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1
Macdonald, Dwight I. "Synthesis of podophyllotoxin and analogs." Thesis, University of Ottawa (Canada), 1987. http://hdl.handle.net/10393/5371.
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Hammonds, Timothy Robin. "Antiviral effects of podophyllotoxin derivatives." Thesis, University of Nottingham, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335849.
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Beard, A. "Synthesis of analogues of podophyllotoxin." Thesis, University of Reading, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376237.
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Vanderwal, Christopher D. "Attempted enantioselective total synthesis of podophyllotoxin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ36752.pdf.
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Pullockaran, Anie Jose. "Synthesis of labelled precursors of podophyllotoxin." Thesis, Virginia Tech, 1989. http://hdl.handle.net/10919/46060.
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<p>Podophyllotoxin is an aryltetralin lignan and anticancer agent produced by the <i>Podophyllum</i>
and some other species and is extracted from Podophyllin in up to 30 percent yield. Little definitive
information is available on the biosynthetic pathways to podophyllotoxin. Administering various
specifically labelled precursors into intact plants and tissue cultures can give a much improved
insight into the lignan biogenesis. The first part of the work has been to the synthesis of two
diastereotopically labelled with <sup>2</sup>H at C-4. Desoxypodophyllotoxin is the penultimate intermediate of
the podophyllotoxin pathway and specifically labelled compounds can be used for the C-4
hydroxylation studies. Doubly <sup>2</sup>H labelled desoxypodophyllotoxin at C-4 was also prepared which
can be used for a control experiment. This work also led to the unambiguous assignment of the
proton nmr of desoxypodophyllotoxin. A second part of the work has been the synthesis of p-coumarlc acid, a known lignan precursor, doubly labeled with <sup>2</sup>H or <sup>2</sup>H and
<sup>13</sup>C
at the C-3â position.
This labeling was selected because the availability of a C-3-labeled monomeric precursor would
thus make possible the isolation and study of dimeric compounds labeled at this key positions.
These compounds were synthesized, and their identity and stereochemistry were determined by
spectroscopic and analytical techniques. The isotopic incorporation of these compounds was 95%
d, or d<sub>2</sub> (or greater), as determined by mass spectral analysis.</p><br>Master of Science
6
Neidigh, Kurt Alan. "Studies on the biosynthesis of podophyllotoxin : synthesis of labelled yatein and matairesinol, two potential precursors of podophyllotoxin /." This resource online, 1992. http://scholar.lib.vt.edu/theses/available/etd-09192009-040255/.
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Baur, Wendy L. "Study of Podophyllotoxin Biosynthesis in Podophyllum species /." Thesis, This resource online, 1990. http://scholar.lib.vt.edu/theses/available/etd-03122009-040904/.
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Reeve, Maxwell Marco. "Synthetic approaches to prephenate analogues and podophyllotoxin." Thesis, University of Edinburgh, 1986. http://hdl.handle.net/1842/12852.
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Oliva, Francisco. "The Anti-cancer Properties of Podophyllotoxin Analogues." Youngstown State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1579197212456721.
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Garden, Hermann Jörn. "Biotechnological production of podophyllotoxin by linum album suspension cultures." [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=970145098.
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LeBlanc, Denise. "Studies directed towards the total synthesis of podophyllotoxin analogues." Thesis, University of Ottawa (Canada), 1988. http://hdl.handle.net/10393/5514.
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Huffman, Olivia G. "Drug Discovery: identification of Anticancer Properties of Podophyllotoxin Analogues." Youngstown State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1588874335556129.
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Hazell, Sarah Jane. "Synthesis of analogues of podophyllotoxin as potential anti-cancer compounds." Thesis, University of Reading, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386781.
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Poon, Hon-suen. "Michael initiated cascade reaction sequences and their application in target synthesis." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246237.
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Freed, James C. "The synthesis of C-2 substituted analogues of podophyllotoxin and etoposide." Thesis, University of Ottawa (Canada), 1987. http://hdl.handle.net/10393/5404.
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Uden, Wilhelmus van. "The production of podophyllotoxin and related cytotoxic lignans by plant cell cultures." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 1992. http://irs.ub.rug.nl/ppn/293040230.
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Alliot, Julien. "Synthèse de composés anorexigènes, antidépresseurs et anticancéreux." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112218/document.
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Au cours de ce travail, nous nous sommes intéressés à la synthèse de composés biologiquement actifs. Dans un premier temps, nous avons étudié la déshydratation des macrocarpals A et B en vue d’obtenir un accès semi-synthétique rapide au macrocarpal G qui possède des propriétés anorexigèniques.Dans un second temps, nous avons développé une nouvelle synthèse énantiosélective du Lévomilnacipran qui est un antidépresseur qui vient de recevoir son autorisation de mise sur le marché aux Etats-Unis et au Canada. Cette synthèse de novo nous a permis d’obtenir le produit actif en neuf étapes avec un rendement global de 32 % et un excès énantiomérique conservé de 88 %. Nous avons ensuite mis au point une synthèse énantiosélective du 1,4-benzodioxane F17807. Cette synthèse en quatre étapes repose sur une étape clé de SNAr du (S)-isopropylidèneglycerol sur un fluorophénol. Cette étape permet d’introduire l’information chirale qui sera maintenue tout au long de la synthèse puisque le produit final est isolé avec un excès énantiomérique de 98 %.Nous avons également synthétisé des analogues du dérivé d’épipodophyllotoxine, F14512. Ces stéréoisomères sont des impuretés qui peuvent apparaitre dans la formulation finale du principe actif. Pour finir, nous avons imaginé de nouvelles formulations nanométriques du composé F14512 afin que celui-ci s’auto-assemble en micelle. Pour cela, quatre amphiphiles ont été synthétisés et les premiers tests montrent une internalisation préférentielle au niveau des tumeurs ou des cellules surexprimant le STP en fonction de leur fonctionnalisation<br>This thesis deals with the synthesis of biologically active compounds. In the first chapter, we developed a semi-synthetic process for the exo-dehydration of macrocarpals A and B to get access to macrocarpal G which is a drug known for its anorexigenic activity. The second chapter is dealing with the enantioselective synthesis of the anti-depressive drug Levomilnacipran which has recently been approved by the FDA. This de novo synthesis was performed in 9 steps with an overall yield of 32 % and with an enantiomeric excess of 88 % which was maintained throughout our synthesis. In the third chapter we worked on a novel route for the enantioselective synthesis of the antipsychotic drug F17807. Our four-step synthesis of the 1,4-benzodioxan unit relied, as the key step, on the SNAr reaction of optically active (S)-isopropylidenglycerol on a properly functionalized fluorophenol and subsequent transformations. F17807 was produced with an ee of 98%.The fourth chapter reports our investigations for the synthesis of three stereoisomers of F14512 which is a targeted epipodophyllotoxin-based anticancer drug.Finally, new nanometric formulations of F14512 were designed in the fifth chapter. Four different drug-containing amphiphilic compounds were synthesized, assembled into the corresponding micelles, and evaluated as delivery systems. Preliminary in vitro and in vivo results indicate that the nanomicelles are highly promising for the targeting of tumors as visualized by fluorescence imaging
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Neidigh, Kurt Alan. "Studies on the biosynthesis of podophyllotoxin:synthesis of labelled yatein and matairesinol, two potential precursors of podophyllotoxin." Thesis, Virginia Tech, 1992. http://hdl.handle.net/10919/44847.
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Podophyllotoxin, a naturally occurring lignan isolated from several species of Podophyllum, is used as a precursor to the clinical chemotherapeutic agents teniposide and etoposide. The biosynthesis of podophyllotoxin is not fully understood, but its optical activity, like that of most lignans, is suggestive of enzyme-mediated processes.
It has been proposed that the formation of podophyllotoxin begins with stereo-controlled coupling of a hydroxy cinnamyl alcohol derivative and a substituted hydroxy Cinnamic acid, although no "coupling" enzyme has been isolated to date. Further biosynthetic modifications of the coupled compound could lead to matairesinol and/or yatein, which have been proposed as potential biological precursors of podophyllotoxin. Although no firm evidence has been obtained to date, conversion of matairesinol to yatein has been postulated. This conversion would, however, involve biosynthetic steps which, though common for hydroxycinnamates, are unprecedented at the dimeric level. Conversion of yatein to podophyllotoxin has been demonstrated, with the conversion involving a stereo-controlled cyclization and subsequent stereospecific hydroxylation.
In order to investigate the biosynthesis of podophyllotoxin, leading from the postulated precursors matairesinol and yatein, a series of stereospecific deuterium-labelled matairesinol and yatein derivatives was proposed and the synthetic methodology for each compound developed. The methodology used to obtain deuterium-labelled compounds can be extended to generating tritium-labelled compounds as well.
With sufficient quantities of a number of the deuterium-labelled compounds, feeding studies can now be carried out in Podophyllum plants. Isolation and analysis of podophyllotoxin, from plants fed with labelled yatein, will allow determination of the stereochemical nature of yatein cyclization. Isolation and analysis of yatein, from plants fed with labelled matairesinol, will indicate whether matairesinol is indeed a precursor to yatein (and, hence, podophyllotoxin). The information obtained from the synthesis and incorporation of such labelled compounds should then provide a clearer understanding of some interesting but, as yet, unestablished biotransformations.<br>Master of Science
19
Vasilcanu, Radu. "Regulation of insulin-like growth factor-1 receptor expression and signaling /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-244-6/.
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Vasilcanu, Daiana. "IGF-1R inhibition : a tool for functional studies of insulin-like growth factors family in malignant cells /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-643-3/.
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Gawde, Archana Jairam. "Bioprospection and by-product utilization of Juniperus virginiana." Master's thesis, Mississippi State : Mississippi State University, 2009. http://library.msstate.edu/etd/show.asp?etd=etd-12142008-132141.
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Borrelli, S. "CHEMICAL APPROACHES FOR IMPROVING DRUG DELIVERY OF KNOWN ANTICANCER COMPOUNDS." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229386.
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Different classes of squalene conjugates have been prepared: the first one containing a disulfide bond that, in the presence of glutathione, is able to trigger the release of a drug unit, the second one containing a tripepidyl sequence selectively cleaved by plasmin and also able to release a drug unit, the last one containinf a fluorescein 5(6)isothiocyanate unit. These compounds are able to self-assemble in water and can improve the delivery of active drugs to tumor tissues and can be helpful in the understanding of nanoparticle cellular uptake.
23
Salako, Adetokunbo Adeniran. "Topoisomerase inhibitors based on podophyllotoxins." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337615.
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Liénard, Philippe. "Synthèse asymétrique de benzoquinolizidines apparentées à la podophyllotoxine." Paris 11, 1991. http://www.theses.fr/1991PA112274.
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Gautret, Philippe. "Conception, synthèse et étude des propriétés chimiques et biochimiques d'analogues de la podophyllotoxine." Lille 1, 1994. http://www.theses.fr/1994LIL10163.
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Nous avons étudié les relations structure-activité dans la famille de la podophyllotoxine (inhibiteur de la polymérisation de la tubuline) et de l'étoposide (inhibiteur de l'activité de la topoisomérase II). Nous avons ainsi mis en évidence l'intérêt de nouveaux isostères des podophyllotoxines et des 4'-déméthylépipodophyllotoxines possédant un squelette tétracyclique original. D'un point de vue chimique, nous avons mis au point une méthode de synthèse facile et rapide de cette famille hétérocyclique. L'un de ces nouveaux analogues de la podophyllotoxine est un poison du fuseau et présente une activité qui est du même ordre de grandeur que celle des meilleurs inhibiteurs de la polymérisation de la tubuline. Ce bioisostère de la podophyllotoxine pourra servir de matière première à la synthèse de nouveaux inhibiteurs de l'activité de la topoisomerase II.
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Mouton, Carole. "La podophyllotoxine et ses dérivés inhibant la polymérisation de la tubuline et/ ou l'ADN-topoisomérase II." Paris 5, 1994. http://www.theses.fr/1994PA05P153.
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Nguyen, Dinh Vu. "Synthèse de composés antidépresseurs et anticancéreux - Contribution méthodologique à la réactivité des époxydes et des dérivés organiques du bismuth." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS374/document.
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Au cours de ce travail, nous nous sommes intéressés à la synthèse d'un analogue de Milnacipran, une molécule commercialisée sous le nom d'Ixel pour son activité anti-dépresseur. Il s'agit d'un cyclobutane trisubstitué portant deux centres stéréogènes contigus. L'objectif est de développer une voie de synthèse efficace et transposable à la version énantiosélective.Nous avons également travaillé sur la formulation nanométrique d'épiPodophyllotoxines, un produit naturel biologiquement active. Nous avons imaginé une architecture moléculaire permettant à la molécule de s'auto-assembler en micelle, ainsi elle peut être transportée de manière efficace au tumeur cancéreux. Les études in vitro et in vivo ont apporté des résultats prometteurs vis-à-vis du potentiel thérapeutique de notre nano-objet. Enfin nous avons étudié au cours de cette thèse deux méthodologies: la réactivité des époxydes en milieu alcalin fort et les dérivés d'organobismuth pour les réactions d'oxydation. Ces derniers ont été exploités afin d'oxyder des hydroxylamines en nitrone dans des conditions douces, permettant de réaliser le tandem oxydation/cycloaddition 1,3 dipolaire in situ avec des alcynes tendus<br>My PhD thesis mainly involves the enantioselective synthesis of the Milnacipran's analog, a trisubstituted cyclobutane bearing two contiguous stereogenic centers. We have devised a conventional approach which consists of an intramolecular SN2 cyclization. After an acidic treatment, the key intermediate lactone was isolated with an ee > 99%, which was converted to the Milnacarre with no erosion of the ee value. We have also interested in the nanometric formulation of Podophyllotoxine derivatives. The natural product was designed to bear a hydrophilic and hydrophobic side chain. Its micellar solution was evaluated in vitro, in vivo and the obtained resuls were shown to be promising.We have also studied two methodologies: the reactivity of glycidyl ether toward alkyllithium reagents and oxydation of hydroxylamines to nitrone using triphenylbismuth carbonate. We observed in the former case an original rearrangement of the substrate to a vicinal diol, while in the latter case we have developped a mild condition to perform an tandem oxydation/1,3-dipolar cycloaddition in situ with a strained alkyne
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Meneyrol, Jérôme. "Synthèse de nouveaux hétérolignanes dérivés de la podophyllotoxine en séries 1-Aza et 4-Aza." Paris 5, 2001. http://www.theses.fr/2001PA05P626.
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Les lignanes constituent une famille de produits naturels possédant des propriétés pharmacologiques intéressantes en particulier dans le domaine des antitumoraux. L'objectif de notre travail était d'obtenir de nouveaux hétérolignanes apparentés à la podophyllotoxine et plus particulièrement en série 1-aza et 4-aza, deux série encore très peu étudiées. Notre laboratoire a récemment breveté des 4-aza-2,3-déhydropodophyllotoxines à propriétés antitumorales par inhibition de la polymérisation de la tubuline. Le chapitre I est une étude bibliographique sur les hétérolignanes. L'accès à la 1-azapodophyllotoxine semble être extrêmement difficile. Quatre voies, présentées dans le chapitre II, ont été étudiées. Seules des 1-aza-2,3-déhydropodophyllotoxines à lactones inversées ont été obtenues [. . . ]
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Vitale, Maxime. "Synthèse d'analogues de la podophyllotoxine par une nouvelle séquence palladocatalysée : alkylation allylique - couplage de Hiyama." Paris 6, 2004. http://www.theses.fr/2004PA066504.
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Aillerie, Alexandre. "Organocatalyse : réduction asymétrique par transfert d’hydrogène et synthèse de nouveaux catalyseurs." Thesis, Lille 1, 2014. http://www.theses.fr/2014LIL10185.
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Le contrôle de la chiralité est un critère déterminant dans la synthèse de molécules chirales biologiquement actives. De nombreuses tétrahydroquinoléines chirales ont démontré des activités biologiques tout à fait remarquables, en particulier dans le traitement du cancer. L’un des systèmes de réduction asymétrique permettant d’accéder à ces composés d’intérêt thérapeutique combine une source d’hydrure organique et un catalyseur acide de Brønsted chiral. Ce système est basé sur une approche biomimétique des cofacteurs NADH et NADPH impliqués dans de très nombreux métabolismes redox. En suivant cette méthodologie en accord avec le développement durable, diverses molécules hétérocycliques azotées énantiopures potentiellement anticancéreuses ont été ainsi préparées. La première synthèse énantiosélective de dérivés de 4-azapodophyllotoxines avec ce procédé de réduction a été mise au point. Une méthodologie innovante, basée sur la possibilité de générer in situ la source d’hydrure a également été développée. De plus, de nouveaux organocatalyseurs dérivés de l’acide phospholanique et du ferrocènes ont également été synthétisés et évalués au sein de transformations chimiques<br>The control of chirality is crucial in the synthesis of chiral active biologically molecules. Numerous chiral tetrahydroquinolines have revealed outstanding biological activities, particularly in the treatment of cancer. One of the asymmetric reduction systems to access these compounds of medicinal interest combines an organic hydride source and a chiral Brønsted acid catalyst. This system is based on a biomimetic approach of NADH and NADPH cofactors involved in many redox metabolisms. Following this methodology in agreement with the sustainable development, various enantiopure nitrogen-based heterocycles have been prepared as potential anticancer drugs. The first enantioselective synthesis of 4-azapodophyllotoxine derivatives using this reduction process has been set up. An innovative methodology, based on the possibility to generate in situ the hydride source has also been developed. Moreover, news organocatalysts derived from phospholanic acid and ferrocene have also been synthesized and evaluated within chemical transformations
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Duca, Maria. "Nouveaux inhibiteurs de topoisomérase II dérivés de la 4'-déméthylépipodophyllotoxine dirigés sur des séquences spécifiques de l'ADN : conception, synthèse et applications." Paris, Muséum national d'histoire naturelle, 2005. http://www.theses.fr/2005MNHN0008.
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La topoisomérase II est une enzyme ubiquitaire, essentielle à la viabilité de tous les organismes, qui contrôle et modifie l'état topologique de l'ADN en coupant transitoirement les deux brins de la double-hélice d'ADN. Cette enzyme est la cible cellulaire d'un grand nombre de molécules, comme les dérivés de la 4'-déméthylépipodophillotoxine: ces molécules stabilisent le complexe transitoire ADN/TopoII, où chaque brin de l'ADN est coupé et lié de façon covalente à une sous-unité de l'enzyme, et empêchent ainsi la religation de l'ADN. Parmi les dérivés de la 4'-déméthylépipodophyllotoxine, l'étoposide est couramment utilisé en thérapie anticancéreuse, mais il présente des limitations importantes. Nous avons donc synthétisé de nouvelles séries de dérivés de la podophyllotoxine en modifiant deux parties de la molecule: le substituant en position 4 et le cycle lactonique D. Nous avons ensuite vérifié pour chaque dérivé l'activité d'inhibition de l'enzyme topoisomerase II et certains produits ont montré une activité superieure à celle de l'étoposide. Le couplage d'agents antitumoraux, inhibiteurs de topoisomérase I, à des oligonucléotides formant une triple-hélice (OFT) permet de diriger la coupure par la topoisomérase I vers une cible spécifique dans la cellule, comme l'ADN d'un agent pathogène ou une famille de gènes impliqués dans le processus tumoral. Dans cette perspective, nous avons couplé les dérivés le plus actifs à des OFT et étudié la capacité de ces conjugués à diriger la coupure par la topoisomérase II spécifiquement au site triple-hélice. Après la validation de la stratégie in vitro, nous avons employé les conjugués dans un contexte cellulaire. Nous avons choisi comme cible le gène mdr1, responsable de la résistance multiple aux médicaments, et obtenu l'inhibition de son expréssion par un conjugué OFT-daunorubicine<br>DNA topoisomerase II is an ubiquitous and essential enzyme that modulates DNA topology by passing an intact DNA double helix through a transient double-stranded break. This enzyme plays critical roles in a number of DNA processes. Topoisomerase II is the primary cellular target for a large number of anticancer agents, like 4'-demethylepipodophillotoxin derivatives. These molecules stabilise the DNA/TopoII complex, and induce DNA breaks. This action converts topoisomerase II into a potent cellular toxin that fragments the genome and induces cell death. Among 4'-demethylepipodophyllotoxin derivatives, etoposide is widely used in anticancer therapy, however it presents several limitations, such as poor water solubility, development of drug resistance, metabolic inactivation and toxic effects. Therefore, we synthesized new series of etoposide analogs by introducing different substituents in 4-position, like carbamate or sulfonamide chains. Then we evaluated the effect on topoisomerase II and the cytotoxicity. The conjugation of antitumor agents, such as topoisomerase I inhibitors, allowed to direct the cleavage mediated by topoisomerase I to specific sites of the genome. On this basis we synthesized new conjgates between the new topoisomerase II inhibitors and triplex forming oligonucletides (TFO) and evaluated their ability to recruit topoisomerase II and direct its cleavage to specific DNA sequences. This targeting strategy allows to obtain topoisomerase II-mediated DNA cleavage at specific sequences of DNA, like a gene involved in cancer development. We choose to target mdr1 gene which is responsible of multidrug resistance. We obtained the inhibition of its expression by using a conjugate TFO-daunorubicine. These conjugates are also a biochemical tool to study the molecular mechanism of action of etoposide and its analogs
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Charruault, Lise. "Nouvelles voies d'accès à des carbo- et hétérocycles fonctionnalisés en milieu organoaqueux : catalyse asymétrique et application synthétique." Paris 6, 2003. https://pastel.archives-ouvertes.fr/pastel-00001083.
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MERESSE, PHILIPPE. "Conception, synthese et evaluation biologique d'agents antitumoraux : analogues structuraux de l'etoposide, de la podophyllotoxine et de la 4-demethylepipodophyllotoxine." Paris 6, 2000. http://www.theses.fr/2000PA066327.
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L'etoposide (vp-16), derive hemisynthetique de la podophyllotoxine, est un medicament anticancereux notamment employe dans le traitement du cancer du poumon a petites cellules et du cancer des testicules. Poison de la topoisomerase ii, le vp-16 induit des coupures de l'adn par stabilisation d'un complexe clivable adn/enzyme. La toxicite hematologique, le developpement de resistance, l'inactivation metabolique, et la faible hydrosolubilite de l'etoposide sont autant de facteurs limitants qui justifient la synthese d'analogues presentant une meilleure efficacite therapeutique. Dans un premier temps, nous decrivons l'hemisynthese d'un derive pour lequel le domaine aromatique du vp-16 a ete etendu. Le cycle a de type methylenedioxy de l'etoposide a ainsi ete remplace par un cycle pyridazine. Dans ce contexte, une strategie basee sur la reaction de couplage de stille est mise en uvre. L'homologation du cycle -lactonique de la podophyllotoxine et de la 4-demethylepipodophyllotoxine (4-dmep) en cycles -lactoniques a ensuite ete etudiee. Plusieurs approches ont ete successivement developpees pour acceder aux differents homologues : olefination de wittig et reaction de cyanation. D'autre part, un derive retrolactonique de la 4-dmep a ete synthetise. Finalement, nous avons developpe un type de substitution originale de la position c-4 de la 4dmep et de ses analogues lactoniques precedemment synthetises. Des derives de type carbamate aromatique et aliphatique ont ainsi ete prepares. Une synthese efficace du npf, un derive amine en c-4 de la 4-demethylepipodopophylloxine, est par ailleurs decrite. Dans le dernier chapitre, nous rapportons l'evaluation biologique des differents composes synthetises au cours de ce travail. Des mesures
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Scott, Andrew James. "The total synthesis of (-)-podophyllotoxin." Phd thesis, 2004. http://hdl.handle.net/1885/148638.
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Jeftic, Tanya Dushanka. "Nitrogen-containing derivatives of naphthoquinone and podophyllotoxin." Thesis, 2012. http://hdl.handle.net/10539/11385.
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M.Sc., Faculty of Science, University of the Witwatersrand, 2011<br>In the initial, methodological part of this MSc project we intended to expand upon and improve various aspects of the ultrasound accelerated, iodine catalyzed, conjugate addition reaction of amines with 1,4-naphthoquinones first reported by Ji and co-workers in Synthetic Communications (2008, 38, 1201-1211). In recent times, the synthesis of 2-amino-1,4-naphthoquinones has become a heated area of research as a direct consequence of their multitude of diverse pharmaceutical activities; including anticancer, antimalarial, antifungal and trypanocidal properties.
Sonochemical transformations, reactions accelerated by ultrasound irradiation, have attracted considerable attention of late due to the shorter reaction durations, higher yields and milder reaction conditions associated with these processes. Additionally, as a result of its unique catalytic properties, iodine has been extensively exploited in diverse, atom-economical and accelerated organic reactions to afford the corresponding products in excellent yields with high selectivity.
With these considerations in mind a combinative library of eleven 2-amino-1,4-naphthoquinones with promising anticancer activity were successfully constructed in moderate to exceptional yields, with greatly reduced reaction times, 60 - 90 minutes, using the environmentally friendly, protic solvent ethanol.
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XIN-HUI, CAI, and 蔡馨慧. "New amino derivatives of podophyllotoxin as antitumor agents." Thesis, 1992. http://ndltd.ncl.edu.tw/handle/11751801029500143138.
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碩士<br>台北醫學院<br>藥學研究所<br>80<br>Podophyllotoxin lignans 用於治療疾病的歷史已超過一千年，目前臨床上使用甚廣
的etoposide(VP-16)即是podophyllotoxin 之半合成衛生物。Etoposide 在臨床治療
肺部小細胞癌、睪丸癌等扮演著很重要的角色，最近更被用來治療AIDS所引起的卡波
氏肉瘤。
本實驗室楊藏雄等於1973年曾自蓮葉桐(Hernandia ovigera L.)中抽取出多量的
desoxypodophyllotoxin ，因此今以此為原料合成etoposide 類似化合物。經由Wohl
-Ziegler bromination'demethylation、SN1 substitution reaction 等步驟將
etoposide 第4 位的-O- 以-N- 取代，如piperidine、morpholine、glucosamine 和
cyclohexylamine 等合成4'-demethyl-4cyclohexylamino-4-desoxypodophyllotoxin
(20)、4'-demethyl-4-piperidyl-4-desoxypodophyllotoxin (21)、和4'-demethyl
-4-morpholyl-4-4-desoxypodophyllotoxin (22) ，且各分離出α-form 和β-form
以供比較活性試驗。
我們另從八角蓮中抽取得podophyllotoxin ，經由修飾的Kuhn's method 也成功的合
成出化合物20、21、22。
除了針對desoxypodophyllotoxin 和podophyllotoxin 第4 位作異立體取代基
(isosteric substitution)的修飾，亦對lactone ring修飾，即以
desoxypodophyllotoxin 為原料，與上述之amine 反應得到amide 類的衍生物：
desoxypicropodophyllinic acid cyclohexylamide (27)、
desoxypicropodophyllinic acid piperazide (28) 和desoxypicropodophyllinic
acid morpholide (29)。
初步活性試驗的結果顯示：化合物20b 即4'-demethyl-4β-cyclohexylamino-4-
desoxypodophyllotoxin 對引起protein-linked DNA breakage 作用有很好的活性，
幾乎是etoposide 的二位強。至於其它項目的活性試驗則尚委託進行中。
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Hegde, Ganesh Lakshminarayan. "Synthetic studies in the field of analogues of podophyllotoxin." Thesis, 2002. http://hdl.handle.net/2009/1380.
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蘇曉平. "天然抗癌物Podophyllotoxin的合成研究". Thesis, 1987. http://ndltd.ncl.edu.tw/handle/50948820115937067543.
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Garden, Hermann Jörn [Verfasser]. "Biotechnological production of podophyllotoxin by linum album suspension cultures / by Hermann Jörn Garden." 2003. http://d-nb.info/970145098/34.
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Olšar, Jiří. "Podofylotoxin v jalovci virginském (Juniperus virginiana)." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-412102.
Full textAbstract:
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy Student: Jiří Olšar Supervisor: doc. PharmDr. Tomáš Siatka, CSc. Title of diploma thesis: Podophyllotoxin in eastern red cedar (Juniperus virginiana) This thesis describes the optimisation of the extraction process for quantity determination of podophyllotoxin in the leaves of Juniperus virginiana L. This determination was conducted through three different methods: the extraction in ultrasound bath, the extraction in the orbital shaker and the maceration in cold environment of 4 řC. Extractions were affected by various factors which were monitored, for instance time of extraction, temperature, and extraction solvents. The most efficient method appears to be the extraction in ultrasound bath with the use of methanol or a combination of phosphate buffer with ethyl-acetate.
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Chen, Jia-Yang, and 陳家揚. "Inhibition of cancer cell growth and migration of podophyllotoxin derivative in lung cancer cells and its mechanistic study." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/27983230102059497562.
Full textAbstract:
碩士<br>國立臺灣師範大學<br>生命科學研究所<br>95<br>Since 1982, cancer had been the leading cause disease of death in Taiwan, and the mortality of lung cancer has risen most dramatically in both men and women. Recently, the improvement in surgical and radiotherapeutic remedy, and more and more chemotherapy drugs including many potential anti-cancer drugs investigated from nature plant such as Taxol, Vinorelbin, and Camptothecin had been developed. However, the serious side effects and the potent in drug resistance of these drugs, still remain difficult for their development as anti-cancer drugs.
Podophyllotoxin is a nature compound purified from Podophyllum peltatum. It has strong polymerization inhibition ability toward the cell skeleton microtubule. It prevents the cell from normal mitosis and causes G2/M arrest of the cell, finally results in cell apoptosis. Podophyllotoxin had been used as medicine in different countries for thousand of years. However, its poor selectivity to normal/tumor cells and serious side effects after drug treatment prevent it from the usage as anti-cancer drugs.
Ching001, a podophyllotoxin derivatives developed from Dr. Wen-Shan Li at Institute of Chemistry of Academia Sinica in Taiwan. Ching001 was modified for the purpose to be a potential anti-cancer drug. In the present study, we found that novel podophyllotoxin derivative Ching001 had highly cytotoxicity toward different lung cancer cell lines, whereas Ching001 showed low cytotoxicity to the normal lung cell line. In addition, it prevented lung cancer cell from mitosis by inhibiting the polymerization of microtubule and causing cell cycle arrest at G2/M phase. These events eventually led to apoptosis through inhibition of the expression of anti-apoptosis factor Bcl-2 and activation of the expression of apoptosis protease caspase-9. Importantly, Ching001 could effectively inhibit the highly metastasis potential lung cancer cell line CL1-5 through inhibit actin filament construction signaling factors Rac and Rho to inhibit the filopodia or lamellipodia construction. In migration assay experiment, we proved that Ching001 treatment could inhibit the cell from migration in vitro. In the animal model test, 2 mg/kg Ching001 treatment could apparently inhibit the tumor growth for 15days and the effect was stronger than Taxol treatment at same dosage. The hematology and biochemistry tests of nude mice blood samples as well as tissue staining indicated that Ching001 treatment did not distinctively influence the normal function of vitality in animal model. In addition, tumor tissue staining showed that after Ching001 treatment, it induced apoptosis of tumor cells and led to tumor nodule shrinkage.
According to the experiments described above, we believed that novel podophyllotoxin derivative Ching001 will be a potential anti-cancer drug. It may be a good anti-metastasis agent as well.
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Sahbaz, Yasemin. "Aryl tetralin lignans : synthetic studies and a literature review." Master's thesis, 2010. http://hdl.handle.net/1885/150453.
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Šandová, Kateřina. "Rostlinné explantátové kultury jako potenciální zdroj fenylpropanoidů II." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-396781.
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1 ABSTRACT Charles University in Prague Faculty of pharmacy in Hradec Králové Department of pharmacognosy Student: Kateřina Šandová Supervisor: PharmDr. Marie Kašparová, PhD. Title of diploma thesis: Plant tissue cultures as a potential source of phenylpropanoids II. This diploma thesis deals with the monitoring of jasmonic acid biotic elicitation impact on the production of podophyllotoxin in Juniperus virginiana suspension culture. The monitoring was carried out in two varieties of J. virginiana: var. 'Glauca' (7th and 19th passage) and var. 'Hetzii' (7th passage). The elicitation of the suspension culture was performed in 4 jasmonic acid concentrations: 0.005 mmol/l, 0.05 mmol/l, 0.5 mmol/l, 5 mmol/l. Samples were taken after 6, 24, 48 and 168 hours of elicitation. The best podophyllotoxin production increase was observed in the suspension culture of Juniperus virginiana var. 'Glauca' (7th passage). To achieve this result, the concentration of elicitor was 5 mmol/l and elicitor was applied for 168 hours. The podophyllotoxin production percentage was 0.067% and production increased by 179% over the control. Keywords: Juniperus virginiana, suspension cultures, podophyllotoxin, elicitation
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Vargovčíková, Veronika. "Produkce podofylotoxinu v explantátové kultuře Juniperus virginiana." Master's thesis, 2018. http://www.nusl.cz/ntk/nusl-388715.
Full textAbstract:
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy Student: Veronika Vargovčíková Supervisor: PharmDr. Marie Kašparová, Ph.D. Title of diploma thesis: Production of podophyllotoxin by plant tissue cultures of Juniperus virginiana Key words: Juniperus virginiana, callus cultures, suspension cultures, podophyllotoxin Elicitor and precursor adding method can be used to enhance the production of secondary metabolites in explantate cultures. This master's thesis is focused on the evaluation of the effects of biotic elicitor (salicylic acid) and phenylpropanoid metabolism precursor (cinnamic acid) on podophylotoxin production in Juniperus virginiana (var. 'Glauca' and 'Hetzii') suspension cell culture. Suspension cultures were cultivated on Schenk and Hildebrandt medium at 25řC and circadial period of 16 hours light and 8 hours dark. Medium contained 15 mg.l-1 ascorbic acid and growth regulators 3.0 mg.l-1 , α-naphthaleneacetic acid, 0.2 mg.l-1 kinetin. The effects of salicylic acid aqueous solution 0.01 mmol.l-1 , 0.10 mmol.l-1 , 1.00 mmol.l-1 , 10.0 mmol.l-1 and cinnamic acid 60% alcohol solution 0.10 mmol.l-1 , 1.00 mmol.l-1 , 10.0 mmol.l-1 , 100 mmol.l-1. were examined after 6, 24, 48 and 168 hours. Podophylotoxin content was evaluated using HPLC method. In 'Glauca'...
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Dohnalová, Gabriela. "Rostlinné explantátové kultury jako potenciální zdroj fenylpropanoidů I." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-405081.
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Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy Candidate: Gabriela Dohnalová Supervisor: PharmDr. Marie Kašparová, Ph.D. Title of diploma thesis: Plant tissue cultures as a potential source of phenylpropanoids I Explant cultures are the source of plant secondary metabolites. However, the production of secondary metabolites is usually low in explant cultures. Production can be increased by a method called elicitation. The basic prerequisite for successful elicitation is, among other things, finding a suitable elicitor, its concentration and optimal time of elicitor action on plant culture in vitro. The aim of this study was to observe the influence of lead chloride and ferrous sulfate (in four concentrations) on the production of podophyllotoxin in the suspension cultures of Juniperus virginiana L. (variety Hetzii and Glauca). The culture was cultured on Schenk and Hildebrandt nutrient medium with addition of 3.0 mg.l-1 α-naphthylacetic acid, 0.2 mg.l-1 kinetin and 15 mg.l-1 ascorbic acid. Cultivation proceed in 25 řC temperature and 16 hours light/8 hours dark period. Subsequently, the determination of the content of podophyllotoxin by HPLC was performed. Juniperus virginiana L. variety Hetzii produces a higher amount of podophyllotoxin than the Glauca...
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Long, Zsofia Banhegyi. "Incidence and clinical relevance of abnormal complete blood counts in survivors of childhood cancer." 2005. http://edissertations.library.swmed.edu/pdf/LongZ032105/LongZsofia.pdf.
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Urbanová, Nikola. "Studium sekundárních metabolitů v rostlinných explantátových kulturách II." Master's thesis, 2018. http://www.nusl.cz/ntk/nusl-382789.
Full textAbstract:
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy Student: Nikola Urbanová Supervisor: PharmDr. Marie Kašparová, Ph.D. Title of diploma thesis: The study of secondary metabolites in plant tissue cultures II The aim of this work was to determine the effect of the potential elicitor chitosan on production of podophyllotoxin in callus and suspension cultures of Juniperus virginiana Glauca variety and suspension cultures of Juniperus virginiana Hetzii variety. Schenk and Hildebrandt medium supplemented with α-naphtylacetic acid (3.0 mg/l), kinetin (0.2 mg/l) and ascorbic acid (15.0 mg/l) was used for the cultivation. Chitosan solutions of various concentrations (0.001; 0.01; 0.1; 1 g/100 ml) were affecting the cultures for 6, 24, 48 and 168 hours. The content of chitosan was determined by HPLC. Higher values of podophyllotoxin content were measured in cultures derived from the Glauca variety. The best chitosan effect on podophyllotoxin production was manifested in callus cultures after 24 hours application of 0.001 g/100ml concentration. A podophyllotoxin content of 0.210 % was determined, which was about 320 % higher in comparison with the control. The maximum content (0.140 %) in suspension culture was induced by 24-hours application of a 0.1 g/100 ml concentration;...
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Srbová, Lenka. "Explantátová kultura Juniperus virginiana L. jako perspektivní zdroj podofylotoxinu." Master's thesis, 2016. http://www.nusl.cz/ntk/nusl-345025.
Full textAbstract:
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy Student: Lenka Srbová Supervisor: PharmDr. Marie Kašparová, Ph.D. Title of diploma thesis: Tissue culture of Juniperus virginiana L. as a promising source of podophyllotoxin. The diploma thesis deals with the cultivation of Juniperus virginiana tissue cultures. A growth was observed at Juniperus virginiana two years old culture (variety 'Glauca' and 'Grey Owl') after adding various concentrations of phenylalanine (1 mmol.l-1, 10 mmol.l-1 and 100 mmol.l-1 ) at selected time intervals. The results show that the highest increase in callus fresh weight was detected at Juniperus virginiana variety 'Grey Owl', particularly on the 14th day after adding 10 mmol.l-1 phenylalanine. Suspension culture was successfully derived from the Juniperus virginiana two years old callus culture (variety 'Glauca').
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Lisiecki, Kamil. "Synteza lignanów i ich pochodnych z wykorzystaniem procesu fotocyklizacji." Doctoral thesis, 2019. https://depotuw.ceon.pl/handle/item/3461.
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This dissertation concerns the stereoselective synthesis of compounds from the group of aryltetralins and aryldihydronaphthalenes belonging to the cyclolignans family. Its aim is to broaden the knowledge about the methods of cyclolignans synthesis by examining the complex and fascinating photochemistry of derivatives of bisbenzylidenesuccinic acid (fulgenic acid). Undertaking this subject was dictated by the lack of general, cheap and highly stereoselective methods of synthesis of this type of chemical systems. In addition, photochemical cyclization of fulgenic acid derivatives, leading to cyclolignans, has been a little studied and rarely used as a synthetic tool.
Dissertation begins with a short chapter defining the purpose and assumptions of the work. Then, in Chapter 2, I reviewed the literature on lignans. This review consists of six subchapters. In subchapters 2.1.-2.3. I discussed the general characteristics of lignans as chemical compounds, the history of research on them and their biosynthesis. Subchapter 2.4. is devoted to the description of the best-known cyclolignan - podophyllotoxin, focusing primarily on its biological properties. The next subchapter 2.5. is a description of previously developed methods of podophyllotoxin synthesis, with particular emphasis on photocyclization of fulgenic acid derivatives. In the last subchapter of this part, I described the most important ideas of organic photochemistry and photochemical reactions carried out under flow conditions.
Chapter 3 is devoted to the description of the results of my own research. In subchapter 3.1. I presented the formal synthesis of (–)-podophyllotoxin that I developed. Its pivotal element is the use of L-prolinol as a source of chirality and photocyclization, carried out under flow conditions. The next subchapter contains a description of the first total synthesis of (+)- epigalcatin that I developed. The 11-step synthetic path confirms the usefulness of the proposed methodology in the synthesis of cyclolignans which are not available from natural sources. Subchapter 3.3. refers to attempts to use L-proline as a chiral auxiliary in the synthesis of cyclolignans, during which I discovered a rare reaction during which a photolytic cleavage of the amide bond occurs under the influence of visible light. I have also presented the possible use of the bisbenzylidenesuccinyl platform as a photolabile protecting group for secondary amines. In the penultimate subchapter 3.4. I included a description of the unexpected regioselectivity in the photocyclization during the synthesis of (1R)-methylpodophyllotoxin. Thanks to the obtained results, I have defined some general rules regarding the photocyclization of chiral 2,3-bisbenzylidenesuccinates. The last part of this chapter is a description of the preliminary cytotoxicity results of compounds obtained during my research. These results showed that the first known heterodimer of podophyllotoxin and benzothiazole, synthesized by me, was much more active against the majority of the tested tumor cell lines than podophyllotoxin.
Chapter 4 contains a summary of the research and conclusions.
Chapter 5 is devoted to the experimental part. It starts with general information on the used reagents, the preparation of solvents and the equipment used to characterize obtained products. The pivotal subchapter 5.2. is an accurate description of the experiments which were carried out, including analytical data of the newly obtained compounds.
The dissertation ends with a list of the cited scientific literature.<br>Niniejsza rozprawa dotyczy stereoselektywnej syntezy związków z grupy arylotetralin i arylodihydronaftalenów, należących do rodziny cyklolignanów. Jej celem jest poszerzenie wiedzy na temat metod syntezy cyklolignanów poprzez zbadanie złożonej i fascynującej fotochemii pochodnych kwasu bisbenzylidenobursztynowego (kwasu fulgenowego). Podjęcie tej tematyki było podyktowane brakiem ogólnych, tanich i wysoce stereoselektywnych metod syntezy tego typu układów. Dodatkowo, fotochemiczna cyklizacja pochodnych kwasu fulgenowego, prowadząca do cyklolignanów, była dotąd mało zbadanym i rzadko stosowanym narzędziem syntetycznym.
Pracę rozpoczyna krótki rozdział definiujący cel i założenia pracy. Następnie, w rozdziale 2., przedstawiłem przegląd literatury dotyczącej lignanów. Przegląd ten składa się z sześciu podrozdziałów. W podrozdziałach 2.1.-2.3. omówiłem ogólną charakterystykę lignanów jako związków chemicznych, historię badań nad nimi oraz ich biosyntezę. Podrozdział 2.4. poświęciłem opisowi najlepiej poznanego cyklolignanu – podofilotoksynie, skupiając się przede wszystkim na jej właściwościach biologicznych. Kolejny podrozdział 2.5. to opis opracowanych dotąd metod syntezy podofilotoksyny, ze szczególnych naciskiem na fotocyklizację pochodnych kwasu fulgenowego. W ostatnim z podrozdziałów tej części opisałem najważniejsze idee fotochemii organicznej i reakcji fotochemicznych realizowanych w warunkach przepływowych.
Rozdział 3. poświęcony jest opisowi wyników badań własnych. W podrozdziale 3.1. przedstawiłem opracowaną przeze mnie formalną syntezę (–)-podofilotoksyny. Jej kluczowym elementem jest wykorzystanie L-prolinolu jako źródła chiralności oraz fotocyklizacja, przeprowadzona w warunkach przepływowych. Następny podrozdział zawiera opis pierwszej totalnej syntezy (+)-epigalcatyny. Przeprowadzona przeze mnie 11-sto etapowa ścieżka syntetyczna, potwierdza użyteczność opracowanej metodologii w syntezie cyklolignanów niedostępnych w źródłach naturalnych. Podrozdział 3.3. dotyczy próby wykorzystania L-proliny jako pomocnika chiralnego w syntezie cyklolignanów, w trakcie której odkryłem rzadką reakcję, podczas której dochodzi do fotolitycznego rozerwania wiązania amidowego pod wpływem światła widzialnego. Przedstawiłem również możliwe wykorzystanie platformy bisbenzylidenobursztynylowej jako fotolabilnej grupy zabezpieczającej aminy drugorzędowe. W przedostatnim podrozdziale 3.4. zawarłem opis nieoczekiwanej regioselektywności fotocyklizacji podczas próby syntezy (1R)-metylopodofilotoksyny. Dzięki otrzymanym wynikom określiłem pewne ogólne reguły dotyczące fotocyklizacji chiralnych 2,3-bisbenzylidenobursztynianów. Ostatnia część tego rozdziału to opis wstępnych wyników cytotoksyczności związków otrzymanych w trakcie realizacji moich badań. Wykazały one, że zsyntetyzowany przeze mnie pierwszy znany heterodimer podofilotoksyny i benzotiazolu, był o wiele aktywniejszy, względem większości przebadanych linii komórek nowotworowych, niż podofilotoksyna.
Rozdział 4. zawiera podsumowanie przeprowadzonych badań oraz wnioski z nich płynące.
Rozdział 5. poświęcony jest części doświadczalnej. Rozpoczyna się on od ogólnych informacji dotyczącej stosowanych odczynników, przygotowania rozpuszczalników oraz sprzętu użytego do scharakteryzowania otrzymanych produktów. Kluczowy podrozdział 5.2. to dokładny opis przeprowadzonych eksperymentów, łącznie z danymi analitycznymi nowo otrzymanych związków chemicznych.
Dysertację kończy spis cytowanej literatury naukowej.
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Charruault, Lise. "Nouvelles voies d'acces a des carbo- et heterocycles fonctionnalises en milieu organoaqueux catalyse asymetrique et application synthetique." Phd thesis, 2003. http://pastel.archives-ouvertes.fr/pastel-00001083.
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Ce manuscrit présente le développement de réactions de cyclisation de diènes ou d'énynes 1,6 catalysées par des complexes de métaux de transition en milieu organoaqueux et leur application à la synthèse de lignanes. L'utilisation d'une monophosphine trisulfonée (TPPTS) a permis l'étude de deux réactions illustrant le principe d'économie d'atomes. La réaction de métallo-ène a été réalisée en présence de Ni(cod)2/TPPTS pour conduire efficacement à des diènes cycliques. Des réactions d'hydroxy- et de méthoxycyclisation ont été réalisées avec deux systèmes catalytiques complémentaires: PdCl2/TPPTS et PtCl2/TPPTS. Des études mécanistiques basées sur des expériences de deutération ont été conduites. Un nouveau système catalytique a été mis au point: l'utilisation du platine en association avec une monophosphine atropoisomère (Ph-BINEPINE) et des sels d'argent a permis le développement d'une version énantiosélective des réactions d'hydroxy- et de méthoxycyclisation. Les excès énantiomériques obtenus peuvent atteindre 85%. En outre, la réaction d'hydroxycyclisation en présence de palladium a été utilisée avec succès pour conduire au squelette aryltétraline, précurseur de la podophyllotoxine.