Synthese und Struktur-Aktivitäts-Beziehungen von Flavonoiden - PDF

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Synthese und Struktur-Aktivitäts-Beziehungen von Flavonoiden Vom Fachbereich Chemie der Technischen Universität Darmstadt zur Erlangung des akademischen Grades eines Doktor rerum naturalium (Dr. rer. nat.)

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Synthese und Struktur-Aktivitäts-Beziehungen von Flavonoiden Vom Fachbereich Chemie der Technischen Universität Darmstadt zur Erlangung des akademischen Grades eines Doktor rerum naturalium (Dr. rer. nat.) genehmigte Dissertation vorgelegt von Dipl.-Chem. Sophie PEUCHN aus Saint-Brieuc, Frankreich Berichterstatter: Prof. Dr. W.-D. Fessner Mitberichterstatter: Prof. Dr. H.-J. Lindner Tag der Einreichung: Tag der mündlichen Prüfung: Darmstadt 2004 D17 N rdre : 2628 de la thèse THÈSE présentée DEVANT L UNIVESITÉ DE ENNES 1 Pour obtenir le grade de : DCTEU DE L UNIVESITÉ DE ENNES 1 Mention : CHIMIE PA Sophie PEUCHN Équipe d accueil : École Doctorale : Composante universitaire : UM 6509-Électrochimie et rganométalliques Sciences de la Matière de ennes UF Structure et Propriété de la Matière TITE DE LA THÈSE : Synthèses et Étude des elations Structure-Fonction des Flavonoides Soutenue le 9 février 2004 devant la commission d Examen M. H. BUCHHLZ M. W.-D. FESSNE M. C. MINET M. W.PAULUS M. H.-J. LINDNE CMPSITIN DU JUY : Merck KGaA Darmstadt Technische Universität Darmstadt Université de ennes 1 Université de ennes 1 Technische Universität Darmstadt apporteur Directeur Directeur Examinateur apporteur Chaque difficulté rencontrée doit être l occasion d un nouveau progrès. Every encountered difficulty should be the occasion of a new progress. Baron Pierre de Coubertin ( ) à Yves ACKNWLEDGMENTS At first I would like to thank Mr Prof Dr. W.-D. Fessner and Mr Prof Dr. C. Moinet for having allowed me to carry out this Ph.D. in a joint supervision agreement with the Technical University of Darmstadt (Germany) and the University of ennes 1 (France). I thank them for their interests to this Ph.D. and the conversations we had along the last four years. I would like to thank the company Merck KGaA Darmstadt for the financing of my Ph.D. and specially Mr Dr. Herwig Buchholz who gave me the chance, four years ago, to carry out this Ph.D. in his Department of research and development. I thank him for his patience and comprehension face up to difficult events I lived. I thank the whole personne of the department Pigments &D CS, specially the students (Ms Anne Toullec, Ms Delphine Brune and Ms Michaela berle) who helped me in a strategic period to achieve our goal. To the personne of the MS- (Mrs Aschenbrenner), NM-, and UV- (Mrs N. Blatt) departments I am grateful for having measured my samples always in a spontaneous hurry and for their help for the interpretation and characterization of the products. Thanks to the students of the TU Darmstadt to have integrated me in their team even if I was not so often with them. Special thanks to The Mädles Ms Dr. Teresa Mujica Fernaud, Ms Dr. Corinna Wirth, Mrs Dr. Valérie Bicard, Mrs Dipl.-Ing. Irene Piper, Mr Dipl.-Ing. Christian Unger, Mr Dipl.- Ing. Tobias Lang, Ms Dipl.-Chem. Nga Phung, Mr Dr. Thomas Eberle, Bester Man Mr Dipl.-Ing. Matthias Eck, Mrs Barbara einhardt (Mercker or not) for their friendship and the fun we shared together in our extra activities. Je voudrais tout particulièrement remercier M. Dr Christophe Carola: tout d abord pour la correction de ce manuscrit, pour son épaulement tout au long de la thèse, ensuite pour nos délires au labo, nos fous rires, nos matches palpitants et tout le reste Et enfin, je remercie mes parents qui m ont accordée leur confiance et patience tout au long de mes études. Merci pour leurs encouragements et leur soutien durant ces dernières années loin de moi. Merci également à mes deux sœurs Isabelle et Béatrice, mes amis Cathy, Nath, Sandrine, Marie, Judy, Kerstin et Simon, Varinia et Stephen, qui m ont encouragée tout au long de ma thèse. Merci à Berteline pour toutes les solutions II ABBEVATINS AA ABTS Ac AE AF AIBN Akt Ar ATP bp br cat c cdna concd CSY d DMD DMF DMS DNA DPPH EC 50 equiv FAB-MS h HPLC Hz IC 50 I LCL LDA antioxidant activity 2,2 -azino-bis-(3-ethyl-benzothialin)-6-sulfonic acid acetyl antiradical efficiency Algar, Flynn and yamada reaction 2,2 -azobisisobutyronitrile protein kinase B aryl adenosine triphosphate boiling point broad catalyst concentration complementary deoxyribose nucleic acid concentrated correlation spectroscopy doublet dimethyldioxirane dimethylformamide dimethylsulfoxide deoxyribose nucleic acid 2,2-diphenyl-1-picrylhydrazyl hydrat efficient concentration at the steady state equivalent fast atom bombardment mass spectrometry hour(s) high performance liquid chromatography Hertz inhibitory concentration at the steady state infrared lower confident line lithium diisopropylamide LiHMDS m m-cpba min ML mol mp mna NBS NCS NM PCC PC Ph PkB PTK ppm QSA AS S rt s SA t TEAC lithium bis-(trimethylsilyl)amide multiplet m-chloroperoxybenzoic acid minute(s) multiple linear regression mole(s) melting point messenger ribose nucleic acid N-bromosuccinimide N-chlorosuccinimide nuclear magnetic resonance pyridinium chlorochromate polymerase chain reaction phenyl protein kinase B protein kinase part per million quantitative structure activity relationship apport Activité Structure reactive oxygen species room temperature singlet structure activity relationship triplet trolox equivalent antioxidant capacity T EC50 time at EC 50 Ti2 tyrosine kinase expressed in endothelial cells THF tetrahydrofuran tlc thin layer chromatography TMS tetramethylsilane TTA thallium (III) acetate TTN thallium (III) trinitrate TTS thallium (III) toluene-p-sulfonate UCL upper confident line ABSTACT IV ABSTACT Flavonoids are natural polyphenolic compounds that are widely distributed in higher plants. Many of them possess biological activities (radical scavengers, anti-inflammatory...), which are potentially exploitable in the cosmetic field. Furthermore, flavonoids absorb in the UV range, which confers to them UV filter properties. In our laboratory, flavonoids and polyphenol derivatives were investigated to understand which part of the molecule is essential to provide the above mentioned activities. Starting from a mono or polyhydroxylated aromatic compound, simple syntheses of known and new mono and polyphenol compounds have been developed to form a model compound library. By modifying the position of the hydroxyl groups around the benzene ring(s), it was possible to obtain molecules having interesting properties. Among them, the 7- hydroxy-4 -methoxyflavone absorbs not only in the UVB, but also in the UVA ranges with usefully high absorption coefficients. Some of the synthesised molecules possess an ideal chemical structure for scavenging free radical. They have been shown to be more effective antioxidants in vitro than vitamins E on a molar basis. These results have been obtained by modifying either the substitution patterns around the core of the flavonoids or the oxidation level of the molecules (e.g. Bacalein). The biological effects of 7--glucosyl-4 -methoxyflavone were also tested using cdna arrays containing a set of more than 400 genes related to skin functions. Selected compounds of the library were tested for their ability to inhibit protein-tyrosine kinases. ÉSUMÉ V ESUME Les Flavonoides sont des composés polyphénoliques largement distribués dans de nombreuses plantes. La plupart d entre eux possèdent des activités biologiques (piégeur de radicaux, anti-inflammatoires ), très recherchées dans l industrie cosmétique. En outre, les flavonoides absorbent dans la zone des ultraviolets, ce qui leur confère des propriétés de filtres UV. Dans notre laboratoire, les flavonoides et les dérivés polyphénoliques ont été étudiés pour comprendre quelle partie de la molécule est essentielle pour fournir les activités mentionnées ci-dessus. Des synthèses simples à partir d un cycle phényle mono- ou polyhydroxylé, ont permis de produire des composés mono- ou polyphénoliques, connus ou nouveaux, qui ont été rassemblés dans un modèle de bibliothèque. En modifiant la position des groupements hydroxyles autour du (des) cycle(s) benzénique(s), il a été possible d obtenir des molécules très intéressantes. Parmi elles par exemple, le 7-hydroxy-4 -methoxyflavone absorbe dans la zone des UVB et des UVA avec un fort coefficient d absorption. Certaines des molécules synthétisées possèdent une structure chimique idéale en tant que piégeurs de radicaux libres et elles se sont révélées être des antioxydants plus efficace in vitro que la vitamine E, sur des bases molaires. Ces résultats ont été obtenus en jouant soit sur le motif des substitutions autour du corps des flavonoides, soit sur le degré d oxydation des molécules (e.g. Bacalein). Les effets biologiques de la 7--glucosyl-4 -methoxyflavone ont également été testés utilisant des matrices d ADN complémentaire, comprenant une série de plus de 400 gènes relatif aux fonctions de la peau. Des composés sélectionnés dans la bibliothèque ont été testés pour leur capacités d inhiber les protéines tyrosines kinases. ZUSAMMENFASSUNG VI ZUSAMMENFASSUNG Flavonoide sind polyphenolische Verbindungen, die in zahlreichen Pflanzen weit verbreitet sind. Viele von ihnen besitzen biologische Eigenschaften (als adikalfänger, Entzündungshemmer...), die möglicherweise auf kosmetischem Gebiet möglicherweise nutzbar sind. Flavonoide absorbieren beispielsweise im UV-Bereich, was ihnen gute UV- Filtereigenschaften verleiht. In unserem Labor wurden Flavonoide und polyphenolische Derivate untersucht um zu verstehen, welcher Teil des Moleküls für die obengenannten Eigenschaften verantwortlich ist. Ausgehend von mono- oder polyhydroxylierten Aromaten wurden einfache Synthesen von bekannten und neuen, mono- und polyphenolischen Verbindungen entwickelt, die in einer Substanzbibliothek zusammengefasst wurden. Durch Veränderung der Hydroxylierungsposition an den Benzolringen, war es möglich Moleküle mit sehr interessanten Eigenschaften zu erhalten. Unter diesen absorbiert das 7-Hydroxy-4 - methoxyflavon sowohl im UVB-, als auch im UVA- Bereich mit sehr hohen Extinktionskoeffizienten. Einige der synthetisierten Moleküle besitzen beste Voraussetzungen, um als Abfänger für freie adikale zu wirken. Es könnte gezeigt werden, dass diese in vitro auf molarer Basis wirksamere Antioxidanzien sind als Vitamin E. Diese Ergebnisse wurden sowohl durch Variation des Substitutionsmusters um den Kern der Flavonoide als auch des xydationsgrads der Verbindungen erreicht (z.b. Bacalein). Die biologische Wirkung von 7--Glucosyl-4 -methoxyflavon wurde daruberhinaus mit cdna-matrizen geprüft, welche eine Gruppe von mehr als 400 mit der Haut assoziierte Gene enthalten. Ausgesuchte Verbindungen der Musterbibliothek wurden außerdem darauf hin untersucht, inwieweit sie in der Lage sind Tyrosine-Kinasen zu hemmen. INDEX VII INDEX ACKNWLEDGMENTS ABBEVATINS ABSTACT ESUME ZUSAMMENFASSUNG INDEX I II IV V VI VII INTDUCTIN 1 PAT I 3 CHAPTE 1: GENEAL INFMATINS 4 1. GENEAL INTDUCTIN T THE FLAVNIDS Definition Structures Nomenclature Distribution in the nature Properties 8 2. SYNTHESES The biosynthetic pathway Chemical syntheses The most important intermediates to obtain Chalcones β-diketones Cyclisation of the intermediates Chalcones β-diketones ther syntheses n flavonoids Epoxidation of flavones Epoxidation of Chalcones From other precursors Photochemical synthesis QUANTITATIVE STUCTUE ACTIVITY ELATINSHIP (QSA) Definition The advantages and disadvantages of QSA Advantages of QSA Disadvantages of QSA CNCLUSIN 23 INDEX VIII CHAPTE 2: THE SYNTHESES F FLAVNIDS PECUSS INTDUCTIN SYNTHESES F THE ACETPHENNES Friedel-Crafts reaction Syntheses of the 2,3-dihydroxyacetophenone (12b) SYNTHESES F α-substituted ACETPHENNES Precursors of flavonols Precursors of isoflavonoids PLYACETYLATIN F PHENL CNCLUSIN 34 CHAPTE 3: NEW SYNTHETIC UTES T FLAVNIDS INTDUCTIN SYNTHESES F FLAVNES Building Block Approach A new procedure with Lithium hydroxide A modified Baker-Venkataraman rearrangement for the synthesis of flavonoids CSMETIC SLUBILIZATIN CNCLUSIN 48 PAT II 49 CHAPTE 4: STUCTUE- 13 C NUCLEA MAGNETIC ESNANCE ASSIGNMENT ELATINSHIP INTDUCTIN STUCTUE- 13 C NM ASSIGNMENT ELATINSHIP Flavones A- and C-rings Introduction of one hydroxyl group Introduction of several hydroxyl groups B-ring Introduction of hydroxyl groups Introduction of methoxyl groups / methylation of hydroxyl groups Nature of the substituents Flavonol, Flavanone, Flavanonol Introduction of 3-H Double bond between C-2 and C Isoflavones CNCLUSIN 68 INDEX IX CHAPTE 5: STUCTUE-UV ACTIVITY ELATINSHIP INTDUCTIN UV ABSPTIN SPECTA Flavones Band (I) Bathochromic effect Hypsochromic effect Band (II) Bathochromic effect Hypsochromic effect thers Auxochromes Glycosidic Substituent Band (I) Band (II) Chloro- and aminosubstitutents Band (I) Band (II) Flavonol, Flavanone, Flavanonol Band (I) Band (II) Isoflavones Band (I) Band (II) CNCLUSIN 87 CHAPTE 6: STUCTUE ANTIXIDANT ACTIVITY ELATINSHIP INTDUCTIN ANTIXIDANT ACTIVITY Definition of the antioxidant activity Mechanisms of the antioxidant action Methods of the in vitro antioxidant activity Trolox Equivalent Antioxidant Capacity (TEAC) DPPH assay STUCTUE-ANTIXIDANT ACTIVITY ELATINSHIP TEAC Influence of the hydroxyl group position on the A-ring Influence of the substitutions on the B-ring DPPH assay A-ring ne hydroxyl group Several hydroxyl groups B-ring and its substitution patterns C-2-C-3 Double bond and 3-hydroxyl group CNCLUSIN 106 INDEX X CHAPTE 7: CSMETIC AND PHAMACEUTICAL APPLICATINS INTDUCTIN SKIN-FCUSED CDNA TEST NA expression study using DNA chips Data analysis PTEIN KINASES INHIBITS TESTS Definition Protein kinase receptors Protein kinases inhibitors CNCLUSIN 114 CNCLUSIN 115 CNCLUSIN 120 ZUSAMMENFASSUNG 126 EXPEIMENTAL PAT GENEAL EXPEIMENTAL PCEDUE PAT Chemicals Melting point Nuclear Magnetic esonance spectroscopy Mass spectroscopy UV-vis spectroscopy Elementary analyses HPLC chromatography Antioxidant activity (radical scavenger potential) TEAC (Trolox Equivalent Antioxidant Activity) DPPH Assay: The free radical scavenging method GENEAL PCEDUES F THE SYNTHESES General procedures for the syntheses of acetophenones BF 3 -Friedel-Crafts procedure Methyllithium procedure (Alkyl-de-oxido-substitution) Grignard procedure AlCl 3 -Friedel-Crafts procedure Houben-Hoesch procedure General procedures of deprotection AlCl 3 -deprotection procedure BBr 3 -demethylation procedure (for acetophenone) BBr 3 -demethylation procedure (for flavonoids) General procedures for the synthesis of flavonoids Procedure A Procedure B Procedure C 140 INDEX XI 3. CMPUNDS Precursors of flavonoids (Chapter 2) Precursors of flavones (2-Hydroxyphenyl)-ethanone (12a) (2,3-Dihydroxyphenyl)-ethanone (12b) (2,4-Dihydroxyphenyl)-ethanone (12c) (2,5-Dihydroxyphenyl)-ethanone (12d) (2,6-Dihydroxyphenyl)-ethanone (12e) (2,3,4-Trihydroxyphenyl)-ethanone (12f) (6-Hydroxybenzo[1,3]dioxol-5-yl)-ethanone (12g) (2,4,6-Trihydroxyphenyl)-ethanone (12h) (2,4,5-Trihydroxyphenyl)-ethanone (12i) Acetic acid 2-hydroxyphenyl ester (57) (2,3-Dimethoxyphenyl)-ethanone (59a) (2-Hydroxy-3-methoxyphenyl)-ethanone (59b) Precursors of flavonols (2,4-Dihydroxyphenyl)-2-methoxyethanone (63a) (2,4,6-Trihydroxyphenyl)-2-methoxyethanone (63b) (1-Imino-2-methoxyethyl)-benzene-1,3,5-triol hydrochloride (65b) Precursors of isoflavonoids (2,4-Dihydroxyphenyl)-2-phenylethanone (67a) (2,4-Dihydroxyphenyl)-2-(4-methoxyphenyl)-ethanone (67b) Polyacetophenones (3-Acetyl-2,4,6-trihydroxyphenyl)-ethanone (68) Acetic acid 3,5-diacetoxyphenyl ester (69) (3,5-diacetyl-2,4,6-trihydroxyphenyl)-ethanone (70) Flavones (Chapter 3) Phenyl-4-oxo-4H-1-benzopyran (24) Hydroxy-2-phenyl-4-oxo-4H-1-benzopyran (73) Hydroxy-2-phenyl-4-oxo-4H-1-benzopyran (74) Hydroxy-2-phenyl-4-oxo-4H-1-benzopyran (75) ,8-Dihydroxy-2-phenyl-4-oxo-4H-1-benzopyran (76) ,7-Dihydroxy-2-phenyl-4-oxo-4H-1-benzopyran (77) ,7-Dihydroxy-2-phenyl-4-oxo-4H-1-benzopyran / Chrysin (78) ,6,7-Trihydroxy-2-phenyl-4-oxo-4H-1-benzopyran / Baicalein (79) (4-Methoxyphenyl)-4-oxo-4H-1-benzopyran (80) Hydroxy-2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran / Pratol (82) Hydroxy-2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran (83) Hydroxy-2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran (84) ,8-Dihydroxy-2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran (85) ,7-Dihydroxy-2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran/Acacetin (87) (3,4-Dimethoxyphenyl)-4-oxo-4H-1-benzopyran (88) Hydroxy-2-(3,4-dimethoxyphenyl)-4-oxo-4H-1-benzopyran (90) Hydroxy-2-(3,4-dimethoxyphenyl)-4-oxo-4H-1-benzopyran (91) Hydroxy-2-(3,4-dimethoxyphenyl)-4-oxo-4H-1-benzopyran (92) ,8-Dihydroxy-2-(3,4-dimethoxyphenyl)-4-oxo-4H-1-benzopyran (93) ,7-Dihydroxy-2-(3,4-dimethoxyphenyl)- 4-oxo-4H-1-benzopyran (94) ,7-Dihydroxy-2-(3,4-dimethoxyphenyl)- 4-oxo-4H-1-benzopyran/Luteolin 3,4 - dimethyl ether (95) (3,4,5-Trimethoxyphenyl)-4-oxo-4H-1-benzopyran (96) 174 INDEX XII Hydroxy-2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1-benzopyran (98) Hydroxy-2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1-benzopyran (99) Hydroxy-2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1-benzopyran (100) ,8-Dihydroxy-2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1-benzopyran (101) ,7-Dihydroxy-2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1-benzopyran / Prosogerin E (102) ,7-Dihydroxy-2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1-benzopyran (103) (4-Hydroxyphenyl)-4-oxo-4H-1-benzopyran (104) Hydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran (106) Hydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran (107) Hydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran (108) ,8-Dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran (109) ,7-Dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran (111) (3,4-Dihydroxyphenyl)-4-oxo-4H-1-benzopyran (112) Hydroxy-2-(3,4-dihydroxyphenyl)-4-oxo-4H-1-benzopyran (114) Hydroxy-2-(3,4-dihydroxyphenyl)-4-oxo-4H-1-benzopyran (115) Hydroxy-2-(3,4-dihydroxyphenyl)-4-oxo-4H-1-benzopyran (116) ,8-Dihydroxy-2-(3,4-dihydroxyphenyl)-4-oxo-4H-1-benzopyran (117) ,7-Dihydroxy-2-(3,4-dihydroxyphenyl)-4-oxo-4H-1-benzopyran / Luteolin (119) (3,4,5-Trihydroxyphenyl)-4-oxo-4H-1-benzopyran (120) Hydroxy-2-(3,4,5-trihydroxyphenyl)-4-oxo-4H-1-benzopyran (124) ,8-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-4-oxo-4H-1-benzopyran (125) ,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-4-oxo-4H-1-benzopyran (126) ,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-4-oxo-4H-1-benzopyran (127) Hydroxy-2-(4-chlorophenyl)-4-oxo-4H-1-benzopyran (128) Hydroxy-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran (129) Hydroxy-2-(4-aminophenyl)-4-oxo-4H-1-benzopyran (130) Benzo[1,3]dioxol-5-yl-[1,3]dioxolo[6,7]-4-oxo-4H-1-benzopyran (131) ,7-Dihydroxy-3-methoxy-2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran / Kaempherol 3,4 -dimethyl ether (138) Flavonoid esters (Chapter 3) Benzoic acid 2-phenyl-4-oxo-4H-1-benzopyran-7-yl ester (139) Benzoic acid 2-phenyl-4-oxo-4H-1-benzopyran-6-yl ester (140) Methoxy-benzoic acid 2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran-7-yl ester (141) Methoxybenzoic acid 2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran-6-yl ester (142) Methoxybenzoic acid 5-hydroxy-2-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran- 7-yl ester (143) ,4-Dimethoxybenzoic acid 2-(3,4-dimethoxyphenyl)-4-oxo-4H-1-benzopyran-7-yl ester (144) ,4-Dimethoxy-benzoic acid 2-(3,4-dimethoxyphenyl)-4-oxo-4H-1-benzopyran-6-yl ester (145) ,4-Dimethoxybenzoic acid 5-hydroxy-2-(3,4-dimethoxyphenyl)-4-oxo-4H-1- benzopyran-7-yl ester (146) Bis 3,4-dimethoxybenzoic acid 2-(3,4-dimethoxyphenyl)-4-oxo-4H-1-benzopyran- 6,7-yl ester (147) ,4,5-Trimethoxybenzoic acid 2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1-benzopyran- 7-yl ester (148) 204 INDEX XIII ,4,5-Trimethoxybenzoic acid 2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1-benzopyran- 6-yl ester (149) ,4,5-Trimethoxybenzoic acid 5-hydroxy-2-(3,4,5-trimethoxyphenyl)-4-oxo-4H-1- benzopyran-7-yl ester (150) ,4,5-Trimethoxybenzoic acid 8-hydroxy-2-(3,4,5-trimethoxyphenyl)- 4-oxo-4H-1- benzopyran-7-yl ester (151) Benzo[1,3]dioxole-5-carboxylic acid 2-benzo[1,3]dioxol-5-yl-5-hydroxy-4-oxo-4H- 1-benzopyran-7-yl ester (152) ,4,5-Trimethoxybenzoic acid 2-[1-hydroxy-3-oxo-3-(3,4,5-trimethoxyphenyl)- propenyl]-phe
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