@phdthesis{Qamar2012, author = {Qamar, Riaz-ul}, title = {Synthesis of functionalized molecular probes for bioorthogonal metabolic glycoengineering}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-73378}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Biomolecules are difficult to investigate in their native environment. The vast complexity of cellular systems and seldom availability of chemical reactions compatible with the physiological milieu make it a challenging task. Bioorthogonal chemical reactions serve as a key to achieve selective ligation, whose components must react rapidly and selectively with each other under physiological conditions in the presence of the plethora of functionalities necessary to sustain life. In this dissertation, we focused on the synthesis of chemical reporters and probe molecules for bioorthogonal labeling through click reaction. Initially, sialic acid derivatives with a linker containing terminal alkyne functionality were synthesized. After the synthesis of azide derivatives of fluorescent dyes as counter partners, they were conjugated with sialic acids through Cu(I) catalyzed alkyne azide cycloaddition (CuAAC). The successful in vitro conjugation of Sia and fluorescent dyes was followed by metabolic tagging of human larynx carcinoma (HEp-2) and the carcinoma of Chinese hamster ovary (CHO­K1) with alkynated Sia that were subsequently ligated with fluorescein azide. Finally, the stained cells were subjected to fluorescent microscopy to obtain their images. To enable the click reaction compatible to in vivo applications, the reactivity of cyclooctyne was enhanced by two different approaches. In a first approach, following the Bertozzi's strategy, two fluorine atoms were introduced adjacent to the alkyne to lower the LUMO. In a second strategy the ring strain of cyclooctyne was attempted to be enhanced by the introduction of an amide group. In addition, glutarimide derivatives with free amino and carboxylic acid functional groups were synthesized by domino-Michael addition-cyclization-reaction.}, subject = {Click-Chemie}, language = {en} } @phdthesis{Mayerhoeffer2012, author = {Mayerh{\"o}ffer, Ulrich}, title = {Synthese, Eigenschaften und funktionale Anwendungen von NIR absorbierenden Squarainen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69428}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Zusammenfassend l{\"a}sst sich festhalten, dass die in dieser Abreit vorgestellten Squaraine herausragend gute NIR-Absorptions- und NIR-Emissionseigenschaften aufweisen, die sie f{\"u}r zahlreiche Anwendungen interessant machen. Dar{\"u}ber hinaus konnte gezeigt werden, dass ihre besondere cis-Konfiguration und ihr daraus resultierendes Dipolmoment zu vorteilhaften Anordnungen in d{\"u}nnen Filmen und in Blends mit PCBM f{\"u}hren. Diese Strukturen zeigen f{\"u}r dipolare Molek{\"u}le beeindruckende Exzitonen- und Ladungstransporteigenschaften, die vielversprechende Anwendungen in der organischen Elektronik wie in hier untersuchten l{\"o}sungsprozessierten BHJ-Solarzellen oder auch in OFETs erwarten lassen.}, subject = {Supramolekulare Chemie}, language = {de} } @phdthesis{Loedige2012, author = {Loedige, Melanie}, title = {Synthese und Evaluierung neuartiger Wirkstoffklassen gegen Infektionskrankheiten : antimalariale Hybrid-Verbindungen bestehend aus etablierten Arzneistoffen sowie aus Nphthylisochinolin-Alkaloiden und bekannten Arzneistoffen, Struktur-Wirkungs-Beziehungen der neuartigen, antileishmanial wirksamen tert-Butyloxycarbonylbenzylamino-Strukturelemente, Aminochinolinium-Verbindungen gegen bin{\"a}re Toxine aus Bacillus anthracis, Clostridium perfringens und Clostridium botulinum}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76412}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Infektionskrankheiten geh{\"o}ren weltweit immer noch zu den h{\"a}ufigsten Todesursachen, und auch wenn die Gef{\"a}hrdung in den Industriestaaten erheblich reduziert werden konnte, nimmt die Bedeutung von {\"u}bertragbaren Krankheiten wieder zu. Verursacht wird dies zum einen durch die F{\"a}higkeit der Keime gegen die eingesetzten Arzneistoffe verschiedenartige Resistenzmechanismen zu entwickeln, zum anderen auch dadurch, dass neuartige Infektionskrankheiten entstehen. Aus diesem Grund bleibt die Entwicklung neuer Medikamente ein st{\"a}ndiger Wettlauf mit der Anpassungsf{\"a}higkeit der Infektionserreger, und gerade dies spielt eine große Rolle f{\"u}r vernachl{\"a}ssigte und armutsassoziierte Krankheiten wie z.B. Tuberkulose, Malaria und HIV/AIDS, die in den Entwicklungsl{\"a}ndern große Krankheitslasten und so auch hohen volkswirtschaftlichen Schaden verursachen. Protozoische Parasiten wie die Erreger der Malaria und der Leishmaniose sind besonders trickreich, denn sie wechseln zwischen Vektor (z.B. M{\"u}cke) und Wirt (z.B. Mensch) und durchleben so verschiedene Stadien eines komplexen Entwicklungszyklus, von denen sich jedes einzelne Stadium wie ein 'anderer' Organismus verh{\"a}lt. Hierdurch ist die therapeutische Behandlung erschwert, und f{\"u}r die dauerhafte Eradikation der Parasiten und f{\"u}r die Hemmung ihrer Transmission, um letztlich eine Resistenzentwicklung der Medikamente zu verhindern, m{\"u}ssen Wirkstoffe m{\"o}glichst gegen alle Stadien {\"a}hnlich gut wirken. Die Konzeptionierung solcher Verbindungen, ihr strukturelles Design und schließlich ihre Synthesen waren Ziel der hier vorliegenden Arbeit, um neue aktive Vertreter gegen protozoische und bakterielle Erreger und Toxine bereitzustellen. Die Konzeptionierung und Synthese von Hybridmolek{\"u}len aus bew{\"a}hrten Arzneistoffen wurde als innovativer Ansatz zur Behandlung der Malaria verfolgt. Eine strukturell neue Wirkstoffklasse mit sehr guten spezifischen Aktivit{\"a}ten und interessanten Struktur-Aktivit{\"a}ts-Beziehungen gegen Promastigoten und gegen Amastigoten von L. major wurde entdeckt. Auf der Suche nach neuen Verbindungen, die bin{\"a}re Toxine von Bacillus anthracis Anthrax-Toxin), Clostridium perfringens (Iota-Toxin) und Clostridium botulinum C2-Toxin) hemmen k{\"o}nnen, wurden neben 4-Aminochinolin-Verbindungen neue Aminochinolinium-Salze konzipiert, synthetisiert und in Target-basierten Assays durch Titrationsexperimente und Stromfluktuationsanalysen bzw. in In-vitro-Experimenten auf ihre Wirksamkeit getestet.}, subject = {Malaria}, language = {de} } @phdthesis{Schlosser2012, author = {Schlosser, Felix}, title = {Synthese und Charakterisierung kovalent gebundener Perylenbisimid-Makrozyklen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71811}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Eine Reihe von Acetylen-verkn{\"u}pften Perylenbisimid(PBI)-Makrozyklen mit unterschiedlicher Ringgr{\"o}ße wurde durch Palladium-katalysierte Homokupplung synthetisiert und mit Hilfe von Recycling-GPC getrennt. Diese Makrozyklen wurden durch NMR-Spektroskopie und Massenspektrometrie charakterisiert und weiterhin die photophysikalischen Eigenschaften durch UV/Vis-Absorptions- und Fluoreszenzemissions-Messungen untersucht. Die Selbstorganisation dieser PBI-Makrozyklen zu hochgeordneten Nanostrukturen auf HOPG-Oberfl{\"a}chen wurde mittels Rasterkraftmikroskopie untersucht.}, subject = {Makrocyclische Verbindungen}, language = {de} } @article{WolterAizezersFenneletal.2012, author = {Wolter, Steffen and Aizezers, Janis and Fennel, Franziska and Seidel, Marcus and W{\"u}rthner, Frank and K{\"u}hn, Oliver and Lochbrunner, Stefan}, title = {Size-dependent exciton dynamics in one-dimensional perylene bisimide aggregates}, series = {New Journal of Physics}, volume = {14}, journal = {New Journal of Physics}, number = {105027}, doi = {10.1088/1367-2630/14/10/105027}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135190}, year = {2012}, abstract = {The size-dependent exciton dynamics of one-dimensional aggregates of substituted perylene bisimides are studied by ultrafast transient absorption spectroscopy and kinetic Monte-Carlo simulations as a function of the excitation density and the temperature in the range of 25-90 degrees C. For low temperatures, the aggregates can be treated as infinite chains and the dynamics is dominated by diffusion-driven exciton-exciton annihilation. With increasing temperature the aggregates dissociate into small fragments consisting of very few monomers. This scenario is also supported by the time-dependent anisotropy deduced from polarization-dependent experiments.}, language = {en} } @phdthesis{Berberich2012, author = {Berberich, Martin}, title = {Rylene Bisimide-Diarylethene Photochromic Systems for Non-Destructive Memory Read-out}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-73517}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Diese Doktorarbeit zeigt deutlich verbesserte aus Rylenbisimiden und Diarylethenen aufgebaute, photochrome Systeme f{\"u}r das nicht-destruktive Auslesen von Fluoreszenz. Dabei wird die Fluoreszenz der Emittereinheit durch photoinduzierten Elektronentransfer nur zu einer isomeren Form des Photochromes gel{\"o}scht. Die Triebkraft f{\"u}r den Fluoreszenz-l{\"o}schenden Elektronentransfer wurde mittels Rehm-Weller-Gleichung berechnet. Die erhaltenen Systeme erf{\"u}llen die notwendigen Anforderungen f{\"u}r ein nicht-destruktives Auslesen in einem auf Schreiben, Auslesen und L{\"o}schen basierenden fluoreszierenden Datenspeicher.}, subject = {Photochromie}, language = {en} } @phdthesis{Bischof2012, author = {Bischof, Sebastian Klaus}, title = {Qsar-geleitete Synthese von strukturell vereinfachten antiplasmodialen Naphthylisochinolinen und Synthese von antiprotozoischen Arylchinolinium-Salzen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76601}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Die Malaria und andere Infektionskrankheiten sind immer noch die Haupttodesursache in Entwicklungsl{\"a}ndern. Durch das jahrzehntelange Vers{\"a}umnis, neue Wirkstoffe zu entwickeln, und durch die rasante Ausbreitung von Resistenzen gegen herk{\"o}mmliche Medikamente sind in vielen Regionen der Erde besorgniserregende Zahlen {\"u}ber Neuinfektionen und Todesf{\"a}lle zu beobachten. Die Suche nach neuen Wirkstoffen ist daher dringend erforderlich und die Hauptaufgabe des Sonderforschungsbereichs 630 an der Universit{\"a}t W{\"u}rzburg. An diesem interdisziplin{\"a}ren Projekt beteiligt sich unsere Forschungsgruppe vor allem mit der Naturstoffklasse der Naphthylisochinolin-Alkaloide. Neben ihren interessanten strukturellen Eigenschaften haben mehrere Vertreter dieser Sekund{\"a}rmetabolite vielversprechende Aktivit{\"a}ten gegen Plasmodien, Leishmanien und Trypanosomen. Dioncophyllin C (24), das bisher wirksamste Naphthylisochinolin gegen P. falciparum, zeigt nicht nur eine exzellente Aktivit{\"a}t in vitro, sondern auch in vivo. In Kooperation mit der Forschergruppe von K. Baumann (Braunschweig) f{\"u}hrte man QSAR-Studien durch, um die f{\"u}r die biologische Wirkung entscheidenden Strukturmerkmale zu identifizieren und neue vereinfachte Analoga der Leistruktur 24 vorzuschlagen. Ziel der vorliegenden Arbeit war aufbauend auf Vorarbeiten in unserer Gruppe die Darstellung von strukturell vereinfachten Derivaten des Naturstoffs 24. Die Ergebnisse der biologischen Untersuchungen sollten ausgewertet und somit neue Struktur-Wirkungs-Beziehungen aufgestellt werden. Weiterhin sollten auch Chinolinium-Salze, die man als Analoga der N,C-verkn{\"u}pften Naphthylisochinoline ansehen kann, synthetisiert werden und innerhalb des SFB 630 und bei unseren Partnern am Schweizerischen Tropen- und Public-Health-Institut auf ihre biologische Aktivit{\"a}t untersucht werden. Man erhoffte sich neben m{\"o}glichen antiinfektiven Eigenschaften auch R{\"u}ckschl{\"u}sse auf Struktur-Wirkungs-Beziehungen. Zus{\"a}tzlich sollte die synthetische und analytische chemische Expertise unseren Kooperationspartnern in zwei Projekten außerhalb des SFB 630 zur Verf{\"u}gung gestellt werden. Dabei handelte es sich einerseits um die Strukturaufkl{\"a}rung von Biosyntheseintermediaten mit Hilfe der HPLC-NMR-Kopplung und andererseits um die Darstellung langkettiger Aldehyde f{\"u}r die biologische Untersuchung des Pr{\"a}-Penetrationsprozesses eines getreidesch{\"a}digenden Pilzes.}, subject = {Malaria}, language = {de} } @phdthesis{Shao2012, author = {Shao, Changzhun}, title = {Programming Self-assembly: Formation of Discrete Perylene Bisimide Aggregates}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69298}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {The objective of this thesis focuses on the development of strategies for precise control of perylene bisimide (PBI) self-assembly and the in-depth elucidation of structural and optical features of discrete PBI aggregates by means of NMR and UV/Vis spectroscopy. The strategy for discrete dimer formation of PBIs is based on delicate steric control that distinguishes the two facets of the central perylene surface. The strategy applied in this thesis for accessing discrete PBI quadruple and further oligomeric stacks relies on backbone-directed PBI self-assembly. For this purpose, two tweezer-like PBI dyads bearing the respective rigid backbones, diphenylacetylene (DPA) and diphenylbutydiyne (DPB), were synthesized. The distinct aggregation behavior of these structurally similar PBI dyads can be ascribed to the intramolecular distance between the two PBI chromophores imparted by the DPA and DPB spacers.}, subject = {Farbstoff}, language = {en} } @article{MessiNdjokoIosetHertleinAmslingeretal.2012, author = {Messi, Bernadette Biloa and Ndjoko-Ioset, Karine and Hertlein-Amslinger, Barbara and Lannang, Alain Meli and Nkengfack, Augustin E. and Wolfender, Jean-Luc and Hostettmann, Kurt and Bringmann, Gerhard}, title = {Preussianone, a New Flavanone-Chromone Biflavonoid from Garcinia preussii Engl.}, series = {Molecules}, volume = {17}, journal = {Molecules}, number = {5}, doi = {10.3390/molecules17056114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130881}, pages = {6114 - 6125}, year = {2012}, abstract = {A new flavanone-chromone biflavonoid, preussianone (1), has been isolated from the leaves of Garcinia preussii, along with four known biflavonoids. The absolute stereostructures were elucidated by chemical, spectroscopic, and chiroptical methods. The biological properties of the new biflavonoid against several bacterial strains were evaluated.}, language = {en} } @phdthesis{Zhang2012, author = {Zhang, Guoliang}, title = {Phytochemical Research on Two Ancistrocladus Species, Semi-Synthesis of Dimeric Naphthylisoquinoline Alkaloids, and Structure Optimization of Antitumoral Naphthoquinones}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-72734}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Plant-derived natural products and their analogs continue to play an important role in the discovery of new drugs for the treatment of human diseases. Potentially promising representatives of secondary metabolites are the naphthylisoquinoline alkaloids, which show a broad range of activities against protozoan pathogens, such as plasmodia, leishmania, and trypanosoma. Due to the increasing resistance of those pathogens against current therapies, highly potent novel agents are still urgently needed. Thus, it is worthy to discover new naphthylisoquinoline alkaloids hopefully with pronounced bioactivities by isolation from plants or by synthesis. The naphthylisoquinoline alkaloids are biosynthetically related to another class of plant-derived products, the naphthoquinones, some of which have been recently found to display excellent anti-multiple myeloma activities without showing any cytotoxicities on normal blood cells. Multiple myeloma still remains incurable, although remissions may be induced with co-opted therapeutic treatments. Therefore, more potent naphthoquinones are urgently required, and can be obtained by isolation from plants or by synthesis. In detail, the results in this thesis are listed as follows: 1) Isolation and characterization of naphthylisoquinoline alkaloids from the stems of a Chinese Ancistrocladus tectorius species. Nine new naphthylisoquinoline alkaloids, named ancistectorine A1 (60), N-methylancistectorine A1 (61), ancistectorine A2 (62a), 5-epi-ancistectorine A2 (62b), 4'-O-demethylancistectorine A2 (63), ancistectorine A3 (64), ancistectorine B1 (65), ancistectorine C1 (66), and 5-epi-ancistrolikokine D (67) were isolated from the Chinese A. tectorius and fully characterized by chemical, spectroscopic, and chiroptical methods. Furthermore, the in vitro anti-infectious activities of 60-62 and 63-66 have been tested. Three of the metabolites, 61, 62a, and 62b, exhibited strong antiplasmodial activities against the strain K1 of P. falciparum without showing significant cytotoxicities. With IC50 values of 0.08, 0.07, and 0.03 μM, respectively, they were 37 times more active than the standard chloroquine (IC50 = 0.26 μM). Moreover, these three compounds displayed high antiplasmodial selectivity indexes ranging from 100 to 3300. According to the TDR/WHO guidelines, they could be considered as lead compounds. In addition, seven alkaloids, 69-74 (structures not shown here), were isolated from A. tectorius that were known, but new to the plant, together with another fourteen known compounds (of these, only the structures of the three main alkaloids, 5a, 5b, and 78 are shown here), which had been previously found in the plant. The three metabolites ancistrocladine (5a), hamatine (5b), and (+)-ancistrocline (78) were found to show no or moderate activities against the MM cell lines. 2) Isolation and characterization of naphthylisoquinoline alkaloids from the root bark of a new, botanically yet undescribed Congolese Ancistrocladus species. An unprecedented dimeric Dioncophyllaceae-type naphthylisoquinoline alkaloid, jozimine A2 (84), as first recognized by G. Bauckmann from an as yet undescribed Ancistrocladus species, was purified and characterized as part of this thesis. Its full structural assignment was achieved by spectroscopic and chiroptical methods, and further confirmed by an X-ray diffraction analysis, which had never succeeded for any other dimeric naphthylisoquinoline alkaloids before. Structurally, the dimer is composed of two identical 4'-O-demethyldioncophylline A halves, coupled through a sterically hindered central axis at C-3',3'' of the two naphthalene moieties. Pharmacologically, jozimine A2 (84) showed an extraordinary antiplasmodial activity (IC50 = 1.4 nM) against the strain NF54 of P. falciparum. Beside jozimine A2 (85), another new alkaloid, 6-O-demethylancistrobrevine C (84), and four known ones, ancistrocladine (5a), hamatine (5b), ancistrobrevine C (86), and dioncophylline A (6) were isolated from the Ancistrocladus species, the latter in a large quantity (~500 mg), showing that the plant produces Ancistrocladaceae-type, mixed-Ancistrocladaceae/Dioncophyllaceae-type, and Dioncophyllaceae-type naphthyl- isoquinoline alkaloids. Remarkably, it is one of the very few plants, like A. abbreviatus, and A. barteri, that simultaneously contain typical representatives of all the above three classes of alkaloids. 3) Semi-synthesis of jozimine A2 (85), 3'-epi-85, jozimine A3 (93) and other alkaloids from dioncophylline A (6). The dimeric naphthylisoquinoline alkaloids, jozimine A2 (85) and 3'-epi-85, constitute rewarding synthetic targets for a comparative analysis of their antiplasmodial activities and for a further confirmation of the assigned absolute configurations of the isolated natural product of 85. They were semi-synthesized in a four-step reaction sequence from dioncophylline A (6) in cooperation with T. B{\"u}ttner. The key step was a biomimetic phenol-oxidative dimerization at C-3' of the N,O-dibenzylated derivative of 89 by utilizing Pb(OAc)4. This is the first time that the synthesis of such an extremely sterically hindered (four ortho-substituents) naphthylisoquinoline alkaloid - with three consecutive biaryl axes! - has been successfully achieved. A novel dimeric naphthylisoquinoline, jozimine A3 (93), bearing a 6',6''-central biaryl axis, was semi-synthesized from 5'-O-demethyldioncophylline A (90) by a similar biomimetic phenol-oxidative coupling reaction as a key step, by employing Ag2O. HPLC analysis with synthetic reference material of 3'-epi-85 and 93 for co-elution revealed that these two alkaloids clearly are not present in the crude extract of the Ancistrocladus species from which jozimine A2 (85) was isolated. This evidences that jozimine A2 (85) is very specifically biosynthesized by the plant with a high regio- and stereoslectivity. Remarkably, the two synthetic novel dimeric naphthylisoquinoline alkaloids 3'-epi-85 and 93 were found to display very good antiplasmodial activities, albeit weaker than that of the natural and semi-synthetic product 85. Additionally, the two compounds 3'-epi-85 and 93 possessed high or moderate selectivity indexes, which were much lower than that of 85. However, they can still be considered as new lead structures. Two unprecedented oxidative products of dioncophylline A, the diastereomeric dioncotetralones A (94a) and B (94b), were synthesized from dioncophylline A (6) in a one-step reaction. Remarkably, the aromatic properties in the "naphthalene" and the "isoquinoline" rings of 94a and 94b are partially lost and the "biaryl" axis has become a C,C-double bond, so that the two halves are nearly co-planar to each other, which has never been found among any natural or synthetic naphthylisoquinoline alkaloid. Their full structural characterization was accomplished by spectroscopic methods and quantum-chemical CD calculations (done by Y. Hemberger). The presumed reaction mechanism was proposed in this thesis. In addition, one of the two compounds, 94a, exhibited a highly antiplasmodial activity (IC50 = 0.09 μM) with low cytotoxicity, and thus, can be considered as a new promising lead structure. Its 2'-epi-isomer, 94b, was inactive, evidencing a significant effect of chirality on the bioactivity. Of a number of naphthylisoquinoline alkaloids tested against the multiple-myeloma cell lines, the three compounds, dioncophylline A (6), 4'-O-demethyldioncophylline A (89), and 5'-O-demethyldioncophylline A (90) showed excellent activities, even much stronger than dioncoquinones B (10), C (102), the epoxide 175, or the standard drug melphalan. 4) Isolation and characterization of bioactive naphthoquinones from cell cultures of Triphyophyllum peltatum. Three new naphthoquinones, dioncoquinones C (102), D (103), and E (104), the known 8-hydroxydroserone (105), which is new to this plant, and one new naphthol dimer, triphoquinol A (107), were isolated from cell cultures of T. peltatum in cooperation with A. Irmer. Dioncoquinone C (102) showed an excellent activity against the MM cells, very similar to that of the previously found dioncoquinone B (10), without showing any inhibitory effect on normal cells. The other three naphthoquinones, 103105, were inactive or only weakly active. 5) Establishment of a new strategy for a synthetic access to dioncoquinones B (10) and C (102) on a large scale for in vivo experiments and for the synthesis of their analogs for first SAR studies. Before the synthesis of dioncoquinone B (10) described in this thesis, two synthetic pathways had previously been established in our group. The third approach described here involved the preparation of the joint synthetic intermediate 42 with the previous two routes. The tertiary benzamide 135 was ortho-deprotonated by using s-BuLi/TMEDA, followed by transmetallation with MgBr2▪2Et2O, and reaction with 2-methylallyl bromide (139). It resulted in the formation of ortho-allyl benzamide 140, which was cyclized by using methyl lithium to afford the naphthol 42. This strategy proved to be the best among the established three approaches with regard to its very low number of steps and high yields. By starting with 136, this third strategy yielded the related bioactive natural product, dioncoquinone C (102), which was accessed by total synthesis for the first time. To identify the pharmacophore of the antitumoral naphthoquinones, a library of dioncoquinone B (10) and C (102) analogs were synthesized for in vitro testing. Among the numerous naphthoquinones tested, the synthetic 7-O-demethyldioncoquinone C (or 7-O-hydroxyldioncoquinone B) (145), constitutes another promising basic structure to develop a new anti-MM agent. Furthermore, preliminary SAR results evidence that the three hydroxy functions at C-3, C-5, and C-6 are essential for the biological properties as exemplarily shown through the compounds 10, 102, and 145. All other mixed OH/OMe- or completely OMe-substituted structures were entirely inactive. By a serendipity the expoxide 175 was found to display the best anti-MM activity of all the tested isolated metabolites from T. peltatum, the synthesized naphthoquinones, and their synthetic intermediates. Toxic effects of 175 on normal cells were not observed, in contrast to the high toxicities of all other epoxides. Thus, the anti-MM activity of 175 is of high selectivity. The preliminary SAR studies revealed that the 6-OMe group in 175 is required, thus differed with the above described naphthoquinones (where 6-OH is a requisite in 10, 102, and 145), which evidenced potentially different modes of action for these two classes of compounds. 6) The first attempted total synthesis of the new naturally occurring triphoquinone (187a), which was recently isolated from the root cultures of T. peltatum in our group. A novel naphthoquinone-naphthalene dimer, 187a (structure shown in Chapter 10), was isolated in small quantities from the root cultures of T. peltatum. Thus, its total synthesis was attempted for obtaining sufficient amounts for selected biotestings. The key step was planned to prepare the extremely sterically hindered (four ortho-substituents) binaphthalene 188 by a coupling reaction between the two 2-methylnaphthalene derivatives. Test reactions involving a system of two simplified 2-methylnaphthylboron species and 2-methylnaphthyl bromide proved the Buchwald ligand as most promising. The optimized conditions were then applied to the two true - highly oxygenated - coupling substrates, between the 2-methylnaphthylboron derivatives 210, 211, 213, or 214 and the 2-methylnaphthyl iodides (or bromides) 215 (206), 215 (206), 212 (205), or 212 (205), respectively. Unfortunately, this crucial step failed although various bases and solvent systems were tested. This could be due to the high electron density of the two coupling substrates, both bearing strongly OMOM/OMe-donating function groups. Therefore, a more powerful catalyst system or an alternative synthetic strategy must be explored for the total synthesis of 187a. 7) Phytochemical investigation of the Streptomyces strain RV-15 derived from a marine sponge. Cyclodysidins A-D (216-219), four new cyclic lipopeptides with a- and ß-amino acids, were isolated from the Streptomyces strain RV15 derived from a marine sponge by Dr. U. Abdelmohsen. Their structures were established as cyclo-(ß-AFA-Ser-Gln-Asn-Tyr-Asn-Ser-Thr) by spectroscopic analysis using 2D NMR techniques and CID-MS/MS in the course of this thesis. In conclusion, the present work contributes to the discovery of novel antiplasmodial naphthylisoquinoline alkaloids and antitumoral naphthoquinones, which will pave the way for future studies on these two classes of compounds.}, subject = {Ancistrocladus}, language = {en} }