Transition metal complexes of expanded porphyrins

textOver the last three decades, the rapid development of efficient synthetic routes for the preparation of expanded porphyrin macrocycles has allowed the exploration of a new frontier involving “porphyrin-like” coordination chemistry. This doctoral dissertation describes the author’s exploratory journey into the area of transition metal cation complexation using oligopyrrolic macrocycles. The reported synthetic findings were used to gain new insights into the factors affecting the observed coordination modes and to probe the emerging roles of counter-anion effects, tautomeric equilibria and hydrogenbonding interactions in regulating the metalation chemistry of expanded porphyrins. The first chapter provides an updated overview of this relatively young coordination chemistry subfield and introduces the idea of expanded porphyrins as a diverse family of ligands for metalation studies. Chapter 2 details the synthesis of a series of binuclear complexes and illustrates the importance of metal oxidation state, macrocycle protonation and counter-anion effects in terms of defining the final structure of the observed metal complexes. The binding study reported in Chapter 3 demonstrates a strong positive allosteric effect for the coordination of silver(I) cations in a Schiff base expanded porphyrin. Chapter 4 introduces the use of oligopyrrolic macrocycles for the stabilization of early transition metal cations. Specifically, the preparation of a series of vanadium complexes illustrates the bimodal (i.e., covalent and noncovalent) recognition of the non-spherical dioxovanadium(V) species within the macrocyclic cavities. Experimental procedures and characterization data are reported in Chapter 5.Chemistr

Imaging mobile zinc in biology

Trafficking and regulation of mobile zinc pools influence cellular functions and pathological conditions in multiple organs, including brain, pancreas, and prostate. The quest for a dynamic description of zinc distribution and mobilization in live cells fuels the development of increasingly sophisticated probes. Detection systems that respond to zinc binding with changes of their fluorescence emission properties have provided sensitive tools for mobile zinc imaging, and fluorescence microscopy experiments have afforded depictions of zinc distribution within live cells and tissues. Both small-molecule and protein-based fluorescent probes can address complex imaging challenges, such as analyte quantification, site-specific sensor localization, and real-time detection.National Institute of General Medical Sciences (U.S.) (grant GM065519

Zinc released from olfactory bulb glomeruli by patterned electrical stimulation of the olfactory nerve

Zinc is a trace element with a multitude of roles in biological systems including structural and cofactor functions for proteins. Although most zinc in the central nervous system (CNS) is protein bound, the CNS contains a pool of mobile zinc housed in synaptic vesicles within a subset of neurons. Such mobile zinc occurs in many brain regions, such as the hippocampus, hypothalamus, and cortex, but the olfactory bulb (OB) contains one of the highest such concentrations in the CNS. Zinc is distributed throughout the OB, with the glomerular and granule cell layers containing the highest levels. Here, we visualize vesicular zinc in the OB using zinc-responsive fluorescent probes developed by one of us. Moreover, we provide the first demonstration that vesicular pools of zinc can be released from olfactory nerve terminals within individual glomeruli by patterned electrical stimulation of the olfactory nerve designed to mimic the breathing cycle in rats. We also provide electrophysiological evidence that elevated extracellular zinc potentiates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic events. AMPA receptors are required for the synchronous activation of neurons within individual OB glomeruli, and zinc-mediated potentiation leads to enhanced synaptic summation.National Institute of General Medical Sciences (U.S.) (Grant GM065519)Florida State University. Program in Neuroscience (Council on Research and Creativity

Manganese displacement from Zinpyr-1 allows zinc detection by fluorescence microscopy and magnetic resonance imaging

A paramagnetic manganese complex of a fluorescein-based probe affords a dual-modality zinc sensor featuring an improved fluorescence dynamic range and an MRI readout.National Institute of General Medical Sciences (U.S.) ((Grant GM065519)SBS FoundationNational Institutes of Health (U.S.) (NIH Grant DP2-OD2441)Raymond and Beverley Sackler Foundatio

Biochemistry of mobile zinc and nitric oxide revealed by fluorescent sensors

Biological mobile zinc and nitric oxide (NO) are two prominent examples of inorganic compounds involved in numerous signaling pathways in living systems. In the past decade, a synergy of regulation, signaling, and translocation of these two species has emerged in several areas of human physiology, providing additional incentive for developing adequate detection systems for Zn(II) ions and NO in biological specimens. Fluorescent probes for both of these bioinorganic analytes provide excellent tools for their detection, with high spatial and temporal resolution. We review the most widely used fluorescent sensors for biological zinc and nitric oxide, together with promising new developments and unmet needs of contemporary Zn(II) and NO biological imaging. The interplay between zinc and nitric oxide in the nervous, cardiovascular, and immune systems is highlighted to illustrate the contributions of selective fluorescent probes to the study of these two important bioinorganic analytes.National Science Foundation (Grant Number CHE-0907905)National Institutes of Health (U.S.) (Grant Number GM065519)National Institutes of Health (U.S.) (Grant Number K99GM092970

Analysis of the decision process and identification of the main motivations of the "pop-culture" tourist

Por turismo "pop-culture" se considera como los viajes realizados a lugares que tienen algún tipo de vínculo con películas, libros, música, cómics, etc. Este turismo emergente es especialmente importante cuando las instituciones deben identificar sus estrategias de futuro. El Señor de los anillos revolucionó Turismo en Nueva Zelanda como Drácula en Rumanía. En China puede verse un Optimus Prime gigante. En Liverpool se visitan numerosos lugares relacionados con los Beatles, como la famosa Cavern, los fans de Elvis visitan Graceland, los entusiastas de Harry Potter pueden ir al Alnwick Castle y si buscamos el poblado Mos Espa; de la Guerra de las Galaxias lo podremos encontrar en el desierto de Túnez. En Tarragona es muy visitada la gigantesca estatua de un Mazinger Z. La cultura popular tiene un impacto complejo en la formación de una imagen de destino. La coexistencia de fenómenos de culturas popular globales y las economías regionales ayudan a aumentar la imagen de los destinos y su competitividad.Facultad de Ciencias de la EmpresaUniversidad Politécnica de Cartagen

Ratiometric and intensity-based zinc sensors built on rhodol and rhodamine platforms

Synthetic procedures and product characterization data, zinc binding analysis methods, selectivity and pH dependence charts. This material is available free of charge via the Internet at http://pubs.acs.edu.A xanthene-forming condensation reaction yields rhodol and rhodamine dyes carrying a zinc-binding ligand that includes the aniline-type nitrogen donor of the fluorophores. Upon zinc coordination in neutral aqueous solution, rhodol RF3 behaves as a ratiometric sensor, and rhodamine RA1 acts as a turn-off intensity-based indicator. Both fluorescent compounds bind the divalent zinc cation with micromolar affinity.National Institute of General Medical Sciences (U.S.) (grant GM065519

Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators

The implication of iron in the pathophysiology of colorectal cancer is documented at both the biochemical and epidemiological levels. Iron chelators are therefore useful molecular tools for the study and potential treatment of this type of cancer characterized by high incidence and mortality rates. We report a novel prochelation strategy that utilizes a disulfide redox switch to connect a thiosemicarbazone iron-binding unit with carbohydrate moieties targeting the increased expression of glucose transporters in colorectal cancer cells. We synthesized three glycoconjugates (GA2TC4, G6TC4, and M6TC4) with different connectivity and/or carbohydrate moieties, as well as an aglycone analog (ATC4). The sugar conjugates present increased solubility in neutral aqueous solutions, and the ester-linked conjugates M6TC4 and G6TC4 compete as effectively as d-glucose for transporter-mediated cellular uptake. The glycoconjugates show improved selectivity compared to the aglycone analog and are 6–11 times more toxic in Caco-2 colorectal adenocarcinoma cells than in normal CCD18-co colon fibroblasts

Iron as a Central Player and Promising Target in Cancer Progression

Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer

Iron as a Central Player and Promising Target in Cancer Progression

Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer