Tethered N-Heterocyclic Carbene-Carboranyl Silver Complexes for Cancer Therapy

Silver complexes of tethered N-heterocyclic carbene-carboranyl ligands have been prepared and fully characterized. The first example of silver bonded directly to the cage of o-carborane has been identified in the solid state. The presence of a carboranyl N substituent on the N-heterocyclic carbene significantly enhances the in vitro cytotoxicity of the silver complex against HCT116 p53+/+ and HCT116 p53–/– colon cancer cells in comparison to a phenyl derivative. Conversely, the presence of a carboranyl on the backbone of a xanthine-derived N-heterocyclic carbene decreases the in vitro cytotoxicity of the silver complex in comparison to its phenyl derivative. Stability studies on the xanthine-derived ligands and complexes show that decomposition via deboronation occurs in hydrous dimethyl sulfoxide, which may attribute to the contrasting in vitro behaviors of the carborane-containing complexes

Konjugáty klastrů bóru jako stavební bloky pro přípravu polymerních nanostruktur

Univerzita Karlova v Praze Přírodovědecká fakulta Katedra fyzikální a makromolekulární chemie Autor: Bc. Filip Steiner Vedoucí práce: prof. RNDr. Pavel Matějíček, Ph.D. Konzultant: Ing. Mariusz Uchman, Ph.D. Název diplomové práce: Konjugáty klastrů bóru jako stavební bloky pro přípravu polymerních nanostruktur Abstrakt Tato diplomová práce se zabývá syntézou a supramolekulárním chováním amfifilních konjugátů closo-dodekaborátového dianiontu, [B12H12]2- , s polykationtovým diblokovým kopolymerem poly(ethylen oxid)-b-poly(2-(N, N, N', N'-tetramethylguanidium ethylakrylát), PEOn-b-PGEAm. Konjugáty klastrů bóru byly syntetizovány pomocí exoskeletální, elektrofilem indukované nukleofilní substituce (EINS) a následnou reakcí s různými alifatickými dioly, což vedlo ke vzniku amfifilních molekul činkovitého tvaru. Ty byly následně využity k přípravě nanočástic spoluskládáním s polykationtovými blokovými kopolymery ve vodě. Výsledné nanostruktury byly charakterizovány pomocí statického a dynamického rozptylu světla a spektroskopie NMR. Klíčová slova: klastrové sloučeniny bóru, polymerní nanočástice, spoluskládání, NMR, rozptyl světlaCharles University in Prague Faculty of Science Department of Physical and Macromolecular Chemistry Author: Bc. Filip Steiner Supervisor: prof. RNDr. Pavel Matějíček, Ph.D. Advisor: Ing. Mariusz Uchman, Ph.D. Title: Boron Cluster Conjugates as Building Blocks for the Preparation of Polymeric Nanostructures Abstract This diploma thesis investigates the synthesis and supramolecular behaviour of amphiphilic conjugates of closo-dodecaborate dianion, [B12H12]2- , with polycationic diblock copolymer poly(ethylene oxide)-block-poly(2-(N, N, N', N'-tetramethyl guanidium ethyl acrylate), PEOn-b-PGEAm. The boron cluster dumbbells were synthesised by the exoskeletal, electrophile-induced nucleophilic substitution (EINS) and by subsequently ring-opening reaction with various aliphatic diols, resulting in a hybrid dumbbell molecule. These molecules were used for preparation of nanoparticles by co- assembly with polycationic diblock copolymer in water. Resulted nanostructures were characterised by static and dynamic light scattering and NMR spectroscopy. Keywords: boron cluster compounds, polymeric nanoparticles, co-assembly, NMR, light scatteringKatedra fyzikální a makromol. chemieDepartment of Physical and Macromolecular ChemistryPřírodovědecká fakultaFaculty of Scienc

Samoskládání sloučenin obsahujících borové klastry a jejich spoluskládání s polymery

Táto práce je zaměřena na samoskládání sloučenin obsahujících klastry boru a spoluskládání metallakarboranu kobalt bis(dikarbollidu), COSANu, s hydrofilními polymery. Počátek tohoto výzkumu je spojen s objevem inhibice HIV proteázy COSANem a jeho konjugáty. Z toho důvodu jsme se rozhodli podrobně prozkoumat chování sloučenin obsahujících bórové klastry ve vodném roztoku. Amfifilní charakter několika boranů a karboranů byl prokázán studiem povrchového napětí a agregací, přesto že nemají klasickou amfifilní topologií. V chování COSANu jsme našli podobnosti s klasickými surfaktanty, jako je SDS, zatímco chování menších klastrů s větším povrchovým nábojem se více podobalo látkám hydrotropním nebo chaotropním. Dále jsme taky hledali nejvhodnější systém pro transport metallakarboranů jako léčiv. Na základě předchozích zjištění, že COSAN interaguje s poly(ethylen oxidem), PEO a poly(2-alkyl-2-oxazolinem), POX, jsme připravili nanočástice kombinací obou bloků, včetně různých typů POX. Porovnáním lineárního a hvězdicového kopolymeru jsme ukázali, že architektura polymeru má zásadní vliv na morfologii nanočástic. Navíc jsme také pozorovali různou selektivitu kationtů k PEO a POX, která vedla k rozličným strukturám v závislosti na typu přítomného kationtu. Kationtová selektivita byla také pozorována u...This thesis focuses on the self-assembly of the boron cluster compounds and the coassembly of metallacaborane cobalt bis(dicarbollide), COSAN, with hydrophilic polymers. The research was motivated by the discovery of HIV inhibition by COSAN and its conjugates. Therefore, we decided to study in detail the behavior of boron cluster compounds in water. We demonstrated the amphiphilic character of several boranes and carboranes by the study of surface tension and self-assembly despite the absence of classical amphiphilic topology. The behavior of COSAN showed similarities with classical surfactants, such as SDS, whereas the behavior of smaller clusters with high charge density reminded of hydrotropes or chaotropes. Furthermore, we searched for the most suitable carriers of COSAN for drug delivery. Based on the earlier findings that COSAN interacts with both poly(ethylene oxide), PEO, and poly(2-oxazoline), POX, we prepared nanoparticles by mixing COSAN with block copolymers of various types of POX. Comparing linear and star-like block copolymers, we showed that the polymer architecture has a crucial role in the morphology of nanoparticles. In addition, we proved different selectivity of alkaline cations towards PEO and POX, resulting in the different structures of nanoparticles depending on the present...Katedra fyzikální a makromol. chemieDepartment of Physical and Macromolecular ChemistryPřírodovědecká fakultaFaculty of Scienc

Preparation of Brand New Ligand Architectures Incorporating N-Heterocyclic Carbene Complexes with Carboranyl Substituents: Coordination Chemistry, Catalytic Evaluation and Anticancer Properties

In this thesis two very different types of ligand classes are brought together, namely N-heterocyclic carbenes (NHCs) and carboranes. Chapter one discusses the fundamental structure and bonding involved in these two types of compound. An account of the synthetic strategies employed in the literature for the synthesis of NHCs and carboranes, and the techniques employed to coordinate these ligands to various metal centres is discussed. Chapter two discusses the synthetic strategies explored towards a new hybrid ligand scaffold that fuses N-heterocyclic carbenes (NHCs) and o-carborane. A focal point of this work was to demonstrate the tailorability of this novel ligand system. A detailed account of the techniques employed for the characterisation of these novel ligands is given. Chapter three discusses the synthetic challenges associated with deprotonation of the zwitterionic ligand precursors reported in Chapter 2. A deprotonation study revealed that the ligand must possess an ethyl linker or longer between the imidazolium and the carborane for a free carbene to be isolated. Subsequent coordination to various metal centres, including titanium, iron and rhodium, is explored. The synthesis and full characterisation of RhI-NHC complexes that exhibit closo-carboranyl substituents is described in Chapter four. These complexes display unprecedented chemistry with a rare example of a RhI-metallacycle coordinating through both the NHC and the carbon vertex of the carborane. The catalytic activity of these complexes was probed in the hydrosilylation of acetophenone. Chapter five investigates the application of our NHC-carborane ligands to the higher oxidation states of RhIII and IrIII as well as RuII. We have discovered that the nature of the α-substituent of the NHC, as well as reaction conditions, can determine the vertex at which cyclometallation occurs. A series of IrIII complexes were successfully cyclometallated through the NHC and either a carbon atom or the B3/B6 vertex of the cage. Examination of the Ir complexes in the transfer hydrogenation of acetophenone revealed that cyclometallation through the carborane has a profound effect on the catalytic activity, indicating a bifunctional mechanism and involvement of the carborane moiety. Chapter six describes the diverse coordination modes of NHC-carborane ligands at AgI. The steric nature of the ligand precursor plays a crucial role in the overall stability and the type of silver complex formed, with the first structurally elucidated example of AgI directly bound through the carborane reported. In addition, a series of carboranyl complexes derived from the natural product theobromine were synthesised. The antiproliferative properties of these complexes against the HCT116 (colon) cancer cell line was evaluated

Bis(carboranes) in catalysis : from chelation to metalation

Chapter 1 is an overview of the chemistry of carboranes and their reactivity with particular focus on metalation and use in catalysis. The chemistry of bis(carboranes) is also discussed in detail. A full scope of thesis is also included. Chapter 2 describes the development of synthetic routes using bis(o-carborane) as a chelating ligand to a ruthenium centre. Novel compounds are characterised and suitable species are tested as catalysts in Diels-Alder cycloaddition reactions. Chapter 3 expands on the synthesis of new catalysts exploring substitution reactions on the cages of bis(o-carborane). Octamethyl-bis(o-carborane) is synthesised and used as a ligand to a metal centre. One product is tested as a catalyst in Diels-Alder cycloaddition reactions. Chapter 4 discusses the displacement of arene ligands from arene-ruthenium derivatives of bis(o-carborane) using phosphine and phosphite ligands. This resulted in an experimental and computational study of a novel isomerisation process. The new characteristics and reactivity of these compounds are discussed and suitable compounds are tested as catalysts in Diels-Alder cycloaddition reactions. Chapter 5 introduces bis(m-carborane) as a different type of ligand to a metal centre. The metalation of bis(m-carborane) is discussed using different metal fragments. Chapter 6 outlines the experimental procedures for all new compounds discussed, including synthesis and analysis. Appendix A explores the use of bis(o-carborane) as a ligand on Au(III) metal centres with a comprehensive study of novel compounds. Appendix B summarises the crystallographic data for all compounds studied by XRD in this thesis

Asociační chování karboranů a jejich interakce s polymery v roztocích

Tato diplomová práce se zabývá chováním kobalt bis(dikarbollid)u a jeho derivátů obsahujících polyethylenoxidový linker ve vodném roztoku a roztoku soli a jejich interakcí s některými biokompatibilními polymery. V této práci byl použit diblokový kopolymer poly(ethylenoxid)-block-poly(2-ethyl oxazolin), PEO-PEOX, triblokový kopolymer poly(2- ethyl oxazolin)-block-poly(ethylenoxid)-block-poly(2-ethyl oxa-zolin), PEOX-PEO-PEOX a hvězdicový kopolymer 4-ramenný poly(ethylenoxid)-block-poly(2-methyl oxazolin), 4- ramenný PEO-PMOX. Rozpustnost a změna hydrodynamického poloměru metallakarboranových částic byla studována v závislosti na kationtu příslušné soli. Rozpustnost i velikost částic se mění v závislosti na protiontu metallakarboranu a taky na délce a typu PEG linkeru sloučeniny karboranu. Kobalt bis(dikarbollid) i jeho deriváty tvoří v roztoku s polymery částice tvořené komplexem polymer/caborane. Přídavek polymeru zvyšuje rozpustnost karboranů a ve většině případu snižuje velikost částic v roztoku. Tyto systémy byli studovány pomocí rozptylových technik, UV-VIS spektroskopie, ITC, NMR a SAXS.This diploma thesis deals with the behavior of cobalt bis(dicarbollide) and its derivatives containing polyethylene oxide linkers in aqueous and salted solution and their interactions with some biocompatible block copolymers. In this study we chose diblock copolymer poly(ethylene oxide)-block-poly(2-ethyl oxazoline), PEO-PEOX, triblock copolymer poly(2- ethyl oxazoline)-block-poly(ethylene oxide)-block-poly(2-ethyl oxazoline), PEOX-PEO- PEOX and starlike polymer 4-arm poly(ethylene oxide)-block-poly(2-methyl oxazoline), 4- arm PEO-PMOX. Solubility and change of hydrodynamic radius of metallacarborane particles depending on the cation of corresponding salt solution was studied. Solubility and size of particles changes depending on counterion of metallacarborane and also on the length and type of PEG linker of carborane compound. In solutions with polymer cobalt bis(dicarbollide) and his conjugates form particles composed of complex polymer/caborane. Adding polymer increase solubility of carborane and in most cases it decreases the size of particles in solution. These systems were studied by means of light scattering, UV-VIS spectroscopy, ITC, NMR and SAXS.Katedra fyzikální a makromol. chemieDepartment of Physical and Macromolecular ChemistryFaculty of SciencePřírodovědecká fakult

Thermal and photochemical reactions of large metallaborane clusters and functionalizations of boron nitride nanosheets

The thermal and photochemical pathways of several metallaborane compounds and the functionalization of boron nitride nanosheets have been investigated. The nanosheets have potential applications in Dye Sensitized Solar Cells.Chapters 1 and 3 describe the thermal and photochemical pathways for two metalladecaboranes, [nido -6-Mn(CO) 3 B 9 H 13 ][NMe 4 ] (1.1) and [6-C5Me5-nido-6-RhB9H13] (3.1). Isomerization or cage closure reactions were observed depending on the reaction conditions and the transition metal employed. Characterized products include the firstnido-5 metalladecaborane and ahypercloso-metalladecaborane containing a group 7 transitional metal, compound1.3 and1.4, respectively. Other findings include the facile acid catalyzed cyclic oxonium functionalization of complex1.1, the role of complex3.1 as the catalyst for the [2+2+2] cycloadditions of terminal alkynes, and the formation ofhypercloso-rhodadecaborane3.3 which is the firsthypercloso-metalladecaborane containing the metal rhodium. Chapter 2 describes investigations of the photochemical reactions between metallaboranes and unsaturated molecules. The complex 1.1was found to photoreact with both terminal and internal alkynes to afford the carborane with general formula [7-R-8-R\u27-7,8-nido-C2B9H10][NMe4] (2) in good yield. This represents a novel method for generating the substituted nido-C2B9 complex. Besides alkynes, the investigation of the photoreactions of other unsaturated species with the complex 1.1 were found to generate the [arachno-B9H14]- (2.4) and [nido-B9H12]- (2.5) anions in different relative ratios, depending on the nature of the unsaturated molecules. The complex1.1 was also found to act as an efficient catalyst for isocyanate cyclodimerization under photo-irradiation conditions, representing the first example of a metallaborane complex to catalyse the cyclodimerization of isocyanate. In Chapter 4, an effective and simple noncovalent functionalization and solubilization of boron nitride nanosheets (BNNSs) has been achieved by using polythiophene or polyvinylpyrrolidone as a functionalization polymer with BNNSs. The BNNSs form strong π-π stacking interactions with the polythiophenes and were found to act as a bandgap tuning tool for polythiophene derivatives. A BNNS-polythiophne-TiO2 hybrid nanomaterial was achieved by the covalent binding between TiO2 nanoparticle surfaces and the BNNS-polythiophene unit containing a carboxylic acid functional group. This nanomaterial was then further incorporated into a Dye Sensitized Solar Cells (DSSCs) and the observed enhancement of the performance of the cells is discussed

Stabilisation of latent vacant sites in cationic group 9 phosphine complexes: Synthesis, structure and catalysis

EThOS - Electronic Theses Online ServiceGBUnited Kingdo