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In vitro and in cellulo interactions of platinum and ruthenium anticancer metallodrugs with RNAHostetter, Alethia A., 1981- 03 1900 (has links)
xviii, 125 p. : ill. (some col.) / Since its approval by the FDA in 1978 cisplatin (cis-diamminedichloroplatinum(II)) has revolutionized the treatment of several cancer types, particularly testicular cancer which now has a cure rate greater than 90%. Following the example set by its success, a broad range of antitumor metallodrugs is being developed. One of the most promising of these drugs, currently in Phase Two of clinical trials, is the Ru-based NAMI-A (imadozolium trans -[tetrachloro(dimethylsulfoxide)(imidazole)ruthenate(III)]) which displays low systemic toxicity and strong antimetastatic activity. The majority of anticancer metallodrugs (including NAMI-A and cisplatin) can bind to DNA, which, in many cases, is an important therapeutic target. Much effort has gone into characterizing the DNA binding properties of anticancer metallodrugs. Less study has gone into characterizing the interaction of anticancer mellodrugs with RNA even though RNA is chemically similar to DNA and plays important roles in gene expression and regulation. Focusing on the extensively studied cisplatin, Chapter I covers both what is known about anticancer metallodrug-RNA binding and the information that can be gleaned from DNA binding and drug localization studies. Chapter II provides the details of a kinetic investigation of the in vitro binding of aquated cisplatin to an RNA sequence containing an internal loop derived from the core of the spliceosome, a related RNA hairpin, and the slower reacting DNA hairpin analog. Chapter III follows in cellulo studies with cisplatin-treated S. cerevisiae that demonstrate, using ICP-MS, differences in Pt accumulation in mRNA and rRNA. The effects of cisplatin treatment on S. cerevisiae cell growth and viability were investigated using clonogenic and morphologic assays. In Chapter IV the same protocols were applied in order to investigate Ru accumulation on RNA following S. cerevisiae treatment with NAMI-A. These in cellulo experiments were followed by in vitro binding studies that utilized MALDI-MS to compare Ru interactions with RNA and DNA oligonucleotides following treatment with NAMI-A under different solution conditions, finding enhanced binding in an acidic, reducing environment like that found in tumor tissue. Chapter V pulls together the knowledge gained so far and discusses questions for future investigation.
This dissertation includes both previously published and unpublished coauthored material. / Committee in charge: David Tyler, Chairperson;
Victoria DeRose, Advisor;
Darren Johnson, Member;
Andy Berglund, Member;
Alice Barkan, Outside Member
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Rationally designed ruthenium and osmium pseudo-octahedral complexes with original metabolic and antitumor propertiesMarloye, Mickaël 28 October 2021 (has links) (PDF)
En 2021, les cancers sont toujours une des principales causes de mortalité au niveau mondiale. C'est d'une part, une compréhension croissante des phénomènes biologiques liés au développement des cancers et d'autre part, l'évolution des traitements qui nous ont permis d'obtenir et de constamment accroître les taux de guérison et de rémission pour certains types de cancer (ex. cancers du sein, du poumon, du côlon). Mais malgré une pléthore de traitements antitumoraux et l'évolution de techniques médicales aussi bien curatives que diagnostiques, certains cancers sont toujours des maladies difficiles à traiter et restent associés à des prognostiques très négatifs (ex. cancers du pancréas, du cerveau), dès lors le besoin de nouvelles molécules antitumorales est toujours cruellement nécessaire.Ce travail s'inscrit dans ce contexte de développement de nouveaux complexes métalliques possédant des propriétés anticancéreuses ainsi qu'à leur évaluation biologique et à la compréhension de leur mécanisme d'action. L'intérêt des complexes métalliques comme potentiels agents anti-cancéreux a commencé dans les années 60 par la découverte fortuite de la puissante activité antiproliférative du cisplatine. Cette étape a été déterminante et a orienté plus de cinquante années de recherche. De nos jours, les médicaments à base de platine ont toujours une place importante dans l'arsenal thérapeutique anticancéreux, en effet le cisplatine, le carboplatine et l'oxaliplatine sont administrés chez plus de 50% des patients qui reçoivent une chimiothérapie. Néanmoins l'usage des traitements à base des molécules dérivées de platine soulèvent deux problèmes majeurs ;l'apparition d'effets secondaires sévères due au manque de sélectivité pour les cellules tumorales, ainsi que l'émergence de lignées tumorales résistantes à la suite des traitements à base de dérivés de platine. Ceci explique la raison pour laquelle les chercheurs se sont concentrés sur le développement de nouveaux complexes métalliques à visée anticancéreuse.Le laboratoire de Chimie Pharmaceutique Organique de la faculté de Pharmacie de l'Université Libre de Bruxelles, a acquis au fil des années en expertise dans le développement de complexes de platine possédant de puissante activité antiproliférative. L'intérêt grandissant pour de nouveaux métaux potentiellement anticancéreux a mené notre laboratoire vers une nouvelle thématique de recherche :le développement de complexes métalliques de ruthénium et d'osmium potentiellement anticancéreux. Notre choix s'est arrêté sur ces deux métaux pour deux raisons principales :(1) Ces deux métaux étant consécutifs dans la colonne 8 du tableau période, ils sont censés partager certaines similitudes en termes de réactivité, en raison de la similarité de leurs couchesélectroniques externes. Ceci nous offre donc la possibilité de préparer des composés similaires différant uniquement par la nature du centre métallique (ruthénium ou osmium).(2) De nombreux complexes prometteurs ont été rapportés dans la littérature :trois complexes de ruthénium (KP1019, NKP1339 et NAMI-A) sont entrés en essais cliniques et certains composés d'osmium (azpy-type complexes) sont actuellement intensivement étudiés pour leurs propriétés anticancéreuses liées à des mécanismes catalytiques.Ce travail se veut être un cheminement classique dans le domaine de la chimie médicinale, du design rationnel à la sélection des composés les plus actifs pour une évaluation biologique plus approfondie. Chronologiquement, la première partie de ce travail de thèse a consisté en la synthèse de nouveaux dérivés de ruthénium et d'osmium. Ces composés ont été préparé sur base d'un design rationnel. Nous avons considéré trois approches pour préparer nos complexes :(1) Coupler un groupement biotine (vit B7) afin d'augmenter la sélectivité envers les cellules tumorales qui ont tendance à surexprimer le récepteur à la biotine afin de maintenir leur rapide croissance et division.(2) Coupler un groupement 4-(2-aminoethyl)morpholine afin de favoriser une accumulation toxique intralysosomale avec pour finalité la libération de composés pro-apoptotiques menant à la mort cellulaire.(3) Coupler une chaine alkyl-C16 afin d'augmenter drastiquement la lipophilie des complexes permettant d'augmenter fortement leur accumulation cellulaire et par conséquent leur activité antiproliférative.Parmi ces trois stratégies, l'augmentation de la lipophilie fut la seule à pouvoir confirmer expérimentalement une de nos hypothèses de départ. La suite logique de ce travail fut consacrée à la compréhension des mécanismes d'activation et d'action de ces nouveaux complexes possédant une puissante activité antiproliférative. Les résultats obtenus durant ces six années de thèse furent donc reportés et divisés en deux parties principales dans la section « Results » de la façon suivante :Une première partie est essentiellement consacrée aux complexes de ruthénium et d’osmium couplés à la biotine et la 4-(2-aminoethyl)morpholine n’ayant démontré qu’une très faible activité antiproliférative sur un panel de quatre lignées cancéreuses. Cette partie rapporte la synthèse et la caractérisation de six nouveaux complexes de ruthénium et d’osmium, leur évaluation biologique préliminaire ainsi le recours à une approche computationnelle afin de mettre en évidence la « non-réactivité » de ces complexes.La seconde et majeure partie de ce travail est axée sur une étude en profondeur de nos quatre nouveaux complexes portant une chaine alkyl-C16. Ces complexes possèdent à la une importante composante lipophile et une composante ionique leur conférant un caractère mixte en termes de lipophile et d'hydrophile, c'est pourquoi nous avons décidé de les nommer complexes amphiphiles. L'évaluation biologique préliminaire de cette série de complexes amphiphiles a révélé une puissante activité antiproliférative avec des valeurs d'IC50 inférieures à 1 μM sur un panel de lignées cellulaires humaines cancéreuses, ce qui nous a permis de confirmer notre hypothèse originale. Dans le cadre d'un sujet de recherche de chimie médicinale, la suite logique et par extension la plus grande partie de ce travail, a donc été consacrée en grande partie à comprendre les mécanismes et les voies moléculaires impliquées dans l'activité antitumorale de cette série de complexes amphiphiles. Malgré la très grande quantité de complexes de ruthénium et d'osmium reportés depuis plusieurs décennies, les mécanismes cellulaires responsables de l'activité anticancéreuse restent assez vagues et aucun consensus général n'a pu être établi. Après de nombreuses hypothèses établies rationnellement et réfutées expérimentalement, nous avons pu établir nous avons pu établir un potentiel mécanisme d'action lié au métabolisme mitochondrial. Ceci nous a permis de contribuer à notre échelle, à la recherche de la compréhension des mécanismes d'action antiprolifératif des complexes de ruthénium et d'osmium. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished
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Anticancer activity of electron-deficient metal complexes against colorectal cancer in vitro modelsAzmanova, Maria, Soldevila-Barreda, Joan J., Bani Hani, H., Lord, Rianne M., Pitto-Barry, Anaïs, Picksley, Steven M., Barry, Nicolas P.E. 26 September 2019 (has links)
Yes / An evaluation of the in vitro cytotoxicity of nine electron-deficient half-sandwich metal complexes towards two colorectal cancer cell lines (HCT116 p53+/+, HCT116 p53-/-) and one normal prostate cell line (PNT2) is presented herein. Three complexes were found to be equally cytotoxic towards both colorectal cancer cell lines, suggesting a p53-independent mechanism of action. These complexes are 12 to 34 more potent than cisplatin against HCT116 p53+/+ and HCT116 p53-/- cells. Furthermore, they were found to exhibit little or no cytotoxicity towards PNT2 normal cells, with selectivity ratios greater than 50. To gain an insight into the potential mechanisms of action of the most active compounds, their effects on the expression levels of a panel of genes were measured using qRT-PCR against treated HCT116 p53+/+ and HCT116 p53-/- cells, and cell cycle analysis was carried out. / The Royal Society grant UF150295, The Academy of Medical Sciences grant SFB003\1170
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Anticancer water-soluble organoruthenium complexes: synthesis and preclinical evaluationPitto-Barry, Anaïs, Azmanova, Maria, Rafols, Laia, Cooper, Patricia A., Seaton, Colin C., Shnyder, Steven 18 July 2022 (has links)
Yes / The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on ROS production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay. / The support of the Royal Society (University Research Fellowship No. URF150295, and RGF\EA\201001), the Academy of Medical Sciences/ The Wellcome Trust/ The Government Department of Business, Energy and Industrial/ The British Heart Foundation Springboard Award (SBF003\1170), and the CNRS is acknowledged. LRP is supported by a PhD studentship funded by the University of Bradford.
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Synthesis, Characterization And Anticancer Activity Of Copper(I) Phosphine ComplexesSanghamitra, Nusrat Jahan Mobassarah 03 1900 (has links) (PDF)
No description available.
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Síntese e caracterização de complexos de cobre e zinco com anti-inflamatórios não-esteróides e estudo da interação com o biopolímero quitosana / Synthesis and characterization of copper and zinc complexes with anti-inflammatory drugs and studies on their interaction with the chitosan biopolymerMartins, Douglas de Jesus 04 October 2013 (has links)
O presente trabalho teve como principal objetivo o estudo da interação de complexos de cobre e de zinco contendo fármacos anti-inflamatórios não-esteróides (FAINEs) com o biopolímero quitosana. Foram preparados alguns complexos já reportados na literatura como os complexos de cobre com indometacina, ibuprofeno e naproxeno e os complexos de zinco com indometacina, para os quais foram incluídos estudos adicionais de caracterização. Também foram sintetizados complexos inéditos de cobre com cetoprofeno e de zinco com ibuprofeno e meloxicam. Estudou-se a interação de alguns dos metalofármacos com microesferas de quitosana reticuladas com glutaraldeído, preparadas pelo método de coacervação. Investigou-se também materiais obtidos por spray-drying, resultantes da interação dos metalofármacos de Cu-ibuprofeno e Cu-indometacina, e do fármaco indometacina, com quitosana. Esses materiais foram submetidos a ensaios preliminares de avaliação macroscópica da lesão intestinal in vivo. Os compostos e materiais obtidos foram caracterizados por análise elementar, espectroscopia eletrônica, espectroscopia vibracional FTIR, difratometria de raios X de pó (DRX), e análise térmica (TG/DTG/DSC). / The present work aimed the study of interactions between copper and zinc complexes containing non-steroidal anti-inflammatory drugs with the chitosan biopolymer. Complexes already reported in the literature such as copper with indomethacin, ibuprofen and naproxen and zinc with indomethacin were prepared and additional characterization studies were performed. New complexes of copper and zinc with ketoprofen, ibuprofen and meloxicam were also synthesized. The interactions of some metallodrugs with microspheres of chitosan cross-linked with glutaraldeyde, prepared by the coacervation method were studied. Materials prepared by spray-drying method, resulting from the interactions of copper-ibuprofen and copper-indomethacin metallodrugs, and from the Indomethacin drug, with chitosan were also investigated. These materials were submitted to preliminary assays to evaluate the macroscopic intestinal damage in vivo. The compounds and materials were basically characterized by elemental analysis, electronic spectroscopy, FTIR vibrational spectroscopy, powder X-rays diffractometry, and thermal analysis (TG/DTG/DSC).
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Síntese e caracterização de complexos de cobre e zinco com anti-inflamatórios não-esteróides e estudo da interação com o biopolímero quitosana / Synthesis and characterization of copper and zinc complexes with anti-inflammatory drugs and studies on their interaction with the chitosan biopolymerDouglas de Jesus Martins 04 October 2013 (has links)
O presente trabalho teve como principal objetivo o estudo da interação de complexos de cobre e de zinco contendo fármacos anti-inflamatórios não-esteróides (FAINEs) com o biopolímero quitosana. Foram preparados alguns complexos já reportados na literatura como os complexos de cobre com indometacina, ibuprofeno e naproxeno e os complexos de zinco com indometacina, para os quais foram incluídos estudos adicionais de caracterização. Também foram sintetizados complexos inéditos de cobre com cetoprofeno e de zinco com ibuprofeno e meloxicam. Estudou-se a interação de alguns dos metalofármacos com microesferas de quitosana reticuladas com glutaraldeído, preparadas pelo método de coacervação. Investigou-se também materiais obtidos por spray-drying, resultantes da interação dos metalofármacos de Cu-ibuprofeno e Cu-indometacina, e do fármaco indometacina, com quitosana. Esses materiais foram submetidos a ensaios preliminares de avaliação macroscópica da lesão intestinal in vivo. Os compostos e materiais obtidos foram caracterizados por análise elementar, espectroscopia eletrônica, espectroscopia vibracional FTIR, difratometria de raios X de pó (DRX), e análise térmica (TG/DTG/DSC). / The present work aimed the study of interactions between copper and zinc complexes containing non-steroidal anti-inflammatory drugs with the chitosan biopolymer. Complexes already reported in the literature such as copper with indomethacin, ibuprofen and naproxen and zinc with indomethacin were prepared and additional characterization studies were performed. New complexes of copper and zinc with ketoprofen, ibuprofen and meloxicam were also synthesized. The interactions of some metallodrugs with microspheres of chitosan cross-linked with glutaraldeyde, prepared by the coacervation method were studied. Materials prepared by spray-drying method, resulting from the interactions of copper-ibuprofen and copper-indomethacin metallodrugs, and from the Indomethacin drug, with chitosan were also investigated. These materials were submitted to preliminary assays to evaluate the macroscopic intestinal damage in vivo. The compounds and materials were basically characterized by elemental analysis, electronic spectroscopy, FTIR vibrational spectroscopy, powder X-rays diffractometry, and thermal analysis (TG/DTG/DSC).
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On Metal Speciation and Bioavailability in the Biosphere via Estimation of Metal-Ligand Thermodynamic PropertiesJanuary 2019 (has links)
abstract: Due to analytical limitations, thermodynamic modeling is a lucrative alternative for obtaining metal speciation in chemically complex systems like life. However, such modeling is limited by the lack of equilibrium constant data for metal-complexation reactions, particularly for metal-organic species. These problems were ameliorated estimating these properties from 0-125°C for ~18,000 metal complexes of small molecules, proteins and peptides.
The estimates of metal-ligand equilibrium constants at 25°C and 1 bar were made using multiple linear free energy relationships in accordance with the metal-coordinating properties of ligands such as denticity, identity of electron donor group, inductive effects and steric hindrance. Analogous relationships were made to estimated metal-ligand complexation entropy that facilitated calculation of equilibrium constants up to 125°C using the van’t Hoff equation. These estimates were made for over 250 ligands that include carboxylic acids, phenols, inorganic acids, amino acids, peptides and proteins.
The stability constants mentioned above were used to obtain metal speciation in several microbial growth media including past bioavailability studies and compositions listed on the DSMZ website. Speciation calculations were also carried out for several metals in blood plasma and cerebrospinal fluid that include metals present at over micromolar abundance (sodium, potassium, calcium, magnesium, iron, copper and zinc) and metals of therapeutic or toxic potential (like gallium, rhodium and bismuth). Metal speciation was found to be considerably dependent on pH and chelator concentration that can help in the selection of appropriate ligands for gallium & rhodium based anticancer drugs and zinc-based antidiabetics. It was found that methanobactin can considerably alter copper speciation and is therefore a suitable agent for the treatment of Wilson Disease. Additionally, bismuth neurotoxicity was attributed to the low transferrin concentration in cerebrospinal fluid and the predominance of aqueous bismuth trihydroxide. These results demonstrate that metal speciation calculations using thermodynamic modeling can be extremely useful for understanding metal bioavailability in microbes and human bodily fluids. / Dissertation/Thesis / Doctoral Dissertation Biochemistry 2019
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Preclinical Anticancer Activity of an Electron-Deficient Organoruthenium(II) ComplexSoldevila-Barreda, Joan J., Azmanova, Maria, Pitto-Barry, Anaïs, Cooper, Patricia A., Shnyder, Steven, Barry, Nicolas P.E. 04 September 2020 (has links)
Yes / Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt-resistance mechanisms. Electron-deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron-deficient organoruthenium complex [(p-cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53−/−), and non-small cell lung H460 cancer cell lines. It shows no cross-resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53-independent. In vivo evaluation in the hollow-fibre assay across a panel of cancer cell types and subcutaneous H460 non-small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow-up, this work is the first preclinical study of electron-deficient half-sandwich complexes and highlights their promise as anticancer drug candidates. / UF150295/Royal Society; University of Bradford; Government Department of Business, Energy and Industrial Strategy; SBF003\1170/British Heart Foundation Springboard Award; AMS_/Academy of Medical Sciences/United Kingdom
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Evaluation of the toxicity of two electron-deficient half-sandwich complexes against human lymphocytes from healthy individualsHabas, Khaled S.A., Soldevila Barreda, Joan J., Azmanova, Maria, Rafols, Laia, Pitto-Barry, Anaïs, Anderson, Diana, Barry, Nicolas P.E. 29 October 2020 (has links)
Yes / Electron‐deficient half‐sandwich complexes are a class of under‐studied organometallics with demonstrated potential as metallodrug candidates. The present study investigates the effect of two 16‐electron organoruthenium complexes ([( p‐ cym)Ru(benzene‐1,2‐dithiolato)] ( 1 ) and [( p ‐cym)Ru(maleonitriledithiolate)] ( 2 )) on the cell viability of non‐immortalised human lymphocytes from healthy individuals. The genotoxic effects of 1 and 2 in lymphocytes using the Comet and cytokinesis‐block micronucleus assays is also investigated. Gene expression studies were carried out on a panel of genes involved in apoptosis and DNA damage repair response. Results show that the two 16‐electron complexes do not have significant effect on the cell viability of human lymphocytes from healthy individuals. However, an increase in DNA damage is induced by both compounds, presumably through oxidative stress production. / This project was supported by the Royal Society (University Research Fellowship No. UF150295 to NPEB), the University of Bradford (RDF Award), and by the Academy of Medical Sciences/the Wellcome Trust/ the Government Department of Business, Energy and Industrial Strategy/ the British Heart Foundation Springboard Award [SBF003\1170 to NPEB].
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