F. Christopher Pigge

Cyclometallated Pt(II) complexes possessing hydrophobic 2-phenylpyridine (ppy) ligands and hydrophilic acetonylacetone (acac) ligands have been investigated for their ability to detect amyloid fibrils via luminescence response. Using hen egg-white lysozyme (HEWL) as a model amyloid protein, Pt(II) complexes featuring benzanilide-substituted ppy ligands and ethylene glycol-functionalized acac ligands demonstrated enhanced luminescence in the presence of HEWL fibrils, whereas Pt(II) complexes lacking complementary hydrophobic/hydrophilic ligand sets displayed little to no emission enhancement. An amphiphilic Pt(II) complex incorporating a bis(ethylene glycol)-derivatized acac ligand was additionally found to trigger restructuring of HEWL fibrils into smaller spherical aggregates. Amphiphilic Pt(II) complexes were generally non-toxic to SH-SY5Y neuroblastoma cells, and several complexes also exhibited enhanced luminescence in the presence of Aβ₄₂ fibrils associated with Alzheimer's disease. This study demonstrates that easily prepared and robust (ppy)Pt^II(acac) complexes show promising reactivity toward amyloid fibrils and represent attractive molecular scaffolds for design of small-molecule probes targeting amyloid assemblies.

4-Picoline derivatives are converted to the corresponding aryl picolyl sulfones upon treatment with aryl sulfonyl chlorides and Et₃N in the presence of catalytic DMAP. The reaction proceeds smoothly for a variety of alkyl and aryl picolines using a range of aryl sulfonyl chlorides. The reaction is believed to involve N-sulfonyl 4-alkylidene dihydropyridine intermediates and results in formal sulfonylation of unactivated picolyl C-H bonds.

²⁰³Pb and ²¹²Pb have emerged as promising theranostic isotopes for image-guided α-particle radionuclide therapy for cancers. Here, we report a cyclen-based Pb specific chelator (PSC) that is conjugated to tyr³-octreotide via a PEG₂ linker (PSC-PEG-T) targeting somatostatin receptor subtype 2 (SSTR2). PSC-PEG-T could be labeled efficiently to purified ²¹²Pb at 25 °C and also to ²¹²Bi at 80 °C. Efficient radiolabeling of mixed ²¹²Pb and ²¹²Bi in PSC-PEG-T was also observed at 80 °C. Post radiolabeling, stable Pb(II) and Bi(III) radiometal complexes in saline were observed after incubating [²⁰³Pb]Pb-PSC-PEG-T for 72 h and [²¹²Bi]Bi-PSC-PEG-T for 5 h. Stable [²¹²Pb]Pb-PSC-PEG-T and progeny [²¹²Bi]Bi-PSC-PEG-T were identified after storage in saline for 24 h. In serum, stable radiometal/radiopeptide were observed after incubating [²⁰³Pb]Pb-PSC-PEG-T for 55 h and [²¹²Pb]Pb-PSC-PEG-T for 24 h. In vivo biodistribution of [²¹²Pb]Pb-PSC-PEG-T in tumor-free CD-1 Elite mice and athymic mice bearing AR42J xenografts revealed rapid tumor accumulation, excellent tumor retention and fast renal clearance of both ²¹²Pb and ²¹²Bi, with no in vivo redistribution of progeny ²¹²Bi. Single-photon emission computed tomography (SPECT) imaging of [²⁰³Pb]Pb-PSC-PEG-T and [²¹²Pb]Pb-PSC-PEG-T in mice also demonstrated comparable accumulation in AR42J xenografts and renal clearance, confirming the theranostic potential of the elementally identical ²⁰³Pb/²¹²Pb radionuclide pair.

The actinyl cation, An(V/VI)O2n+ (n=1,2) is the prevalent species in aqueous systems for uranium and neptunium, yet the full extent in which the oxygen atoms(oxo) within the cation influence chemical speciation and properties is not yet fully understood. When tightly bound to the actinide center, the oxo groups are thought of as terminal and unable to engage with external species. Beyond the inherent properties associated with the metal center, equatorially coordinated ligands can influence the covalently bound oxo groups, in turn impacting the availability of the axially bound oxygens to participate in additional interactions, such as hydrogen bonding and/or coordination to additional actinyl centers (actinyl-actinyl interactions). Interactions with the oxo atoms can result in a deviation from traditional vibrational signals associated with the linear triatomic [O=An=O] moiety as well as influence stability and overall speciation, all of which can directly impact identification of radioactive materials in environmental systems and the radiochemical separations of nuclear waste and related materials. To understand the role and extent to which the oxo atom can be engaged in solution and solid-state materials a step-by-step approach was taken to delineate the specific chemical environments which promote these oxo-interactions and evaluation of the spectral signals of the An(V/VI)O2n+ (n=1,2) when it participates in interactions of varied strength. The objective of my thesis work was to determine how the spectroscopic properties and physical properties of actinyl species change upon varying the coordination through differing degrees of interactions (hydrogen bonds, direct covalent interactions, polymerization) in solution and solid state. Within the scope of actinyl studies, projects were developed looking at three specific actinyl cations: the uranyl (VI) cation [UO2]2+, the neptunyl(V) cation [NpO2]+ and the neptunyl (VI) cation [NpO2]2+. Throughout the studies the fundamental differences of [U(VI)O2]2+, [Np(V)O2]1+ and [Np(VI)O2]2+ to participate with neighboring donor molecules capable of hydrogen bonding or coordinate to alkali cations is explored. The conditions that led to the formation of actinyl-actinyl interactions for [Np(V)O2]+ in solution phase and crystalline materials is also focused on. The changes in vibrational bands of the actinyl cation was found to occur via shifts of the symmetric ν1 or the activation of traditionally Raman inactive bands. Species that display strong bonds to the oxo, particularly interactions to secondary actinyl moieties, show multiple unique Raman vibrational bands separate than that of an uncoordinated O=An=O moiety. This dissertation significantly enhances our understanding of the coordination chemistry and corresponding vibrational features of the actinyl cation in aqueous environments.

4-Alkylpyridines are converted into conjugated 1,1-disubstituted alkenyl pyridines (vinyl pyridines) upon treatment with excess ethyl chloroformate, triethylamine, and Eschenmoser’s salt. The reaction proceeds under mild conditions via alkylidene dihydropyridine intermediates.

Aldehyde-derived imidazolidines participate as hydride donors in intramolecular reductive Heck-type reactions. N,N'-Diphenylimidazolidines prepared from ortho-alkynyl benzaldehydes underwent regio- and stereoselective palladium-catalyzed hydroarylation followed by formal 1,5-hydride transfer and reductive elimination to afford substituted alkenes and imidazolium moieties, the latter conveniently converted in situ to ring-opened benzanilides to simplify product isolation. Internal alkynes were converted to trisubstituted alkenes via a syn hydroarylation process, while a terminal alkyne was converted to a cis alkene via a formal trans hydroarylation reaction. Benzanilide products could be converted to carboxylic acid derivatives under basic conditions, resulting in the net conversion of alkynyl aldehydes to alkenyl carboxylic acids. A styrene derivative with an attached N,N'-dimethylbenzimidazoline hydride donor was also found to undergo an analogous hydroarylation/benzimidazoline oxidation to give a diarylethane product.

Dihydroartemisinin (DHA) is an FDA-approved antimalarial drug that has been repurposed for cancer therapy because of its preferential antiproliferative effects on cancer versus normal cells. Mitochondria represent an attractive target for cancer therapy based on their regulatory role in proliferation and cell death. This study investigates whether DHA conjugated to innately fluorescent N-alkyl triphenylvinylpyridinium (TPVP) perturbs mitochondrial functions resulting in a differential toxicity of cancer versus normal cells. TPVP-DHA treatments resulted in a dose-dependent toxicity of human melanoma and pancreatic cancer cells, whereas normal human fibroblasts were resistant to this treatment. TPVP-DHA treatments accumulated cancer cells in the G1-phase of the cell cycle, which was also associated with a significant inhibition of the mTOR-metabolic and ERK1/2-proliferative signaling pathways. TPVP-DHA treatments perturbed mitochondrial functions, which correlated with increases in mitochondrial fission. In summary, TPVP mediated mitochondrial targeting of DHA enhanced cancer cell toxicity by perturbing mitochondrial functions and morphology.

Multiple myeloma is a bone marrow cancer and is responsible for the death of approximately 12,000 people yearly in the United States. Multiple myeloma is the second most common blood cancer and is characterized by the over-production and secretion of monoclonal antibodies. This can cause patients to have immune dysfunction, bone destruction, and ultimately kidney failure. Currently, multiple myeloma is not considered curable. One ideal treatment for this disease would be to target the Rab proteins, which play a role in trafficking of monoclonal proteins. This might be done by targeting the geranylgeranylation of Rab proteins by diminishing the synthesis of the IBP substrate geranylgeranyl diphosphate (GGPP) via inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS). Our research team has developed one class of GGDPS inhibitors, known as isoprenoid triazole bisphosphonates, and found them to be potent and selective towards GGPDS inhibition in the nM concentration range. A series of modifications at different locations of the bisphosphonates has been achieved, and the new compounds have both higher potency towards GGDPS inhibition. Compounds modified at the ꙍ position lacked biological activity but were able to alter in vivo biodistribution through linkage to a drug delivery agent. A series of modifications at the α position was accomplished, and these compounds were demonstrated to have an impact on GGPDS. These findings encourage future efforts to improve cellular entry of these bisphosphonates and to enhance potency by incorporating these modifications into other isoprenoid triazole bisphosphonate structures.