<p> A new rigid, dianionic ligand, 4,5-bis(2,6-diisopropylanilido)-2,7-di-tert-butyl-9,9-dimethylxanthene {[XA₂]}, has been designed for use in the chemistry of the actinides. Pro-ligand H2[XA₂] (1) was synthesized by the Hartwig-Buchwald coupling of 4,5-dibromo-2,7-di-tert-butyl-9,9-dimethylxanthene with 2,6-diisopropylaniline. </p> <p> Stable alkali metal salts of the [XA₂] ligand, K₂(dme)₂[XA₂] (2) and Na₂[XA₂] (3), were accessible by deprotonation of H₂[XA₂] with KH or NaH in dme or toluene, respectively. The thermally unstable lithium salt of McConville's 2,6-bis(2,6diisopropylanilidomethyl)pyridine {Li₂[BDPP], 4} was isolated by deprotonation of pro-ligand H₂[BDPP] with nBuLi or LiCH₂SiMe₃ in hexanes at low temperature. Reaction of [ThCl₄(dme)₂] with Li₂[BDPP] or M₂(dme)_n[XA₂] (M = K, n = 2; M = Na, n = 0) resulted in the formation of pentagonal bipyramidal [LThCl₂(dme)] complexes {L = [BDPP], 5; [XA₂], 6}. Subsequent reaction of the dichloride complexes with LiCH₂SiMe₃ gave base-and salt-free dialkyl complexes [LTh(CH₂SiMe₃)₂] {L = [BDPP], 9; [XA₂], 10}, which are stable for days in solution at 90 and 70 °C, respectively. Reaction of 5 with LiNEt₂ or 10 with H₂NPh provided [(BDPP)Th(NEt₂)₂] (11) and [(XA₂)Th(NHPh)₂] (28), respectively. </p> <p> An alternative route to [(BDPP)ThCl₂(dme)] (5) and [LTh(CH₂SiMe₃)₂] (9 and 10) involved combination of two or four equivalents of LiCH₂SiMe₃ with [ThCl₄(dme)₂], followed by addition of H₂L. These reactions likely proceed by alkane elimination from dialkyl or tetraalkyl thorium intermediates. The solid-state structure of [(BDPP)Th(CH₂SiMe₃)₂] (9) suggests the presence of α-agostic C-H-Th interactions for both alkyl groups. In solution, 9 and 10 exhibit temperature-dependent ¹J_C-H coupling constants for ThCH₂, consistent with an equilibrium between products participating in aagostic C-H-Th bonding to a greater or lesser extent, with more agostic products favored at lower temperatures. Reaction of Li₂[BDPP] (4) with [(BDPP)ThCl₂(dme)] (5) at 0 °C, or the reaction of [(BDPP)Th(CH₂SiMe₃)₂] (9) with H₂[BDPP] at 100 °C resulted in the formation of extremely sterically encumbered [Th(BDPP)₂] (8), which adopts a highly distorted six-coordinate geometry with the four anilido groups arranged in an approximate tetrahedron around thorium. A his-ligand complex was not accessible with the [XA₂] ancillary ligand, presumably due to increased ligand rigidity. </p> <p> Addition of two equivalents of PhCH₂MgCl to [LThCl₂(dme)] yielded solvent-free [LTh(CH₂Ph)₂] {L = [XA₂] (12) and [BDPP] (13)]. The ¹J_C-H coupling constants in both complexes {120 and 139 Hz for 12; 127 and 138 Hz for 13} are indicative of η¹- and η²- or η³-coordinated benzyl ligands in solution; polyhapto benzyl coordination was also observed in the solid state. </p> <p> Reaction of [LThCl₂(dme)] with two equivalents of nBuLi provided highly soluble [LTh(nBu)₂] {L = [BDPP] (14), [XA₂] (15)]. These β-hydrogen-containing compounds are remarkably thermally stable, showing no sign of decomposition after days at 60 and 80 °C, respectively. Combination of [(BDPP)ThCl₂(dme)] (5) with three equivalents of MeLi yielded the thorium trimethyl 'ate' complex [(BDPP)ThMe₃{Li(dme)}] (16), which underwent thermal decomposition over 3 days at room temperature to produce the metalated complex [(BDPP*)Th(µ-Me)₂Li(dme)] (17) {BDPP* = 2,6-{NC₅H₃(CH₃NAr)(CH₂N {C₆H₃iPr(CMe₂)-2,6})}; Ar = 2,6-diisopropylphenyl; donor atoms in BDPP* are underlined}. Reaction of two equivalents of complex 16 with one equivalent of [(BDPP)ThCl₂(dme)] (5) yielded the dimethyl complex [(BDPP)ThMe₂] (18) which decomposes rapidly at room temperature to form a mixture of unidentified products. Labeling studies using ¹³CD₃ groups revealed that thermal decomposition of 16 and 18 occurs via a straightforward a-bond metathesis pathway. </p> <p> Reaction of [LThCl₂(dme)] with Grignard reagents {MeMgBr, L = [BDPP]; PhCH₂MgCl, L = [XA₂]} resulted, under certain conditions, in halide exhange and adduct formation as evidenced by the solid state structure of [{Th(BDPP)Br(µ-Br)₂Mg(µ-Me)(OEt₂)}₂] (19), or ancillary ligand transfer to magnesium to produce [(XA₂)Mg(dme)] (20). Complex 19 provides insight into the type of intermediates likely involved in undesired halide exchange reactions between d-or f-element halide complexes and Grignard reagents. </p> <p> Reaction of [(XA₂)Th(CH₂Ph)₂] (12) with either one or two equivalents of B(C₆F₅)₃ afforded the first non-carbocyclic actinide alkyl cation, [(XA₂)Th(CH₂Ph)][PhCH₂B(C₆F₅)₃] (21), and a rare example of an actinide dication, [(XA₂)Th][PhCH₂B(C₆F₅)₃]₂ (27). In both 21 and 27 the PhCH₂B(C₆F₅)₃⁻ anion is η⁶-coordinated to thorium. Reaction of neutral dialkyl complex [(XA₂)Th(CH₂SiMe₃)₂] (9) with [Ph₃C][B(C₆F₅)₄] in benzene or toluene at room temperature resulted in the formation of [(XA₂)Th(CH₂SiMe₃)(η⁶-arene)][B(C₆F₅)₄] (arene = C₆H₆, 22; arene = C₇H₈, 23). These complexes were characterized in solution by NMR spectroscopy (21, 22 and 23) and/or in the solid state by X-ray crystallography (22 and 27). In close analogy, [(XA₂)Th(CH₂Ph)₂] (12) reacted with [Ph₃C][B(C₆F₅)₄] in toluene at room temperature to form [(XA₂)Th(η²-CH₂Ph)(η⁶-C₇H₈)][B(C₆F₅)₄] (24). In contrast, related [(BDPP)Th(CH₂Ph)₂] (13) reacted with [Ph₃C][B(C₆F₅)₄] to precipitate a mixture of mononuclear and a dinuclear cations; the dinuclear cation was identified as [(BDPP)Th(η²-CH₂Ph)(µ-η¹:η⁶-CH₂Ph)Th(η¹-CH₂Ph)(BDPP)][B(C₆F₅)₄] (25) by X-ray crystallography. Complexes 22, 23, and 24 are rare examples of arene solvent-separated ion pairs, while complex 21 exists as a tight contact ion pair, and dinuclear 25 exhibits a unique benzyl ligand bridging mode. Cations 21-25 and 27 highlight a pronounced tendency for these systems to engage in arene π-coordination. </p> <p> Preliminary reaction studies with both neutral and cationic thorium complexes supported by the [BDPP] and [XA₂] ancillary ligands demonstrated significant activity for olefin polymerization and hydroamination catalysis. Reactions of 9 and 10 with 4 atm. of hydrogen also suggest that the [BDPP] and [XA₂] ligand frameworks may be suitable for the stabilization of thorium hydride complexes. </p> / Thesis / Doctor of Philosophy (PhD)

No description available.

Nuclear receptors are ligand activated transcription factors, where upon binding with small molecule ligands, these proteins are involved in the regulation of gene expression. To date there are approximately 48 human nuclear receptors known, involved in multiple biological and cellular processes, ranging from differentiation to maintenance of homeostasis. Due to their critical role in transcriptional regulation, these receptors are implicated in several diseases. Currently, 13% of prescribed drugs in the market are NR ligands for diseases such as cancer, diabetes and osteoporosis. In addition to drug discovery, the mechanism of function, mobility and trafficking of these receptors is poorly understood. Gaining insight into the relationship between the function and /or dysfunction of these receptors and their mobility will aid in a better understanding of the role of these receptors. The green fluorescent protein (GFP) has revolutionized molecular biology by providing the ability to monitor protein function and structure via fluorescence. The fluorescence contribution from this biological marker is the chromophore, formed from the polypeptide backbone of three amino acid residues, buried inside 11-stranded â-barrel protein. Synthesis of GFP derivatives of is based on the structure of the arylmethyleneimidazolidinone (AMI), creating a molecule that is only weakly fluorescent. Characterizing these AMI derivatives for other proteins can provide a powerful visualization tool for analysis of protein function and structure. This development could provide a very powerful method for protein analysis in vitro and in vivo. Development of such fluorescent ligands will prove beneficial for the nuclear receptors. In this work, libraries of AMIs derviatives were synthesized by manipulating various R groups around the core structure, and tested for their ability to serve as nuclear receptor ligands with the ability to fluoresce upon binding. The fluorogens are developed for steroidal and non-steroidal receptors, two general classes of nuclear receptors. Specific AMIs were designed and developed for steroid receptor estrogen receptor á (ERá). These ligands are showed to activate the receptor with an EC50 of value 3 ìM and the 10-fold activation with AMI 1 and AMI 2 in comparison to the 21-fold activation observed with natural ERá ligand, 17â-estradiol. These novel ligands were not able to display the fluorescence upon binding the receptor. However, fluorescence localized in nucleus was observed in case of another AMI derivative, AMI 10, which does not activate the receptor. Such ligands open new avenues for developing fluorescent probes for ERá that do not involve fluorescent conjugates attached to a known ERá ligand core. AMIs were also characterized for non-steroidal receptors,specifically the pregnane x receptor (PXR) and retinoic acid receptor á (RARá). To date, fluorogens which turn fluorescence upon binding and activate the receptor have not been developed for these receptors. With respect to PXR, several AMI derivatives were discovered to bind and activate this receptor with a fold-activation better than the known agonist, rifampicin. The best characterized AMI derivative, AMI 4, activates the receptor with an EC50 of value 6.3 ìM and the 154-fold activation in comparison to the 90-fold activation and an EC50 value of 1.3 ìM seen with rifamipicin. This ligand is not only able to activate PXR but also displays fluorescence upon binding to the receptor. The fluroscence pattern was observed around the nucleus. Besides AMI 4, 16 other AMI derivatives are identified that activate PXR with different activation profiles. Thus, a novel class of PXR ligands with fluorescence ability has been developed. The AMI derivatives able to bind and activate RAR, also displayed activation profiles that were comparable to the wild-type ligand, all trans retinoic acid. These ligands activated the receptor with an EC50 value of 220 nM with AMI 109 in comparison to an EC50 value of 0.8 nM with the natural ligand for RARá. When these ligands were tested for fluorescence in yeast, the yeast were able to fluoresce only in the presence of the receptor and the AMI derivative, indicating that these agonists also have the ability to fluoresce.

No description available.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

No description available.

No description available.

No description available.

Multimeric ligands have the potential to be developed as targeted imaging agents and therapeutics for the diagnosis and treatment of cancer. Multimeric ligands consist of multiple binding residues tethered together by a linker and are capable of simultaneous binding to multiple receptors. This dissertation details the proof-of-principle experiments that establish that multimeric ligands bind with an increased affinity and cooperativity compared to their monomeric counterparts. We have chosen to evaluate combinations of ligands for the human melanocortin 4 receptor (hMC4R), human delta-opioid receptor (hdOR), cholecystokinin-B receptor (CCK-BR), and oxytocin receptor (OTR).Multivalent ligands can be homomeric, meaning that all ligands bind to the same receptor type, or they may be heteromeric, meaning that they bind to different types of receptors. We have evaluated homodimer and homotrimer binding to hMC4Rs, and heterodimer binding to hMC4Rs and hdORs. Ligands for the receptors were tethered together using backbones constructed of polyethylene glycol (PEG) units or different combinations of amino acid repeats. The effects of linker length and rigidity on the binding of multivalent ligands have been evaluated. Additionally, this dissertation details the development of a new lanthanide based binding method used to monitor receptor-ligand interactions. This assay makes use of lanthanide labels attached to a peptide that binds specifically to the receptor of interest. The amount of bound ligand is detected using time-resolved fluorescence (TRF). This assay produces results which are highly reproducible, require less setup time and reagents and do not require special waste disposal, all advantages over the traditional radioligand binding assays. This lanthanide based binding assay has been adapted to evaluate ligand binding to the hMC4R and hdOR.

No description available.