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  1. Decavanadate (V 10 O 28 6− or V10) is a paradigmatic member of the polyoxidometalate (POM) family, which has been attracting much attention within both materials/inorganic and biomedical communities due to its unique structural and electrochemical properties. In this work we explored the utility of high-resolution electrospray ionization (ESI) mass spectrometry (MS) and ion exclusion chromatography LC/MS for structural analysis of V10 species in aqueous solutions. While ESI generates abundant molecular ions representing the intact V10 species, their isotopic distributions show significant deviations from the theoretical ones. A combination of high-resolution MS measurements and hydrogen/deuterium exchange allows these deviations to be investigated and interpreted as a result of partial reduction of V10. While the redox processes are known to occur in the ESI interface and influence the oxidation state of redox-active analytes, the LC/MS measurements using ion exclusion chromatography provide unequivocal evidence that the mixed-valence V10 species exist in solution, as extracted ion chromatograms representing V10 molecular ions at different oxidation states exhibit distinct elution profiles. The spontaneous reduction of V10 in solution is seen even in the presence of hydrogen peroxide and has not been previously observed. The susceptibility to reduction of V10 is likely to be shared bymore »other redox active POMs. In addition to the molecular V10 ions, a high-abundance ionic signal for a V 10 O 26 2− anion was displayed in the negative-ion ESI mass spectra. None of the V 10 O 26 cations were detected in ESI MS, and only a low-abundance signal was observed for V 10 O 26 anions with a single negative charge, indicating that the presence of abundant V 10 O 26 2− anions in ESI MS reflects gas-phase instability of V 10 O 28 anions carrying two charges. The gas-phase origin of the V 10 O 26 2− anion was confirmed in tandem MS measurements, where mild collisional activation was applied to V10 molecular ions with an even number of hydrogen atoms (H 4 V 10 O 28 2− ), resulting in a facile loss of H 2 O molecules and giving rise to V 10 O 26 2− as the lowest-mass fragment ion. Water loss was also observed for V 10 O 28 anions carrying an odd number of hydrogen atoms ( e.g. , H 5 V 10 O 28 − ), followed by a less efficient and incomplete removal of an OH˙ radical, giving rise to both HV 10 O 26 − and V 10 O 25 − fragment ions. Importantly, at least one hydrogen atom was required for ion fragmentation in the gas phase, as no further dissociation was observed for any hydrogen-free V10 ionic species. The presented workflow allows a distinction to be readily made between the spectral features revealing the presence of non-canonical POM species in the bulk solution from those that arise due to physical and chemical processes occurring in the ESI interface and/or the gas phase.« less
    Free, publicly-accessible full text available March 29, 2023
  2. Menaquinones are a class of isoprenoid molecules that have important roles in human biology and bacterial electron transport, and multiple methods have been developed for their synthesis. These compounds consist of a methylnaphthoquinone (MK) unit and an isoprene side chain, such as found in vitamin K1 (phylloquinone), K2, and other lipoquinones. The most common naturally occurring menaquinones contain multiple isoprene units and are very hydrophobic, rendering it difficult to evaluate the biological activity of these compounds in aqueous assays. One way to overcome this challenge has been the application of truncated MK-derivatives for their moderate solubility in water. The synthesis of such derivatives has been dominated by Friedel-Crafts alkylation with BF3∙OEt2. This attractive method occurs over two steps from commercially available starting materials, but it generally produces low yields and a mixture of isomers. In this review, we summarize reported syntheses of both truncated and naturally occurring MK-derivatives that encompass five different synthetic strategies: Nucleophilic ring methods, metal-mediated reactions, electrophilic ring methods, pericyclic reactions, and homologation and side chain extensions. The advantages and disadvantages of each method are discussed, identifying methods with a focus on high yields, regioselectivity, and stereochemistry leading to a detailed overview of the reported chemistry availablemore »for preparation of these compounds.« less
  3. SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, making it a promising target for small molecule inhibition. In this study, we sought to establish a proof of concept for our in silico/in vitro hit-to-lead enzyme inhibitor development platform and to identify a lead small molecule candidate for SMYD3 inhibition. We used Schrodinger® software to screen libraries of small molecules in silico and the five compounds with the greatest predicted binding affinity within the SMYD3 binding pocket were purchased and assessed in vitro in direct binding assays and in breast cancer cell lines. We have confirmed the ability of one of these inhibitors, Inhibitor-4, to restore normal rates of cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting wildtype cell behavior. Our results provide a proof of concept for this fast and affordable small molecule hit-to-lead methodology as well as a promising candidate small molecule SMYD3 inhibitor for the treatment of human cancer.
  4. The SET and MYND domain-containing (SMYD) family of lysine methyltransferases are essential in several mammalian developmental pathways. Although predominantly expressed in the heart, the role of SMYD2 in heart development has yet to be fully elucidated and has even been shown to be dispensable in a murine Nkx2-5-associated conditional knockout. Additionally, SMYD2 was recently shown to be necessary not only for lymphocyte development but also for the viability of hematopoietic leukemias. Based on the broad expression pattern of SMYD2 in mammalian tissues, it is likely that it plays pivotal roles in a host of additional normal and pathological processes. In this brief review, we consider what is currently known about the normal and pathogenic functions of SMYD2 and propose specific future directions for characterizing its role in embryogenesis.
  5. In this manuscript, we describe medical applications of each first-row transition metal including nutritional, pharmaceutical, and diagnostic applications. The 10 first-row transition metals in particular are found to have many applications since there five essential elements among them. We summarize the aqueous chemistry of each element to illustrate that these fundamental properties are linked to medical applications and will dictate some of nature’s solutions to the needs of cells. The five essential trace elements—iron, copper, zinc, manganese, and cobalt—represent four redox active elements and one redox inactive element. Since electron transfer is a critical process that must happen for life, it is therefore not surprising that four of the essential trace elements are involved in such processes, whereas the one non-redox active element is found to have important roles as a secondary messenger.. Perhaps surprising is the fact that scandium, titanium, vanadium, chromium, and nickel have many applications, covering the entire range of benefits including controlling pathogen growth, pharmaceutical and diagnostic applications, including benefits such as nutritional additives and hardware production of key medical devices. Some patterns emerge in the summary of biological function and medical roles that can be attributed to small differences in the first-row transition metals.
  6. Menaquinones are lipoquinones that consist of a headgroup (naphthoquinone, menadione) and an isoprenyl sidechain. They function as electron transporters in prokaryotes such as Mycobacterium tuberculosis. For these studies, we used Langmuir monolayers and microemulsions to investigate how the menaquinone headgroup (menadione) and the menahydroquinone headgroup (menadiol) interact with model membrane interfaces to determine if differences are observed in the location of these headgroups in a membrane. It has been suggested that the differences in the locations are mainly caused by the isoprenyl sidechain rather than the headgroup quinone-to-quinol reduction during electron transport. This study presents evidence that suggests the influence of the headgroup drives the movement of the oxidized quinone and the reduced hydroquinone to different locations within the interface. Utilizing the model membranes of microemulsions and Langmuir monolayers, it is determined whether or not there is a difference in the location of menadione and menadiol within the interface. Based on our findings, we conclude that the menadione and menadiol may reside in different locations within model membranes. It follows that if menaquinone moves within the cell membrane upon menaquinol formation, it is due at least in part, to the differences in the properties of headgroup interactions with the membranemore »in addition to the isoprenyl sidechain.« less