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PEGylated micelles for diagnostic and therapy against solid tumors
Hoang, Stéphane ; Hrubý, Martin (advisor) ; Frochot, Céline (referee) ; Bianco, Alberto (referee)
Title : PEGylated micelles for diagnostic and therapy against solid tumors. Keywords : micelles, ferrocene, photolysis, vectorization, nanoparticle, singlet oxygen Abstract : Nanomedicine is an emerging field that addresses the challenges faced by conventional medicine. The use of nanometric objects makes it possible to reduce side effects through targeted, specific treatment at reduced doses. Among these nanoparticles, micelles are widely exploited thanks to their small size and high modularity. As a result, their application extends to many fields, including oncology. Indeed, their size enables them to take full advantage of the characteristics of the tumor microenvironment, resulting in increased accumulation and retention of micelles in tumor tissue. Thus, the use of micelles as nanovectors offers a theranostic approach to cancer therapy. In this context, the work presented here is divided into two distinct parts. The first presents the synthesis and formulation of photodegradable PEGylated micelles capable of both generating cytotoxicity and delivering a hydrophobic molecule intracellularly. The second part focuses on the enhancement of the EPR effect by sonoporation, a method considered to be non-invasive. Results on murine models demonstrated the positive effect of this method by greatly improving...
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Ferrocene stibane ligands
Antala, Jakub ; Štěpnička, Petr (advisor) ; Gyepes, Róbert (referee)
5 Title: Ferrocene stibane ligands Author: Jakub Antala Department: Department of Inorganic Chemistry Supervisor: prof. RNDr. Petr Štěpnička, Ph.D., DSc. Abstract: This diploma thesis reports a study into the coordination properties of ferrocene phosphino-stibine Cy2PfcSbPh2 (LCy, Cy = cyclohexyl, fc = ferrocene-1,1'-diyl). Complexes with various transition metals were prepared (RuII , RhIII , PtII , PdII , AuI ), where the ligand binds in monodentate, bridging or chelating mode. Ruthenium(II) and rhodium(III) complexes were prepared from precursors with π-coordinated arene ligands, whereas [MCl2(η2 :η2 cod)] (M = Pd, Pt; cod = 1,5-cyclooctadiene) precursors were used to prepare palladium(II) and platinum(II) complexes and synthesis of gold(I) complexes started from [AuCl(tht)] (tht = tetrahydro- thiophene). In addition, the thesis describes the reactivity of ferrocene phosphino-stibine Ph2PfcSbPh2 (LPh). Specifically, it focuses on the preparation of chalcogenides Ph2P(E)fcSbPh2 (E = O, S, Se) and the corresponding stiborane derivatives Ph2P(E)fcSbPh2(O2C6Cl4) (E = void, O, S, Se), in which the stiborane center bears tetrachloropyrocatechol substituent, which makes it Lewis acidic and potentially prone to behave as an acceptor of electron pair from the Ph2P(E) moiety. The presence of this interaction was...
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Ferrocene acylphosphines
Vosáhlo, Petr ; Štěpnička, Petr (advisor) ; Čermák, Jan (referee) ; Horáček, Michal (referee)
6 Abstract The Thesis is aimed at the synthesis of novel ferrocene-based acylphosphines of the type FcC(O)PR2 and R1 2PfcC(O)PR2 2 (Fc = ferrocenyl, fc = 1,1'-ferrocendiyl), evaluation of their electron-donating capabilities and steric demands. The impact of these features was scrutinized by further coordination and catalytical studies. First, a series of monodentate acylphosphine ligands FcC(O)PR2 was synthesized (PR2 = diphenylphosphino [PPh2], dicyclohexylphosphino [PCy2], di(1-adamantyl)phosphino [PAd2] a 1,3,5,7-tetramethyl-2,4,6-trioxa-8- phosphaadamantyl [PCg]), which underwent oxidation by elemental selenium to give corresponding phosphine selenides used to probe their electron-donating capabilities via measuring 1 JPSe coupling constant. Then, chlorogold complexes were prepared from these ligands to evaluate their catalytic activity in gold-catalysed hydration of alkynes and cyclization of N-propargylbenzamide. Second, the model compound FcC(O)PPh2 was extensively studied as a ligand in palladium(II) complexes. The ligand was smoothly ortho-metallated by Na2[PdCl4] to form chloro-bridged palladium(II) dimer, which reacted with P-, N- and C-donors under cleavage to give monopalladium complexes. One of these complexes, containing trimethylphosphine auxiliary ligand, was alkylated with organometallic...
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Polar ferrocene phosphines with nitrogen-containing linkers
Navrátil, Michal ; Štěpnička, Petr (advisor) ; Dostál, Libor (referee) ; Horáček, Michal (referee)
Title: Polar Ferrocene Phosphines with Nitrogen-Containing Linkers Author: RNDr. Michal Navrátil Supervisor: prof. RNDr. Petr Štěpnička, Ph.D., DSc. Abstract: This Ph.D. thesis describes three series of bridged ferrocene phosphines derived from aminoferrocene. The first series is comprised of homoannular α- and β-aminophosphines 1-3. The α-aminobis(phosphine) 1 was synthesized from aminoferrocene and (diphenylphosphino)- methanol via phospha-Mannich reaction in a 87% yield. This product was formed regardless of the reaction stoichiometry. Later, ligand 1 was utilized as a ligand for group 10 and 11 metal ions. With group 10 metal precursors, the ligand afforded five different square-planar complexes [MX2(1-κP)] (M/X = Ni/Cl, Pd/Cl, Pd/Br, Pd/I, Pt/Cl). In contrast, the complexes of group 11 metals showed varied geometry around the metal centre, ranging from a linear arrangement in [Au2Cl2(1-κP)], cyclic structure in [Au2(1-κP)2][SbF6]2 and tetrahedral arrangement in [M(1-κP)2][X] (M/X = Cu/BF4; Ag/SbF6; Au/SbF6). The cyclic voltammetry measurements suggested that Fe(II) oxidation is the first oxidation process. The attribution was corroborated by DFT calculations of 1 and [PdCl2(1-κP)]. To obtain the analogous monophosphine 2, aminoferrocene was N-methylated prior to the phospha-Mannich reaction. Subsequent...
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Salts of 2-aminoethanol and ferrocene-based acids
Zábranský, Martin ; Štěpnička, Petr (advisor) ; Němec, Ivan (referee)
Combination of the compact but sterically flexible ferrocene scaffold with intermolecular binding potential and conformational variability of (2-hydroxyethyl)ammonium structural motif was utilised in the construction of solid crystalline materials. Crystallisation in systems containing ferrocenecarboxylic, 2-ferrocenylacetic, 3-ferrocenylpropionic, 3-ferrocenyl- acrylic, 3-ferrocenylacrylic, 3-ferrocenylpropiolic, ferrocene-1,1'-dicarboxylic or ferrocene- sulfonic acid with 2-aminoethanol afforded crystals of the corresponding salts. The resulting crystalline products were characterised with the usual methods (proton nuclear magnetic resonance, infrared spectroscopy, elemental analysis) and their crystal structures were determined by means of single-crystal X-ray diffraction analysis. The crystal structures of the salts mentioned above usually contain rather complicated two dimensional networks of charge-assisted hydrogen bonds. With the aim of studying potentially more simple hydrogen-bonded structures, additional crystallisation experiments were conducted in systems of ferrocenecarboxylic acid and 2-(methylamino)ethanol or 2-(dimethylamino)ethanol. These experiments yielded simple salt of the former amine and adducts of salts of both bases with ferrocenecarboxylic acid in the ratio of 1:1. The...
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Synthesis and catalytic properties of phosphinoferrocene guanidine
Bárta, Ondřej ; Štěpnička, Petr (advisor) ; Vojtíšek, Pavel (referee)
Title: Synthesis and catalytic properties of phosphinoferrocene guanidine Author: Ondřej Bárta Institution: Faculty of Science, Charles University in Prague, Department of Inorganic Chemistry Supervisor: prof. RNDr. Petr Štěpnička, Ph.D. Polar phosphine ligands proved to be useful in homogeneous and biphasic catalysis. Most of these phosphines bears anionic functional groups. On the other hand, functionalization of phosphines by cationic substituents is still quite uncommon, although these functional groups possess properties that could improve catalytic performance of the catalyst. In this regard, nitrogenous bases are particularly attractive due to their inherent basicity and the ability to enter into hydrogen bonding interactions. This thesis describes the synthesis of a novel ferrocene-based phosphine functionalized with guanidine moiety, viz. N-[1′-(diphenylphosphino)ferrocenylmethyl]guanidine (3). This compound was obtained by direct guanylation of 1′-(diphenylphosphino)- 1-(aminomethyl)ferrocene (2) (see scheme). Compound 3 was further used to prepare palladium complexes including the unusual zwitterionic complex [PdCl3(3H)]. The molecular structures of the prepared complexes were determined by X-ray diffraction analysis. Catalytic properties of phosphine 3 and complex [PdCl3(3H)] were...
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Synthesis and characterization of bidentate P,N-donor ferrocene ligand
Rezazgui, David ; Schulz, Jiří (advisor) ; Hulla, Martin (referee)
Title: Synthesis and characterization of bidentate P,N-donor ferrocene ligand Author: Bc. David Rezazgui Department: Department of Inorganic chemistry Supervisor: RNDr. Jiří Schulz, Ph.D. The main goal of this thesis was the preparation and characterization of ferrocene ligand 4-[1'-(diphenylphosphino)ferrocen-1-yl]morpholine (compound 3). Compared to structurally similar compounds, compound 3 offers greater geometrical flexibility which might have a positive effect in some applications, for example in catalysis by transition metal complexes. Two new compounds were synthesized along the synthetic route of phosphinoamine 3, the protected amine 1 and morpholine derivate 2. Selenide 4 was prepared in order to determine the basicity of compound 3 via the direct scalar interaction of 77 Se with 31 P. The synthesis comprised phosphinylation of 1,1'-dibromoferrocene, protection of the obtained 1-bromo-1'- (diphenylphosphino)ferrocene with sulfur, azidation and immediate reduction to protected amine 1. Morpholine derivate 2 was subsequently synthesized by cyclization reaction with bis(2-chloroethyl)ether. Phosphinoamine 3 was obtained by deprotection of compound 2 with Raney nickel. Finally, selenide 4 was obtained by the reaction of 3 with KSeCN. All newly prepared compounds were analyzed by NMR and transmission...
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Synthesis and catalytic properties of ferrocenophane phosphines
Škoch, Karel ; Štěpnička, Petr (advisor) ; Veselý, Jan (referee)
6 Title: Sythesis and catalytic properties of ferrocenophane phosphines Author: Karel Škoch Institution: Faculty of Science, Charles University in Prague, Department of Inorganic Chemistry Supervisor: prof. RNDr. Petr Štěpnička, Ph.D. Keywords: ferrocene, ferrocenophane, phosphine ligands, palladium, asymetric catalysis, aza- Morita-Baylis-Hillman reaction, asymetric allylic alkylation Abstract: This Thesis describes the preparation of five sterically and electronically different ferrocene phosphines, (R)-1,1'-[1-(diarylphosphino)propan-1,3-diyl]ferrocenes (R)-1a-e, and a study into their coordination and catalytic properties. The key precursor of the phosphine synthesis, chiral alcohol (R)-2, was prepared according to the procedure described in the literature. Alcohol (R)-2 was converted with retention of configuration to diarylphosphines (R)-1a-e in one-step reaction with trimethylsilylchloride and sodium iodide and then with the corresponding diarylphosphine. Phosphines 1a-e were characterized by NMR and MS methods. For the basic representative 1a the following palladium(II) complexes were prepared: [PdCl(LNC )(1a)] (10, LNC = 2-[(dimethylamino)methyl]phenyl-C1 ,N) and trans- [PdCl2(1a)2] (9a). In addition, the isomeric complex cis-[PdCl2(1a)2] (9b) was isolated from the reaction mixture after catalytic...
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Activation of ferrocene ligands by sandwich complexes of Group 4 metals
Kout, Matyáš ; Štěpnička, Petr (advisor) ; Vojtíšek, Pavel (referee)
This bachelor thesis deals with synthesis, reactivity and characterization of compounds resulting from the reactions of substituted ferrocene ligands with electron- deficient complexes of group 4 transition metals in oxidation state II with the aim of finding experimental conditions for preparation of complexes containing two metal atoms in one molecule. Reactions were performed under inert atmosphere and the products were crystallized. The obtained crystals were subjected to X-ray diffraction analysis and to NMR spectroscopy in order to elucidate molecular structure of the isolated products. Along the way, instability of the prepared compounds towards air oxygen and moisture has surfaced, though it also led to a discovery of several original compounds. Among these, the molecule containing peroxide ligand bonded to zirconocene fragment is worth noting as a fine example of oxygen molecule activation with low oxidative state complexes of transition metals.
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