3-(o-(Methylthio)phenyl)-1-phenylprop-2-en-1-one (48) ¡B1-(o-(methylthio)-phenyl)-3-phenylprop-2-en-1-one (49) and 1-(o-(methylthio)phenyl)-3-phenylprop-2-yn-1-one (50) had been studied by means of pyrolysis and photolysis. Under pyrolytic conditions, compound 48 gave phenanthrene (2) as the major product. Both compounds 49 and 50 gave thioflavone (53) as the major product. Under photolytic conditions, compounds 48-50 gave the expected products 2-benzoylbenzo[b]thiophene (51)¡B 2-benzylidenebenzo[b]thiophen-3-one (52) and thioflavone (53), respectively.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany Candidat: Jana Faberová Supervisor: doc. Ing. Kateřina Macáková, Ph.D. Title of Thesis: Interaction of chalcones with transition metals I. Iron is a biogenic metal element with unpaired d-electrons that plays a key role in the survival of unicellular organisms, plants and mammals. The electron shell of the iron atom is able to easily bind and release electrons and thus contribute to the proper function of the organism. Iron is necessary to ensure the transport of respiratory gases, cell differentiation and the functioning of some specific enzymes. However, despite the clearly positive effect of iron on human health, inappropriately low or high level of iron in the body can cause the development many diseases. Chalcones are plant polyphenols belonging to the family of flavonoids, secondary metabolites of plants. The term chalcone generally refers to a chemical structure with an ,-unsaturated ketone system based on 1,3-diphenylprop-2-en-1-on. These substances have a wide spectrum of biological activities and in the right amount can be good for human health. The aim of this diploma thesis was to monitor the iron-chelating and iron-reducting activity of selected chalcones: isoliquiritigenin, licochalcon A,...

Charles University in Prague Faculty of Phramacy in Hradec Králové Department of Pharmaceutical Botany Candidate: Martina Šulcová Supervisor: Assoc. Prof. Ing. Kateřina Macáková, Ph.D. Title of the diploma thesis: Interaction of chalcones with transition metals II. Copper is one of the essencial elements in human body which is involved in the functioning of many enzymes and metabolic pathways. Although it appears in trace amounts in the body, its functions are irreplaceable. However, the ion level must be kept in balance by the various mechanisms of the body. If there is an excess or deficiency of copper in the body, this condition can lead to the development of health issues. Chalcones are substances belonging to the group of flavonoids. Their polyphenolic structure does not have a closed ring C. Studies describe their anticancer, anti-inflammatory, antiviral, antidiabetic, antibacterial, antioxidant, immunosuppressive and other properties. Chosen substances in the group of dihydrochalcones (naringin dihydrochalcone, neohesperidin dihydrochalcone, phloretin, phlorizin) and chalcones (isoliquiritigenin, licochalcone A) were tested for their chelation and reduction activity of the copper ions in this diploma thesis. The activity was measured at different pH environments (7.5; 6.8; 5.5 and 4.5) and...

Les maladies tropicales provoquées par des parasites protozoaires tels que Trypanosoma brucei, Plasmodium falciparum et Leishmania donovani, infectent des milliards d'individus dans le monde et en tuent des millions chaque année. Actuellement, les phénomènes de résistance face aux thérapies actuelles utilisées pour traiter ces maladies dites " négligées " deviennent inquiétants et problématiques. Par conséquent, la découverte de nouvelles classes de molécules bioactives antiparasitaires est primordiale.C'est dans ce contexte que s'inscrit ce travail de thèse. La cissampeloflavone est un dimère chalcone-flavone isolé en 2003 d’une plante vénézuélienne, Cissampelos pareira. Cette molécule a démontré une bonne activité contre T. brucei (CI50 = 1 µM). Par ailleurs, des études de modélisation moléculaire ont prédit que son dérivé 4-désoxycissampeloflavone possèderait une bonne affinité pour une enzyme essentielle à la survie du parasite. Pour ces raisons, nous avons entrepris la synthèse totale de ces deux molécules originales jamais réalisée à ce jour.Des analogues simplifiés ont d’abord été synthétisés afin de mettre au point le schéma réactionnel pour former la cissampeloflavone et la 4-désoxycissampeloflavone. Ces composés ont pour base commune le noyau benzofurane qui porte soit la " partie chalcone " soit la " partie flavone " de ces dimères. Les deux synthèses totales ont ensuite été entreprises.Ce travail de thèse a notamment permis la création d'une librairie d'analogues benzofuranes polysubstitués, la découverte d'une réaction de méthylénation originale et la formation de nouveaux dérivés furanoflavones. La plupart ont été évalués sur T. brucei, P. falciparum et L. donovani. Plusieurs d'entre eux ont présenté une activité trypanocide intéressante et prometteuse. / Tropical diseases caused by protozoan parasites such as Trypanosoma brucei, Plasmodium falciparum and Leishmania donovani, infect billions of people worldwide and kill millions of them every year. Nowadays, resistance phenomena against actual therapies used to treat these " neglected " diseases are becoming worring and problematic. Therefore, discovery of new classes of antiparasitic bioactive molecules is primordial.This is the aim of this PhD work. Cissampeloflavone is a chalcone-flavone dimer isolated in 2003 from a Venezuelan plant, Cissampelos pareira. This molecule has showed a good activity against Trypanosoma brucei (IC50 = 1 µM). Besides, molecular docking studies have predicted that its derivative 4-desoxycissampeloflavone would possess a good affinity for an essential enzyme for parasite survival. For these reasons, we undertook the total synthesis of these two original molecules never carried out to date.Simplified analogues have been prepared in order to elaborate a synthetic pathway to form cissampeloflavone and 4-desoxycissampeloflavone. These compounds possess the benzofuran ring as common core which bears either the "chalcone part" or the "flavone part" of these dimers. The total syntheses were then undertaken.This PhD work has particularly enabled the creation of a polysubstituted benzofuran library, the discovery of an original methylenation reaction and the formation of new furanoflavone derivatives. Most of them were evaluated on T. brucei, P. falciparum and L. donovani. Several compounds have showed an interesting and promising trypanocidal activity.

La synthèse et la vectorisation d’agents anticancéreux constituent des axes de recherche majeurs du LCSN. De nombreux composés naturels possèdent des propriétés anticancéreuses, mais ils sont abandonnés en raison de leur manque de sélectivité vis-à-vis des cellules cancéreuses ou de leur faible biodisponibilité. Ainsi, un grand intérêt est actuellement porté sur le développement de médicaments spécifiquement vectorisés vers les cellules cancéreuses. Les vecteurs utilisés dans ce travail sont des dérivés de polyamines et des nano objets de type β-cyclodextrines / nanocristaux de cellulose (β-CD/CNCx). Les polyamines vont permettre un ciblage actif des cellules cancéreuses grâce au système de transport de polyamine (PTS) surexprimé dans ces cellules. Les nano objets vont cibler spécifiquement les tumeurs via un ciblage passif dû à l’effet EPR. Les principes actifs employés dans cette étude sont des flavonoïdes, et plus particulièrement des chalcones. En effet, les flavonoïdes, qui constituent une large famille de composés phénoliques naturels, sont connus pour leurs nombreux effets biologiques comme les activités antioxydantes, anti-inflammatoires et anti-prolifératives.L’intérêt du LCSN à la fois pour les chalcones et les agents anticancéreux nous a conduits à concevoir de nouveaux composés antiprolifératifs vectorisés. Ce travail présente dans un premier temps la synthèse de chalcones et l’obtention de dérivés couplés aux différents vecteurs décrits précédemment (motifs polyaminés,β-CD/CNCx) ; un travail sur la synthèse d’une bis-chalcone via le couplage de Suzuki est également exposé.L’ensemble des molécules obtenues est caractérisé par des analyses RMN 1H, 13C et HRMS. Dans une seconde partie, nous présentons l’ensemble des évaluations biologiques des composés précédemment obtenus. Ces évaluations sont réalisées par un test de viabilité cellulaire (test MTT) sur quatre lignées cancéreuses : deux colorectales (HT-29 et HCT-116) et deux prostatiques (PC-3 et DU-145). / Synthesis and vectorization of anticancer agents are major research themes of LCSN. Many natural compoundspossess anti-cancer properties, but they are dropped because of their lack of selectivity to cancer cells or theirlow bioavailability. Thus, great interest is currently focused on the development of drugs specifically vectorizedto cancer cells. The vectors used in this work are polyamine derivatives and nano-objects type β-cyclodextrin /cellulose nanocrystals (β-CD/CNCx). Polyamines allow active targeting of cancer cells through the polyaminetransport system (PTS) overexpressed in these cells. Nano-objects specifically target tumors using a passivetargeting due to the EPR effect. Drugs used in this study are flavonoids, especially chalcones. Indeed,flavonoids, which constitute a large family of natural phenolic compounds, are known for their numerousbiological effects such as antioxidant, anti-inflammatory and anti-proliferative activities. The interest of LCSNfor both chalcones and anticancer agents led us to design new vectorized anti-proliferative compounds. Firstly,this work shows the synthesis of chalcones and their derivatives coupled to various above-described vectors(polyamines units, β-CD/CNCx); a work on the synthesis of a bis-chalcone through the Suzuki coupling reactionis also exposed. All molecules obtained are characterized by 1H NMR, 13C NMR and HRMS analysis. In thesecond part of this work, we present all biological evaluations of compounds previously obtained. Theseassessments are performed through a cell viability test (MTT test) on four cancer cell lines: two colorectal (HT-29 and HCT-116) and two prostate (PC-3 and DU-145) cell lines.

Les deux systèmes nodulaires symbiotiques les plus importants au niveau agronomique et environnemental sont, d'une part, les symbioses Rhizobium-légumineuses qui concernent environ 14 000 espèces, et d'autre part, les symbioses entre les plantes actinorhiziennes (environ 200 espèces) et l'actinomycète du sol Frankia. La plupart des plantes actinorhiziennes sont capables de fixer des quantités d'azote comparable à celles des Légumineuses ; ce sont généralement des plantes pionnières capables de coloniser des environnements pauvres en éléments minéraux. Elles représentent donc un atout écologique important. Si la symbiose Rhizobium-légumineuse est très étudiée, les mécanismes moléculaires à l'origine de la formation des nodules actinorhiziens restent actuellement peu connus. Ainsi, chez les Légumineuses, les flavonoïdes sont des molécules-clefs du processus de nodulation, alors que chez les plantes actinorhiziennes, l'implication des flavonoïdes dans la nodulation reste imprécise. L'objectif de cette thèse était de comprendre l'implication des flavonoïdes au cours de l'interaction symbiotique entre l'arbre actinorhizien tropical Casuarina glauca et son symbiote Frankia. L'analyse d'une base de données d'unigènes couplée à celle de données d'expression de puces à ADN a permis l'identification de huit genes de C. glauca impliqués dans la voie de biosynthèse des flavonoïdes. L'étude de leur expression dans les racines par PCR quantitative au cours d'une cinétique d'infection de C. glauca par Frankia a montré que les transcrits de la chalcone isomerase et de l'isoflavone reductase s'accumulaient très tôt après l'inoculation, suggérant ainsi une implication des isoflavonoïdes dans la symbiose actinorhizienne. Nous avons alors utilisé une stratégie d'ARN interférent pour réduire l'expression du gène de la chalcone synthase, la première enzyme de la voie de biosynthèse des flavonoïdes. La réduction de l'expression du gène de la chalcone synthase a provoqué une réduction significative du taux de flavonoïdes dans les racines ainsi qu'une très forte diminution du taux de nodulation chez les plantes transformées. Une restauration du taux de nodulation a pu être obtenu en présence de naringenin, une molécule centrale de la voie de biosynthèse des flavonoïdes.Nos résultats apportent donc, pour la première fois, une évidence directe de l'implication forte des flavonoïdes au cours de la nodulation des plantes actinorhiziennes. / Nitrogen-fixing root nodulation, confined to four plant orders, encompasses more than 14,000 Leguminosae species, and approximately 200 actinorhizal species forming symbioses with rhizobia and Frankia bacterial species, respectively. Most actinorhizal plants are capable of high rates of nitrogen fixation comparable to the nitrogen fixing symbiosis between legumes and Rhizobium. As a consequence, these plants are able to grow in poor and disturbed soils and are important elements in plant community worldwide. The basic knowledge of the symbiotic interaction between Frankia and actinorhizal plants is still poorly understood, although it offers striking differences with the Rhizobium-legume symbiosis. In the symbiosis between legumes and Rhizobium, flavonoids are key molecules for nodulation. In actinorhizal plants, the involvement of flavonoids in symbiosis is poorly understood, but because of the similarities of the infection process between some actinorhizal plants and legumes, flavonoids were proposed to act as plant signals for the bacteria Frankia. The objective of this thesis was to investigate the involvement of flavonoids during the actinorhizal nodulation process resulting from the interaction between the tropical tree Casuarina glauca and the actinomycete Frankia.Eight C. glauca genes involved in flavonoid biosynthesis were identified from a unigene database and their expression patterns were monitored by quantitative real-time PCR during the nodulation time course. Our results showed that chalcone isomerase and isoflavone reductase transcripts accumulated preferentially early after inoculation with Frankia, suggesting thus for the first time that isoflavonoids are implicated in actinorhizal nodulation. To go deeper in the understanding of the role of these molecules in actinorhizal symbiosis, we used RNA interference strategy to silence chalcone synthase, the enzyme that catalyzes the first committed step of the flavonoid pathway. Knockdown of chalcone synthase expression led to a strong reduction of specific flavonoids levels and resulted in a severely impaired nodulation. Nodule formation could be rescued by supplementation of plants with naringenin, which is an upstream intermediate in flavonoid biosynthesis. Our results provide, for the first time, direct evidence of a strong implication of flavonoids during actinorhizal nodulation.

Malaria is endemic in 106 countries worldwide. This disease is caused by a parasite from the genus Plasmodium. Of the five species that infect humans, Plasmodium falciparum is the most virulent, with over three billion people at risk and around 660 000 deaths reported in 2011. Of these deaths, 91% were in the African region, while 86% were children under the age of five. In light of the widespread development of resistance by malaria parasites against the classic antimalarial drugs, such as chloroquine (CQ) and now the established tolerance towards the widely used artemisinins, an immense need exists for identifying and developing new and effective antiplasmodial drugs. In search for such new antimalarial drugs, three chalcone based series of compounds were prepared and investigated during this study. The first series (Chapter 3) comprised 4-aminoquinolinyl-chalcone amides, which were synthesized through amidation of carboxylic acid-functionalised chalcone with aminoquinolines, using 1,1'-carbonyldiimidazole (CDI) as coupling agent. These compounds were screened alongside CQ against the CQ sensitive (3D7) and CQ resistant (W2) strains of P. falciparum. Cytotoxicity was assessed against the WI-38 cell line. The amide, featuring the 1,6-diaminohexane linker, was found the most active of all these new novel compounds tested. It was found to be as potent as CQ against 3D7, while displaying a two-fold higher activity than CQ against the W2 strain, coupled with good selective antimalarial activity (SI = 435) towards the parasitic cells. The second series (Chapter 4) consisted of aminoferrocenyl-chalcone amides, synthesized through condensation of a chalcone with an aminoferrocenyl. These compounds were screened against the 3D7, and antifolate- and CQ resistant (FCR3) strains of P. falciparum and cytotoxicity was determined against the WI-38 line. The most active compound of this series was the amide, containing the 1,2-diaminoethane linker, which showed 130- and 42 times less potency than CQ against the 3D7 and W2 strains, respectively. The third series of antimalarials (Chapter 5) involved dihydroartemisinyl-chalcone esters, synthesized through esterification of chalcones with DHA. These compounds were screened against 3D7 and W2 strains of P. falciparum, while the cytotoxicity was determined against the WI-38 line. Those esters featuring oxygenated aryl rings were three- to four-fold more potent than current clinically used artesunate against both P. falciparum strains. They were also screened in vitro against a panel of three cancer cell lines consisting of TK-10, UACC-62 and MCF-7. Thermogravimetric analysis revealed that the targeted hybrids were all thermally more stable than DHA as a result of the presence of the chalcone moiety in their structures. This could prove beneficial to the high temperature storage conditions that prevail in most malaria endemic countries. This study resulted in a number of compounds with varying antiplasmodial activity ranges. The compounds in series 3 were overall the most active, due to the incorporation of the highly active dihydroartemisinin pharmacophore. The chalcone moiety, especially, demonstrated a large scope for future development, owing to the ease of synthesis and the relatively low costs involved. The most active compounds of the three series could serve as potential lead compounds in the future development of more effective antimalarial drugs. / PhD (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Malaria is endemic in 106 countries worldwide. This disease is caused by a parasite from the genus Plasmodium. Of the five species that infect humans, Plasmodium falciparum is the most virulent, with over three billion people at risk and around 660 000 deaths reported in 2011. Of these deaths, 91% were in the African region, while 86% were children under the age of five. In light of the widespread development of resistance by malaria parasites against the classic antimalarial drugs, such as chloroquine (CQ) and now the established tolerance towards the widely used artemisinins, an immense need exists for identifying and developing new and effective antiplasmodial drugs. In search for such new antimalarial drugs, three chalcone based series of compounds were prepared and investigated during this study. The first series (Chapter 3) comprised 4-aminoquinolinyl-chalcone amides, which were synthesized through amidation of carboxylic acid-functionalised chalcone with aminoquinolines, using 1,1'-carbonyldiimidazole (CDI) as coupling agent. These compounds were screened alongside CQ against the CQ sensitive (3D7) and CQ resistant (W2) strains of P. falciparum. Cytotoxicity was assessed against the WI-38 cell line. The amide, featuring the 1,6-diaminohexane linker, was found the most active of all these new novel compounds tested. It was found to be as potent as CQ against 3D7, while displaying a two-fold higher activity than CQ against the W2 strain, coupled with good selective antimalarial activity (SI = 435) towards the parasitic cells. The second series (Chapter 4) consisted of aminoferrocenyl-chalcone amides, synthesized through condensation of a chalcone with an aminoferrocenyl. These compounds were screened against the 3D7, and antifolate- and CQ resistant (FCR3) strains of P. falciparum and cytotoxicity was determined against the WI-38 line. The most active compound of this series was the amide, containing the 1,2-diaminoethane linker, which showed 130- and 42 times less potency than CQ against the 3D7 and W2 strains, respectively. The third series of antimalarials (Chapter 5) involved dihydroartemisinyl-chalcone esters, synthesized through esterification of chalcones with DHA. These compounds were screened against 3D7 and W2 strains of P. falciparum, while the cytotoxicity was determined against the WI-38 line. Those esters featuring oxygenated aryl rings were three- to four-fold more potent than current clinically used artesunate against both P. falciparum strains. They were also screened in vitro against a panel of three cancer cell lines consisting of TK-10, UACC-62 and MCF-7. Thermogravimetric analysis revealed that the targeted hybrids were all thermally more stable than DHA as a result of the presence of the chalcone moiety in their structures. This could prove beneficial to the high temperature storage conditions that prevail in most malaria endemic countries. This study resulted in a number of compounds with varying antiplasmodial activity ranges. The compounds in series 3 were overall the most active, due to the incorporation of the highly active dihydroartemisinin pharmacophore. The chalcone moiety, especially, demonstrated a large scope for future development, owing to the ease of synthesis and the relatively low costs involved. The most active compounds of the three series could serve as potential lead compounds in the future development of more effective antimalarial drugs. / PhD (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Made available in DSpace on 2017-07-24T19:38:11Z (GMT). No. of bitstreams: 1 Larissa Sens.pdf: 4559561 bytes, checksum: d3bb440abdcd395ceedbf48196d1cee7 (MD5) Previous issue date: 2014-02-18 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This study presents theoretical results regarding the conformational equilibrium of three diferent chalcones CHALBr (2-propen-1-one, 1-(2-bromophenyl)-3-phenyl), CHALOH (2-Propen-1-one, 3-(4-hydroxyphenyl)-1-phenyl) and CHALBrOH (2-Propen-1-one, 1-(2- bromophenyl)-3-(4-hydroxyphenyl). / Nesse trabalho são apresentados resultados teoricos referentes ao equilibrio conformacional de tres diferentes chalconas, CHALBr [1-(2-bromofenil)-2-propen-3-fenil-1-ona], CHALOH [1-fenil-2-propen-3-(4-hidroxifenil)-1-ona] e CHALBrOH [1-(2-bromofenil)-2-propen-3-(4- hidroxifenil)-1-ona].

Les maladies tropicales provoquées par des parasites protozoaires tels que Trypanosoma brucei, Plasmodium falciparum et Leishmania donovani, infectent des milliards d'individus dans le monde et en tuent des millions chaque année. Actuellement, les phénomènes de résistance face aux thérapies actuelles utilisées pour traiter ces maladies dites " négligées " deviennent inquiétants et problématiques. Par conséquent, la découverte de nouvelles classes de molécules bioactives antiparasitaires est primordiale.C'est dans ce contexte que s'inscrit ce travail de thèse. La cissampeloflavone est un dimère chalcone-flavone isolé en 2003 d'une plante vénézuélienne, Cissampelos pareira. Cette molécule a démontré une bonne activité contre T. brucei (CI50 = 1 µM). Par ailleurs, des études de modélisation moléculaire ont prédit que son dérivé 4-désoxycissampeloflavone possèderait une bonne affinité pour une enzyme essentielle à la survie du parasite. Pour ces raisons, nous avons entrepris la synthèse totale de ces deux molécules originales jamais réalisée à ce jour.Des analogues simplifiés ont d'abord été synthétisés afin de mettre au point le schéma réactionnel pour former la cissampeloflavone et la 4-désoxycissampeloflavone. Ces composés ont pour base commune le noyau benzofurane qui porte soit la " partie chalcone " soit la " partie flavone " de ces dimères. Les deux synthèses totales ont ensuite été entreprises.Ce travail de thèse a notamment permis la création d'une librairie d'analogues benzofuranes polysubstitués, la découverte d'une réaction de méthylénation originale et la formation de nouveaux dérivés furanoflavones. La plupart ont été évalués sur T. brucei, P. falciparum et L. donovani. Plusieurs d'entre eux ont présenté une activité trypanocide intéressante et prometteuse.