS, ORGANOLITHIUM, AND ORGANOZINC 279 REAGENTS 4.7.1.2 REACTIONS WITH WATER-SENSITIVE REAGENTS SUCH AS GRIGNARD REAGENTS, LITHIUM 279 ALKYLS, OR ZINC ORGANYLS [375] ON SOLID PHASES 4.7.2 INDIUM-MEDIATED ALLYLATION OF SUPPORT-BOUND ALDEHYDES 282 4.7.3 SN/PD-MEDIATED C-ALLYLATION OF SOLID-PHASE-BOUND ALDEHYDES 284 4.7.4 METAL-FREE ALKYLATIONS BY ACYL HALIDES ON POLYMERIC SUPPORTS 286 4.7.5 NUCLEOPHILIC AROMATIC SUBSTITUTION WITH C-NUCLEOPHILES 286 4.7.6 PYRIDINE-N-OXIDES 289 4.7.7 TRAPPING PHOSPHORUS YLIDES WITH A KETONE BOUND TO THE SOLID PHASE 289 4.7.8 MICHAEL ACCEPTOR ON SOLID PHASE (ROUTE TO 3,4,6-TRISUBSTITUTED PYRID-2-ONES) 290 4.7.9 SOLID PHASE N-ACYLIMINIUM IONS, IMINES AND GLYOXYLATE CHEMISTRY 291 4.7.10 SOLID-SUPPORTED IMINES AND GLYOXYLATE 294 4.7.11 SOLID-PHASE PICTET-SPENGLER REACTIONS 299 4.7.12 SOLID-PHASE BAYLIS-HILLMAN REACTION 307 4.7.13 4.7.14 4.7.15 4.7.16 4.8 4.8.1 4.8.2 4.8.3 4.8.4 4.8.5 4.9 4.10 5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.10.1 5.10.2 5.11 5.12 5.12.1 5.12.2 5.12.3 5.13 5.14 5.15 5.16 5.17 5.18 5.19 SOLID-PHASE FISCHER INDOLE SYNTHESIS SOLID-PHASE MADELUNG INDOLE SYNTHESIS BORON ENOLATES WITH SUPPORT-BOUND ALDEHYDES SUMMARY OF SOLID-SUPPORTED ELECTROPHILES GENERATION OF CARBANIONS ON SOLID SUPPORTS TRANSITION METAL-MEDIATED CARBANION EQUIVALENT FORMATIONS LEWIS ACID-MEDIATED ELECTROPHILIC SUBSTITUTIONS GENERATION OF STABILIZED CARBANIONS UNDER BASIC CONDITIONS EXPERIMENTAL APPROACH STEREOSELECTIVE ALKYLATIONS ON A CHIRAL SOLID PHASE SOLID-PHASE RADICAL REACTIONS OUTLOOK REFERENCES COMBINATORIAL SYNTHESIS OF HETEROCYCLES EDUARD R. FELDER AND ANDREAS L. MARZINZIK INTRODUCTION BENZODIAZEPINES HYDANTOINS AND THIOHYDANTOINS P-LACTAMS (AZETIDIN-2-ONES) P-SULTAMS IMIDAZOLES PYRAZOLES AND ISOXAZOLES THIAZOLIDINONES TRIAZOLES OXADIAZOLES 1,2,4-OXADIAZOLES 1,3,4-OXADIAZOLES PIPERAZINONES PIPERAZINEDIONES (DIKETOPIPERAZINES) DIKETOPIPERAZINES VIA BACKBONE AMIDE LINKER (BAL) [117] PIPERAZINEDIONES BY ACID CYCLATIVE CLEAVAGE; METHOD A, INCLUDING REDUCTIVE ALKYLATION PIPERAZINEDIONES BY ACID CYCLATIVE CLEAVAGE; METHOD B, INCLUDING S N2 DISPLACEMENT DIKETOMORPHOLINES TRIAZINES PYRIMIDINES INDOLES QUINAZOLINES BENZOPIPERAZINONES AND TETRAHYDROQUINOXALINES TETRAHYDRO-P-CARBOLINES 310 311 312 314 314 320 321 327 334 340 340 347 347 361 361 363 369 375 376 379 384 387 390 396 397 399 401 406 406 409 410 413 413 417 421 428 439 443 5.20 6 6.1 6.2 6.2.1 6.2.1.1 6.2.1.2 6.2.2 6.2.2.1 6.2.2.2 6.2.2.3 6.2.2.4 6.2.2.5 6.3 6.4 6.5 7 7.1 7.2 7.3 7.4 7.5 7.6 7.7 8 8.1 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.2.5 8.2.5.1 8.2.5.2 OUTLOOK REFERENCES POLYMER-SUPPORTED REAGENTS: PREPARATION AND USE IN PARALLEL ORGANIC SYNTHESIS BERTHOLD HINZEN AND MICHAEL G. HAHN INTRODUCTION PREPARATION AND USE OF PSRS COVALENT LINKAGE BETWEEN THE ACTIVE SPECIES AND SUPPORT PSRS PREPARED BY SOLID-PHASE CHEMISTRY PSRS PREPARED BY POLYMERIZATION IMMOBILIZATION USING IONIC INTERACTIONS OXIDANTS REDUCING AGENTS ALKOXIDES BOUND TO A POLYMER SUPPORT HORNER-EMMONS REAGENTS ON SUPPORTS HALOGENATING AGENTS SUPPORT-BOUND SEQUESTERING AND SCAVENGING AGENTS COMBINATION OF PSRS SUMMARY AND CONCLUSION REFERENCES ENCODING STRATEGIES FOR COMBINATORIAL LIBRARIES BERTHOLD HINZEN INTRODUCTION POSITIONAL ENCODING GRAPHICAL/BARCODE ENCODING CHEMICAL ENCODING MASS SPECTROMETRIC ENCODING RADIOFREQUENCY ENCODING CONCLUSION REFERENCES AUTOMATION AND DEVICES FOR COMBINATORIAL CHEMISTRY AND PARALLEL ORGANIC SYNTHESIS CHRISTIAN ZECHEL INTRODUCTION SYNTHESIS GENERAL REMARKS MANUAL SYSTEMS SEMI-AUTOMATED SYSTEMS AUTOMATED SYSTEMS SPECIAL APPLICATIONS PROCESS DEVELOPMENT EQUIPMENT FOR PARALLEL REACTIVE GAS CHEMISTRY 449 449 457 457 459 459 459 483 490 490 492 494 494 495 497 497 509 509 513 513 514 514 514 515 516 516 516 519 519 520 520 522 540 540 546 546 549 8.3 8.4 8.5 8.6 9 9.1 9.1.1 9.1.2 9.1.3 9.1.3.1 9.1.3.2 9.1.3.3 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.3 9.3.1 9.3.2 9.3.2.1 9.3.2.2 9.3.3 9.3.3.1 9.3.3.2 9.3.3.3 9.3.3.4 9.3.4 9.3.5 9.3.6 9.3.6.1 9.3.6.2 9.3.7 9.3.7.1 9.3.7.2 9.3.8 9.3.9 9.3.10 9.3.11 9.3.12 LIQUID-LIQUID EXTRACTION EQUIPMENT FOR HIGH-THROUGHPUT EVAPORATION AUTOMATED SOLID AND RESIN DISPENSING SUPPLIERS COMPUTER-ASSISTED LIBRARY DESIGN ANDREAS DOMINIK INTRODUCTION OPTIMIZING COMBINATORIAL LIBRARIES A COMPUTER-ASSISTED DESIGN STRATEGY WHAT IS DIVERSITY? FIRST EXAMPLES DIVERSITY OF DRUG MOLECULES DIVERSITY AND SIMILARITY HOW DO WE COMPUTE DIVERSITY? AN OVERVIEW DESCRIPTORS CLASSIFICATION AND MAPPING INTERPRETATION OF RESULTS: SUMMARY DESCRIPTORS SIMPLE FILTERS PHYSICO-CHEMICAL CONSTANTS ESTIMATION OF LOGP VALUES ESTIMATION OF PKA VALUES DRUG-LIKENESS THE RULE OF 5 ARTIFICIAL NEURAL NETWORKS FURTHER IMPROVEMENTS OF DRUG-LIKENESS PREDICTION ADME AND TOXICITY PROFILING MOLECULAR FINGERPRINTS SUBSTRUCTURE DESCRIPTORS SINGLE ATOM PROPERTIES ATOM CHARGES ATOMIC LIPOPHILICITY PARAMETERS TOPOLOGICAL INDICES ATOM INDICES MOLECULE INDICES TOPOLOGICAL AUTOCORRELATION AND CROSS-CORRELATION COEFFICIENTS SCAFFOLD-BASED SIMILARITY DESCRIPTORS FROM A PHARMACOPHORE MODEL STEREOCHEMISTRY DESCRIPTORS FROM THE THREE-DIMENSIONAL STRUCTURE 550 551 555 556 559 559 559 560 562 562 562 564 566 566 567 567 568 568 571 571 571 572 572 572 573 573 574 575 575 576 577 577 577 577 578 578 580 580 581 582 9.3.13 9.3.14 9.3.15 POLAR SURFACE AREA (PSA) DISTANCE MATRIX AUTOCORRELATION COEFFICIENTS 9.3.15.1 BASED ON ATOM COORDINATES 9.3.15.2 BASED ON SURFACE PROPERTIES 9.3.15.3 BASED ON POTENTIAL FIELDS 9.3.16 9.3.17 9.4 9.4.1 9.4.1.1 9.4.1.2 9.4.1.3 9.4.1.4 9.4.2 9.4.3 9.4.3.1 9.4.3.2 9.4.3.3 9.4.4 9.4.4.1 9.4.5 9.5 9.5.1 9.5.1.1 9.5.2 9.5.2.1 9.5.3 9.5.4 9.6 9.6.1 9.6.2 9.6.3 9.6.4 9.7 9.7.1 9.7.2 9.7.2.1 9.7.2.2 9.7.2.3 RADIAL BASIS FUNCTION (RBF) VIRTUAL SCREENING CLUSTERING AND MAPPING ALGORITHMS DISTANCE METRIC TANIMOTO COEFFICIENT EUCLIDEAN DISTANCE NONLINEAR DISTANCE SCALING MAHALANOBIS DISTANCE DISSIMILARITY-BASED SELECTION MAPPING-BASED SELECTION NONLINEAR MAPPING SELF-ORGANIZING MAPS MINIMAL SPANNING TREE CLUSTER-BASED SELECTION HIERARCHICAL CLUSTERING ANALYSIS PARTITION-BASED SELECTION STRATEGIES FOR COMPOUND SELECTION OPTIMIZATION BASED ON DIVERSITY OF BUILDING BLOCKS ADVANTAGES OF EDUCT-BASED OPTIMIZATION OPTIMIZATION BASED ON DIVERSITY OF PRODUCT LIBRARIES ADVANTAGES OF PRODUCT-BASED OPTIMIZATION LIBRARY SELECTION EVOLUTIONARY DESIGN CIRCLE COMPARISON OF DESCRIPTORS AND SELECTION METHODS TOPOLOGICAL DESCRIPTORS DESCRIPTORS BASED ON THREE-DIMENSIONAL STRUCTURE CLUSTERING METHODS SUMMARY EXAMPLE LIBRARY OF THROMBIN INHIBITORS VIRTUAL LIBRARY DESIGN FINAL LIBRARY DESIGN MAXIMUM DIVERSITY LIBRARY TARGETED LIBRARY DESCRIPTOR SETS 583 583 583 585 585 586 586 586 587 587 587 589 589 589 589 590 590 591 592 592 592 593 593 594 594 595 595 597 598 599 599 602 602 603 603 605 606 607 607 607 9.7.3 COMPARISON OF THE LIBRARIES 9.7.4 SUMMARY REFERENCES 10 ASSAYS FOR HIGH-THROUGHPUT SCREENING IN DRUG DISCOVERY CHRISTIAN M. APFEL AND THILO ENDERLE 10.1 SCREENING IN DRUG DISCOVERY 10.1.1 THE ROLE OF HTS 10.1.2 OVERVIEW OF SCREENING ASSAYS 10.1.3 REQUIREMENTS FOR SUCCESSFUL HTS 10.1.4 TARGET CLASSES 10.1.4.1 OVERVIEW 10.1.4.2 G-PROTEIN-COUPLED RECEPTORS (GPCR) 10.2 ASSAY METHODS BASED ON DIFFERENT READOUTS 10.2.1 RADIOACTIVITY 10.2.1.1 GENERAL 10.2.1.2 SCINTILLATION PROXIMITY ASSAY (SPA) 10.2.1.3 FLASHPLATETM/SCINTISTRIPTM/CYTOSTAR-TTM 10.2.1.4 INSTRUMENTATION FOR RADIOISOTOPE ASSAYS 10.2.2 COLORIMETRY 10.2.3 FLUORESCENCE 10.2.3.1 GENERAL 10.2.3.2 FLUORESCENCE INTENSITY (FI) 10.2.3.3 FLUORESCENCE POLARIZATION (FP) 10.2.3.4 FLUORESCENCE RESONANCE ENERGY TRANSFER (FRET) 10.2.3.5 TIME-RESOLVED FLUORESCENCE (TRF) 10.2.3.6 FLUORESCENCE LIFETIME (FLT) 10.2.3.7 FLUORESCENCE CORRELATION SPECTROSCOPY (FCS) 10.2.3.8 FLUORESCENT INTENSITY DISTRIBUTION ANALYSIS (FIDA) 10.2.4 CHEMILUMINESCENCE AND BIOLUMINESCENCE 10.2.4.1 GENERAL 10.2.4.2 2+ AEQUORIN CA ASSAY 10.2.4.3 TM ALPHASCREEN 10.2.4.4 TM BRET 10.3 SPECIAL ASSAY APPLICATIONS WITH OPTICAL READOUT 10.3.1 FLUORIMETRIC IMAGING PLATE READER (FLIPR) 10.3.2 REPORTER ASSAYS 10.3.3 ASSAYS BASED ON ENZYME FRAGMENT COMPLEMENTATION (EFC) 10.3.3.1 GENERAL 10.3.3.2 LOW AFFINITY COMPLEMENTATION SYSTEM 10.3.3.3 HIGH AFFINITY COMPLEMENTATION SYSTEM 607 609 610 615 615 615 617 617 619 619 619 621 621 621 622 624 625 626 628 628 631 632 635 637 641 641 641 642 642 643 644 645 646 646 646 648 648 648 648 A.1 A.2 A.3 A.4 A.5 ABBREVIATIONS TRADEMARKS AND SUPPLIERS REFERENCES APPENDIX: CHEMINFORMATICS AND WEB RESOURCES FOR COMBINATORIAL CHEMISTRY BERTHOLD HINZEN AND JOHANNES KOEBBERLING WEBSITES (ONLINE) JOURNALS COMPANIES AND ACADEMIC GROUPS INVOLVED IN COMBINATORIAL CHEMISTRY REACTION DATABASES SUMMARY INDEX 649 650 651 659 659 660 660 661 661 663
adam_txt	WILLI BANNWARTH, BERTHOLD HINZEN (EDS.) COMBINATORIAL CHEMISTRY FROM THEORY TO APPLICATION SECOND REVISED EDITION WILEY- VCH WILEY-VCH VERLAG GMBH & CO. KGAA SERIES EDITORS: PROF. DR. RAIMUND MANNHOLD BIOMEDICAL RESEARCH CENTER MOLECULAR DRUG RESEARCH GROUP HEINRICH-HEINE-UNIVERSITAET UNIVERSTAETSSTRASSE 1 40225 DUESSELDORF GERMANY RAIMUND.MANNHOLD@UNI-DUESSELDORF.DE PROF. DR. HUGO KUBINYI DONNERSBERGSTRASSE 9 67256 WEISENHEIM AM SAND GERMANY KUBINYI@T-ONLINE.DE PROF. DR. GERD FOLKERS COLLEGIUM HELVETICUM STW/ETH ZENTRUM 8092 ZUERICH SWITZERLAND FOLKERS @ COLLEGIUM. ETHZ.CH VOLUME EDITORS: PROF. DR. WILLI BANNWARTH INSTITUT FUER ORG. CHEMIE UND BIOCHEMIE UNIVERSITAET FREIBURG ALBERTSTRASSE 21 79104 FREIBURG GERMANY WILLI.BANNWARTH@ORGANIK.CHEMIE.UNI- FREIBURG.DE DR. BERTHOLD HINZEN BAYER AG POSTFACH 101709 42096 WUPPERTAL BERTHOLD.HINZEN@BAYERHEALTHCARE.COM THIS BOOK WAS CAREFULLY PRODUCED. NEVERTHE- LESS, AUTHORS, EDITORS AND PUBLISHER DO NOT WARRANT THE INFORMATION CONTAINED THEREIN TO BE FREE OF ERRORS. READERS ARE ADVISED TO KEEP IN MIND THAT STATEMENTS, DATA, ILLUSTRA- TIONS, PROCEDURAL DETAILS OR OTHER ITEMS MAY INADVERTENTLY BE INACCURATE. COVER ILLUSTRATION: LIBRARY OF CONGRESS CARD NO. APPLIED FBR. BRITISH LIBRARY CATALOGUING-IN-PUBLICATION DATA: A CATALOGUE RECORD FOR THIS BOOK IS AVAILABLE FROM THE BRITISH LIBRARY DIE DEUTSCHE BIBLIOTHEK - CIP CATALOGUING- IN-PUBLICATION-DATA: A CATALOGUE RECORD FOR THIS PUBLICATION IS AVAILABLE FROM DIE DEUTSCHE BIBLIOTHEK ISBN 3-527-30693-5 2006 WILEY-VCH VERLAG GMBH & CO. KGAA, WEINHEIM PRINTED ON ACID-FREE AND CHLORINE-FREE PAPER ALL RIGHTS RESERVED (INCLUDING THOSE OF TRANS- LATION INTO OTHER LANGUAGES). NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM - BY PHOTOPRINTING, MICROFILM, OR ANY OTHER MEANS - NOR TRANSMITTED OR TRANSLATED INTO A MACHINE LANGUAGE WITHOUT WRITTEN PERMIS- SION FROM THE PUBLISHERS. REGISTERED NAMES, TRADEMARKS, ETC. USED IN THIS BOOK, EVEN WHEN NOT SPECIFICALLY MARKED AS SUCH, ARE NOT TO BE CONSIDERED UNPROTECTED BY LAW. COVER: GRAFIK-DESIGN SCHULZ, FUSSGOENHEIM COMPOSITION: TYPOMEDIA GMBH, OSTFILDEM PRINTING: STRAUSS GMBH, MOERLENBACH BOOKBINDING: LITGES & DOPF BUCHBINDEREI GMBH, HEPPENHEIM PRINTED IN THE FEDERAL REPUBLIC OF GERMANY. TABLE OF CONTENTS 1 1.1 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.3 1.3.1 1.3.2 1.3.3 1.4 1.4.1 1.5 1.5.1 1.5.2 1.6 1.7 2 2.1 2.2 2.2.1 2.2.2 2.2.2.1 2.2.2.2 2.2.2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.3 2.2.3.1 2.2.3.2 PREFACE GENERAL INTRODUCTION LIST OF AUTHORS PURIFICATION PRINCIPLES IN HIGH-SPEED SOLUTION-PHASE SYNTHESIS STEFFEN WEINBRENNER AND C. CHRISTOPH TZSCHUCKE INTRODUCTION LIQUID-LIQUID EXTRACTION AQUEOUS WORK-UP PHASE-SEPARATION TECHNIQUES FLUOROUS BIPHASIC SYSTEMS IONIC LIQUIDS SOLID-PHASE EXTRACTION SILICA GEL AND ALUMINA FLUOROUS SILICA GEL ION EXCHANGE COVALENT SCAVENGERS SOLUTION SCAVENGERS POLYMER-ASSISTED SOLUTION-PHASE CHEMISTRY (PASP) SCAVENGER RESINS RESIN CAPTURE COMPLEX PURIFICATION STRATEGIES CONCLUSION AND OUTLOOK REFERENCES LINKERS FOR SOLID-PHASE ORGANIC SYNTHESIS (SPOS) AND COMBINATORIAL APPROACHES ON SOLID SUPPORTS WILLI BANNWARTH GENERAL LINKERS FOR FUNCTIONAL GROUPS LINKERS FOR CARBOXYL FUNCTIONS LINKERS FOR AMINO FUNCTIONS LINKERS BASED ON BENZYLOXYCARBONYL (Z) LINKER BASED ON TERT-BUTYLOXYCARBONYL (BOC) A URETHANE LINKER CLEAVABLE BY FLUORIDE IONS BENZYL-LINKED APPROACHES FOR SECONDARY AMINES LINKERS BASED ON ACETYLDIMEDONE TRITYL LINKER LINKERS FOR THE ATTACHMENT OF ALCOHOLS OR PHENOLS LINKER BASED ON THE TETRAHYDROPYRANYL (THP) GROUP SILYL LINKER FOR THE ATTACHMENT OF ALCOHOLS XV XVII XXI 1 1 2 2 6 6 9 10 10 11 14 19 19 21 21 24 26 29 29 33 33 34 34 36 36 40 41 42 44 46 50 50 53 2.2.3.3 2.2.3.4 2.2.3.5 2.2.4 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.3.8 2.3.9 2.3.10 2.3.11 2.4 2.4.1 2.4.2 2.4.3 2.5 2.6 2.7 3 3.1 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.2.7 3.2.8 3.2.9 3.2.10 3.2.11 3.2.12 MISCELLANEOUS LINKERS FOR ALCOHOLS SERINE-BASED LINKER FOR PHENOLS CARBOXY-FUNCTIONALIZED RESINS FOR THE ATTACHMENT OF PHENOLS ACETAL LINKER FOR THE PREPARATION OF ALDEHYDES TRACELESS LINKER SYSTEMS APPLICATION OF HOFMANN ELIMINATION IN LINKER DESIGN TRACELESS LINKERS BASED ON SILYL FUNCTIONALIZATION TRACELESS LINKERS BASED ON CC COUPLING STRATEGIES TRACELESS LINKERS BASED ON IR-COMPLEXATION TRACELESS LINKERS BASED ON OLEFIN METATHESIS TRACELESS SYNTHESIS USING POLYMER-BOUND TRIPHENYLPHOSPHINE DECARBOXYLATION-BASED TRACELESS LINKING TRACELESS LINKER BASED ON ARYL HYDRAZIDES TRIAZENE-BASED TRACELESS LINKER TRACELESS LINKER BASED ON SULFONES TRACELESS CONCEPT BASED ON CYCLOADDITION-CYCLOREVERSION PHOTOLABILE LINKER UNITS INTRODUCTION LINKERS BASED ON O -NITROBENZYL PHOTOCLEAVABLE LINKER BASED ON PIVALOYL GLYCOL SAFETY-CATCH LINKERS DUAL LINKERS AND ANALYTICAL CONSTRUCTS SUMMARY AND OUTLOOK REFERENCES CYCLATIVE CLEAVAGE: A VERSATILE CONCEPT IN SOLID-PHASE ORGANIC CHEMISTRY JOSEF PERNERSTORFER PRINCIPLES CARBON-HETEROATOM BOND FORMATION HYDANTOINS PYRAZOLONES 2-AMINOIMIDAZOLONES URAZOLES AND THIOURAZOLES OXAZOLIDINONES DIKETOPIPERAZINE DERIVATIVES 4,5-DIHYDRO-3(2 H )-PYRIDAZINONES DIHYDROPYRIDINES 5,6-DIHYDROPYRIMIDINE-2,4-DIONES 2,4-(1 H ,3 H )-QUINAZOLINEDIONES QUINAZOLIN-4(3 H )-ONES 4-HYDROXYQUINOLIN-2(1 H )-ONES 56 57 58 58 61 61 64 68 71 71 78 80 81 83 85 85 89 89 89 91 93 101 105 105 111 111 112 112 115 116 118 119 120 123 124 125 126 126 128 3.2.13 3.2.14 3.2.15 3.2.16 3.2.17 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.4 3.4.1 3.4.2 3.5 4 4.1 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.2.6.1 4.3 4.3.1 4.3.2 4.3.3 4.4 4.4.1 4.4.2 4.5 4.5.1 4.5.2 4.5.3 4.5.4 4.5.5 3,4-DIHYDROQUINOXALIN-2-ONES 1,4-BENZODIAZEPINE-2,5-DIONES OXACEPHAMS LACTONES TETRAHYDROFURANS FORMATION OF CC BONDS TETRAMIC ACIDS WITTIG-TYPE REACTIONS STILLE REACTIONS S -YLIDES RING-CLOSING METATHESIS MISCELLANEOUS FURANS PHENOLS SUMMARY REFERENCES CC BOND-FORMING REACTIONS WOLFGANG K.-D. BRILL AND GIANLUCA PAPEO GENERAL TRANSITION METAL-MEDIATED VINYLATIONS, ARYLATIONS, AND ALKYLATIONS THE SUZUKI COUPLING THE HECK REACTION THE SONOGASHIRA COUPLING THE STILLE COUPLING REMARKS ON PD-MEDIATED COUPLINGS ON A POLYMERIC SUPPORT EXPERIMENTAL APPROACH MATERIALS AND METHODS MISCELLANEOUS ARYL-ARYL COUPLINGS ULLMANN/WURZ COUPLING ON A POLYMERIC SUPPORT INTERMOLECULAR ALKYL-ALKYL COUPLING NEGISHI COUPLINGS ALKENE METATHESIS REACTIONS RING-CLOSING METATHESIS (RCM) REACTIONS CROSS-METATHESIS (CM) REACTIONS CYCLOADDITION REACTIONS ON A POLYMERIC SUPPORT C1 FRAGMENTS (ADDITIONS OF CARBENES TO ALKENES) ELECTRON-DEFICIENT C2 FRAGMENTS (CYCLOADDITIONS INVOLVING AZOMETHINES, NITRONES, NITRILE OXIDES, AND DIENES) ELECTRON-RICH C2 FRAGMENTS ([2 + 1], [2 + 2], [2 + 3], [2 + 4]-CYCLOADDITIONS, ADDITIONS WITH NITRILE IMINES, NITRILE OXIDES, AND CHALCONES) CX FRAGMENT ON SOLID SUPPORT CCX FRAGMENTS ON THE POLYMERIC SUPPORT 128 129 129 130 133 133 133 134 136 137 137 137 138 138 140 140 143 143 143 144 159 164 172 174 175 175 189 189 190 192 193 195 199 200 201 207 216 224 229 4.5.6 CXC FRAGMENT 233 4.5.7 CXY-FRAGMENT (NITRILE OXIDE ON SOLID PHASE) 235 4.5.8 CCCC FRAGMENTS ON SOLID PHASE 237 4.5.9 CCCX FRAGMENTS ON SOLID SUPPORT 252 4.5.10 CCXC FRAGMENT ON SOLID SUPPORT (GRIECO THREE-COMPONENT CONDENSATION) 254 4.5.11 CXXC FRAGMENT ON SOLID SUPPORT 255 4.5.12 CCX*X FRAGMENT ON SOLID SUPPORT ([4 + 1]-CYCLOADDITION) 257 4.5.13 CYCLOADDITIONS INVOLVING LARGER SUPPORT-BOUND FRAGMENTS: INTRAMOLECULAR 257 HETERO DIELS-ALDER 4.5.14 PAUSON-KHAND AND NICOLAS REACTION 260 4.5.15 C-NITROALKENE ADDITIONS 263 4.6 MULTICOMPONENT REACTIONS (MCRS) 263 4.6.1 UGI FOUR-COMPONENT REACTION 264 4.6.1.1 UGI REACTION WITH SOLID-SUPPORTED ISONITRILES 264 4.6.1.2 UGI REACTION WITH SOLID-SUPPORTED AMINES 267 4.6.1.3 UGI REACTION WITH SOLID-SUPPORTED CARBOXYLIC ACID 269 4.6.1.4 DERIVATIZATION OF BORONIC ACIDS 270 4.6.2 OTHER MCRS USING ISONITRILES 271 4.6.2.1 PETASIS (BORONO-MANNICH) CONDENSATION 271 4.6.2.2 IMIDAZO[1,2-?]PYRIDINES 272 4.6.2.3 BIGINELLI DIHYDROPYRIMIDINES SYNTHESIS 273 4.6.2.4 THIOPHENE SYNTHESIS 275 4.6.2.5 TETRAHYDROPYRIDONES 276 4.6.2.6 CYCLIZATION 278 4.6.2.7 CLEAVAGE 278 4.7 ELECTROPHILES BOUND TO THE POLYMERIC SUPPORT 278 4.7.1 REACTIONS WITH ORGANYLS OF ZN, MG, LI 278 4.7.1.1 REACTIONS INVOLVING GRIGNARD REAGENTS, ORGANOLITHIUM, AND ORGANOZINC 279 REAGENTS 4.7.1.2 REACTIONS WITH WATER-SENSITIVE REAGENTS SUCH AS GRIGNARD REAGENTS, LITHIUM 279 ALKYLS, OR ZINC ORGANYLS [375] ON SOLID PHASES 4.7.2 INDIUM-MEDIATED ALLYLATION OF SUPPORT-BOUND ALDEHYDES 282 4.7.3 SN/PD-MEDIATED C-ALLYLATION OF SOLID-PHASE-BOUND ALDEHYDES 284 4.7.4 METAL-FREE ALKYLATIONS BY ACYL HALIDES ON POLYMERIC SUPPORTS 286 4.7.5 NUCLEOPHILIC AROMATIC SUBSTITUTION WITH C-NUCLEOPHILES 286 4.7.6 PYRIDINE-N-OXIDES 289 4.7.7 TRAPPING PHOSPHORUS YLIDES WITH A KETONE BOUND TO THE SOLID PHASE 289 4.7.8 MICHAEL ACCEPTOR ON SOLID PHASE (ROUTE TO 3,4,6-TRISUBSTITUTED PYRID-2-ONES) 290 4.7.9 SOLID PHASE N-ACYLIMINIUM IONS, IMINES AND GLYOXYLATE CHEMISTRY 291 4.7.10 SOLID-SUPPORTED IMINES AND GLYOXYLATE 294 4.7.11 SOLID-PHASE PICTET-SPENGLER REACTIONS 299 4.7.12 SOLID-PHASE BAYLIS-HILLMAN REACTION 307 4.7.13 4.7.14 4.7.15 4.7.16 4.8 4.8.1 4.8.2 4.8.3 4.8.4 4.8.5 4.9 4.10 5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.10.1 5.10.2 5.11 5.12 5.12.1 5.12.2 5.12.3 5.13 5.14 5.15 5.16 5.17 5.18 5.19 SOLID-PHASE FISCHER INDOLE SYNTHESIS SOLID-PHASE MADELUNG INDOLE SYNTHESIS BORON ENOLATES WITH SUPPORT-BOUND ALDEHYDES SUMMARY OF SOLID-SUPPORTED ELECTROPHILES GENERATION OF CARBANIONS ON SOLID SUPPORTS TRANSITION METAL-MEDIATED CARBANION EQUIVALENT FORMATIONS LEWIS ACID-MEDIATED ELECTROPHILIC SUBSTITUTIONS GENERATION OF STABILIZED CARBANIONS UNDER BASIC CONDITIONS EXPERIMENTAL APPROACH STEREOSELECTIVE ALKYLATIONS ON A CHIRAL SOLID PHASE SOLID-PHASE RADICAL REACTIONS OUTLOOK REFERENCES COMBINATORIAL SYNTHESIS OF HETEROCYCLES EDUARD R. FELDER AND ANDREAS L. MARZINZIK INTRODUCTION BENZODIAZEPINES HYDANTOINS AND THIOHYDANTOINS P-LACTAMS (AZETIDIN-2-ONES) P-SULTAMS IMIDAZOLES PYRAZOLES AND ISOXAZOLES THIAZOLIDINONES TRIAZOLES OXADIAZOLES 1,2,4-OXADIAZOLES 1,3,4-OXADIAZOLES PIPERAZINONES PIPERAZINEDIONES (DIKETOPIPERAZINES) DIKETOPIPERAZINES VIA BACKBONE AMIDE LINKER (BAL) [117] PIPERAZINEDIONES BY ACID CYCLATIVE CLEAVAGE; METHOD A, INCLUDING REDUCTIVE ALKYLATION PIPERAZINEDIONES BY ACID CYCLATIVE CLEAVAGE; METHOD B, INCLUDING S N2 DISPLACEMENT DIKETOMORPHOLINES TRIAZINES PYRIMIDINES INDOLES QUINAZOLINES BENZOPIPERAZINONES AND TETRAHYDROQUINOXALINES TETRAHYDRO-P-CARBOLINES 310 311 312 314 314 320 321 327 334 340 340 347 347 361 361 363 369 375 376 379 384 387 390 396 397 399 401 406 406 409 410 413 413 417 421 428 439 443 5.20 6 6.1 6.2 6.2.1 6.2.1.1 6.2.1.2 6.2.2 6.2.2.1 6.2.2.2 6.2.2.3 6.2.2.4 6.2.2.5 6.3 6.4 6.5 7 7.1 7.2 7.3 7.4 7.5 7.6 7.7 8 8.1 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.2.5 8.2.5.1 8.2.5.2 OUTLOOK REFERENCES POLYMER-SUPPORTED REAGENTS: PREPARATION AND USE IN PARALLEL ORGANIC SYNTHESIS BERTHOLD HINZEN AND MICHAEL G. HAHN INTRODUCTION PREPARATION AND USE OF PSRS COVALENT LINKAGE BETWEEN THE ACTIVE SPECIES AND SUPPORT PSRS PREPARED BY SOLID-PHASE CHEMISTRY PSRS PREPARED BY POLYMERIZATION IMMOBILIZATION USING IONIC INTERACTIONS OXIDANTS REDUCING AGENTS ALKOXIDES BOUND TO A POLYMER SUPPORT HORNER-EMMONS REAGENTS ON SUPPORTS HALOGENATING AGENTS SUPPORT-BOUND SEQUESTERING AND SCAVENGING AGENTS COMBINATION OF PSRS SUMMARY AND CONCLUSION REFERENCES ENCODING STRATEGIES FOR COMBINATORIAL LIBRARIES BERTHOLD HINZEN INTRODUCTION POSITIONAL ENCODING GRAPHICAL/BARCODE ENCODING CHEMICAL ENCODING MASS SPECTROMETRIC ENCODING RADIOFREQUENCY ENCODING CONCLUSION REFERENCES AUTOMATION AND DEVICES FOR COMBINATORIAL CHEMISTRY AND PARALLEL ORGANIC SYNTHESIS CHRISTIAN ZECHEL INTRODUCTION SYNTHESIS GENERAL REMARKS MANUAL SYSTEMS SEMI-AUTOMATED SYSTEMS AUTOMATED SYSTEMS SPECIAL APPLICATIONS PROCESS DEVELOPMENT EQUIPMENT FOR PARALLEL REACTIVE GAS CHEMISTRY 449 449 457 457 459 459 459 483 490 490 492 494 494 495 497 497 509 509 513 513 514 514 514 515 516 516 516 519 519 520 520 522 540 540 546 546 549 8.3 8.4 8.5 8.6 9 9.1 9.1.1 9.1.2 9.1.3 9.1.3.1 9.1.3.2 9.1.3.3 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.3 9.3.1 9.3.2 9.3.2.1 9.3.2.2 9.3.3 9.3.3.1 9.3.3.2 9.3.3.3 9.3.3.4 9.3.4 9.3.5 9.3.6 9.3.6.1 9.3.6.2 9.3.7 9.3.7.1 9.3.7.2 9.3.8 9.3.9 9.3.10 9.3.11 9.3.12 LIQUID-LIQUID EXTRACTION EQUIPMENT FOR HIGH-THROUGHPUT EVAPORATION AUTOMATED SOLID AND RESIN DISPENSING SUPPLIERS COMPUTER-ASSISTED LIBRARY DESIGN ANDREAS DOMINIK INTRODUCTION OPTIMIZING COMBINATORIAL LIBRARIES A COMPUTER-ASSISTED DESIGN STRATEGY WHAT IS DIVERSITY? FIRST EXAMPLES DIVERSITY OF DRUG MOLECULES DIVERSITY AND SIMILARITY HOW DO WE COMPUTE DIVERSITY? AN OVERVIEW DESCRIPTORS CLASSIFICATION AND MAPPING INTERPRETATION OF RESULTS: SUMMARY DESCRIPTORS SIMPLE FILTERS PHYSICO-CHEMICAL CONSTANTS ESTIMATION OF LOGP VALUES ESTIMATION OF PKA VALUES DRUG-LIKENESS THE RULE OF 5 ARTIFICIAL NEURAL NETWORKS FURTHER IMPROVEMENTS OF DRUG-LIKENESS PREDICTION ADME AND TOXICITY PROFILING MOLECULAR FINGERPRINTS SUBSTRUCTURE DESCRIPTORS SINGLE ATOM PROPERTIES ATOM CHARGES ATOMIC LIPOPHILICITY PARAMETERS TOPOLOGICAL INDICES ATOM INDICES MOLECULE INDICES TOPOLOGICAL AUTOCORRELATION AND CROSS-CORRELATION COEFFICIENTS SCAFFOLD-BASED SIMILARITY DESCRIPTORS FROM A PHARMACOPHORE MODEL STEREOCHEMISTRY DESCRIPTORS FROM THE THREE-DIMENSIONAL STRUCTURE 550 551 555 556 559 559 559 560 562 562 562 564 566 566 567 567 568 568 571 571 571 572 572 572 573 573 574 575 575 576 577 577 577 577 578 578 580 580 581 582 9.3.13 9.3.14 9.3.15 POLAR SURFACE AREA (PSA) DISTANCE MATRIX AUTOCORRELATION COEFFICIENTS 9.3.15.1 BASED ON ATOM COORDINATES 9.3.15.2 BASED ON SURFACE PROPERTIES 9.3.15.3 BASED ON POTENTIAL FIELDS 9.3.16 9.3.17 9.4 9.4.1 9.4.1.1 9.4.1.2 9.4.1.3 9.4.1.4 9.4.2 9.4.3 9.4.3.1 9.4.3.2 9.4.3.3 9.4.4 9.4.4.1 9.4.5 9.5 9.5.1 9.5.1.1 9.5.2 9.5.2.1 9.5.3 9.5.4 9.6 9.6.1 9.6.2 9.6.3 9.6.4 9.7 9.7.1 9.7.2 9.7.2.1 9.7.2.2 9.7.2.3 RADIAL BASIS FUNCTION (RBF) VIRTUAL SCREENING CLUSTERING AND MAPPING ALGORITHMS DISTANCE METRIC TANIMOTO COEFFICIENT EUCLIDEAN DISTANCE NONLINEAR DISTANCE SCALING MAHALANOBIS DISTANCE DISSIMILARITY-BASED SELECTION MAPPING-BASED SELECTION NONLINEAR MAPPING SELF-ORGANIZING MAPS MINIMAL SPANNING TREE CLUSTER-BASED SELECTION HIERARCHICAL CLUSTERING ANALYSIS PARTITION-BASED SELECTION STRATEGIES FOR COMPOUND SELECTION OPTIMIZATION BASED ON DIVERSITY OF BUILDING BLOCKS ADVANTAGES OF EDUCT-BASED OPTIMIZATION OPTIMIZATION BASED ON DIVERSITY OF PRODUCT LIBRARIES ADVANTAGES OF PRODUCT-BASED OPTIMIZATION LIBRARY SELECTION EVOLUTIONARY DESIGN CIRCLE COMPARISON OF DESCRIPTORS AND SELECTION METHODS TOPOLOGICAL DESCRIPTORS DESCRIPTORS BASED ON THREE-DIMENSIONAL STRUCTURE CLUSTERING METHODS SUMMARY EXAMPLE LIBRARY OF THROMBIN INHIBITORS VIRTUAL LIBRARY DESIGN FINAL LIBRARY DESIGN MAXIMUM DIVERSITY LIBRARY TARGETED LIBRARY DESCRIPTOR SETS 583 583 583 585 585 586 586 586 587 587 587 589 589 589 589 590 590 591 592 592 592 593 593 594 594 595 595 597 598 599 599 602 602 603 603 605 606 607 607 607 9.7.3 COMPARISON OF THE LIBRARIES 9.7.4 SUMMARY REFERENCES 10 ASSAYS FOR HIGH-THROUGHPUT SCREENING IN DRUG DISCOVERY CHRISTIAN M. APFEL AND THILO ENDERLE 10.1 SCREENING IN DRUG DISCOVERY 10.1.1 THE ROLE OF HTS 10.1.2 OVERVIEW OF SCREENING ASSAYS 10.1.3 REQUIREMENTS FOR SUCCESSFUL HTS 10.1.4 TARGET CLASSES 10.1.4.1 OVERVIEW 10.1.4.2 G-PROTEIN-COUPLED RECEPTORS (GPCR) 10.2 ASSAY METHODS BASED ON DIFFERENT READOUTS 10.2.1 RADIOACTIVITY 10.2.1.1 GENERAL 10.2.1.2 SCINTILLATION PROXIMITY ASSAY (SPA) 10.2.1.3 FLASHPLATETM/SCINTISTRIPTM/CYTOSTAR-TTM 10.2.1.4 INSTRUMENTATION FOR RADIOISOTOPE ASSAYS 10.2.2 COLORIMETRY 10.2.3 FLUORESCENCE 10.2.3.1 GENERAL 10.2.3.2 FLUORESCENCE INTENSITY (FI) 10.2.3.3 FLUORESCENCE POLARIZATION (FP) 10.2.3.4 FLUORESCENCE RESONANCE ENERGY TRANSFER (FRET) 10.2.3.5 TIME-RESOLVED FLUORESCENCE (TRF) 10.2.3.6 FLUORESCENCE LIFETIME (FLT) 10.2.3.7 FLUORESCENCE CORRELATION SPECTROSCOPY (FCS) 10.2.3.8 FLUORESCENT INTENSITY DISTRIBUTION ANALYSIS (FIDA) 10.2.4 CHEMILUMINESCENCE AND BIOLUMINESCENCE 10.2.4.1 GENERAL 10.2.4.2 2+ AEQUORIN CA ASSAY 10.2.4.3 TM ALPHASCREEN 10.2.4.4 TM BRET 10.3 SPECIAL ASSAY APPLICATIONS WITH OPTICAL READOUT 10.3.1 FLUORIMETRIC IMAGING PLATE READER (FLIPR) 10.3.2 REPORTER ASSAYS 10.3.3 ASSAYS BASED ON ENZYME FRAGMENT COMPLEMENTATION (EFC) 10.3.3.1 GENERAL 10.3.3.2 LOW AFFINITY COMPLEMENTATION SYSTEM 10.3.3.3 HIGH AFFINITY COMPLEMENTATION SYSTEM 607 609 610 615 615 615 617 617 619 619 619 621 621 621 622 624 625 626 628 628 631 632 635 637 641 641 641 642 642 643 644 645 646 646 646 648 648 648 648 A.1 A.2 A.3 A.4 A.5 ABBREVIATIONS TRADEMARKS AND SUPPLIERS REFERENCES APPENDIX: CHEMINFORMATICS AND WEB RESOURCES FOR COMBINATORIAL CHEMISTRY BERTHOLD HINZEN AND JOHANNES KOEBBERLING WEBSITES (ONLINE) JOURNALS COMPANIES AND ACADEMIC GROUPS INVOLVED IN COMBINATORIAL CHEMISTRY REACTION DATABASES SUMMARY INDEX 649 650 651 659 659 660 660 661 661 663
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language	English
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series	Methods and principles in medicinal chemistry
series2	Methods and principles in medicinal chemistry
spelling	Combinatorial chemistry from theory to application Willi Bannwarth ...(eds.) 2., rev. ed. Weinheim Wiley-VCH 2006 XXII, 672 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry 26 Chimie combinatoire - Technique ram Composés organiques - Synthèse ram Combinatorial Chemistry Techniques Combinatorial chemistry Kombinatorische Synthese (DE-588)4513555-1 gnd rswk-swf Kombinatorische Synthese (DE-588)4513555-1 s DE-604 Bannwarth, Willi Sonstige (DE-588)11323158X oth Methods and principles in medicinal chemistry 26 (DE-604)BV035418617 26 GBV Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014645368&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Combinatorial chemistry from theory to application Methods and principles in medicinal chemistry Chimie combinatoire - Technique ram Composés organiques - Synthèse ram Combinatorial Chemistry Techniques Combinatorial chemistry Kombinatorische Synthese (DE-588)4513555-1 gnd
subject_GND	(DE-588)4513555-1
title	Combinatorial chemistry from theory to application
title_auth	Combinatorial chemistry from theory to application
title_exact_search	Combinatorial chemistry from theory to application
title_exact_search_txtP	Combinatorial chemistry from theory to application
title_full	Combinatorial chemistry from theory to application Willi Bannwarth ...(eds.)
title_fullStr	Combinatorial chemistry from theory to application Willi Bannwarth ...(eds.)
title_full_unstemmed	Combinatorial chemistry from theory to application Willi Bannwarth ...(eds.)
title_short	Combinatorial chemistry
title_sort	combinatorial chemistry from theory to application
title_sub	from theory to application
topic	Chimie combinatoire - Technique ram Composés organiques - Synthèse ram Combinatorial Chemistry Techniques Combinatorial chemistry Kombinatorische Synthese (DE-588)4513555-1 gnd
topic_facet	Chimie combinatoire - Technique Composés organiques - Synthèse Combinatorial Chemistry Techniques Combinatorial chemistry Kombinatorische Synthese
url	http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014645368&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
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