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We report the first diselenide-based probe for the selective detection of thioredoxin reductase (TrxR), an enzyme commonly overexpressed in melanomas. The probe design involves conjugation of a seminaphthorhodafluor dye with a diselenide moiety. TrxR reduces the diselenide bond, triggering a fluorescence turn-on response of the probe. Kinetic studies reveal favorable binding of the probe with TrxR with a Michaelis-Menten constant (Km ) of 15.89 μm. Computational docking simulations predict a greater binding affinity to the TrxR active site in comparison to its disulfide analogue. In vitro imaging studies further confirmed the diselenide probe exhibited improved signaling of TrxR activity compared to the disulfide analogue.

The current five-year survival rate of less than 5% for pancreatic ductal adenocarcinoma (PDAC) is compounded by late diagnosis, a lack of PDAC-specific intraoperative guidance to ensure complete resection, and the ineffectiveness of current therapies. Previously, utilizing compound 1, a fluorophore with inherent PDAC selectivity, PDAC was visualized both in vivo and ex vivo in a murine model. In the current study, human PDAC tissue is targeted. Compound 1 selectively stains ducts of the adenocarcinoma versus the surrounding stroma, enabling the imaging of PDAC in frozen tissue sections with high contrast. To enhance the potential of 1 for intraoperative applications, the ex vivo staining protocol was optimized for rapid margin assessment, with a final staining time of ~15 min. To measure diagnostic performance, the area under a receiver operating characteristic (ROC) curve was measured for the identification of ductal adenocarcinoma vs. stroma. The bright fluorescence contrast enabled quantitative determination of PDAC (or precancerous PanIN lesions) versus healthy pancreas tissue in human tissue array samples.

Fluorescent small molecules enable researchers and clinicians to visualize biological events in living cells, tissues, and organs in real time. Herein, the focus is on the structure and properties of the relatively rare benzo[ a]xanthenes that exhibit enhanced steric and electronic interactions due to their annulated structures. Three types of fluorophores were synthesized: (i) pH- and solvent-dependent seminaphthorhodafluors, (ii) pH- and solvent-independent seminaphthorhodafluors, and (iii) pH-independent but solvent-sensitive seminaphthorhodamines. The probes exhibited promising far-red to near-infrared (NIR) emission, large Stoke shifts, broad full width at half-maximum (fwhm), relatively high quantum yields, and utility in immunofluorescence staining. Deviation of the π-system from planarity due to changes in the fluorophore ionization state resulted in fluorescence properties that are atypical of common xanthene dyes.

Apart from nicotine, the identity and levels of the ingredients of electronic cigarette liquids are typically not available to consumers. Herein we have identified and quantified synthetic dye additives used in e-liquids. Tartrazine, Brilliant Blue FCF and Allura Red AC were found in six randomly-chosen commercial e-liquids. They were present in amounts comparable to those of dye concentrations in colored foodstuffs. The synthetic dyes found in the e-liquids are generally recognized as safe for ingestion; however, their inhalation toxicity is unknown. The ongoing treatment of e-liquids as foodstuff, for example via the use of ingredients such as sweeteners, synthetic dyes and related non-volatile additives, may increase appeal as well as potential harm without directly enhancing intended medicinal benefits.

Electronic cigarettes enabling enhanced airflow have grown in popularity in recent years. The objective of this study is to show that flow rates modulate the levels of specific aerosol toxicants produced in electronic cigarettes. Flow rates used in various laboratory investigations involving e-cigarettes have varied widely to date, and can thus promote interlaboratory variability in aerosol product profiles. The thermal decomposition of hydroxyacetone and glycolaldehyde is less favorable at lower temperatures, supporting the observations of these products at higher flow rates/lower heating coil temperatures. Higher temperatures promote the formation of acetaldehyde from hydroxyacetone and formaldehyde from both hydroxyacetone and glycolaldehyde. A separate finding is that greater airflow can also expose users to concerning levels of e-liquid solvents. Under the modest conditions studied, propylene glycol aerosol levels are found at above the acceptable inhalation levels defined by NASA, and in range of the generally recognized as safe levels for daily ingestion.

Molecular probes that selectively highlight pancreatic cancer (PC) tissue have the potential to improve pancreatic ductal adenocarcinoma (PDAC) margin assessment through the selective highlighting of individual PC cells. Herein, we report a simple and unique family of systematically modified red and near-infrared fluorescent probes that exhibit a field-effect-derived redshift. Two of thirteen probes distributed to the normal mouse pancreas following systemic administration. One selectively accumulated in genetically modified mouse models of PDAC. The probe exhibited intracellular accumulation and enabled visualization of four levels of the structure, including the whole organ, resected tissue, individual cells, and subcellular organelles. In contrast to the small-molecule probes reported previously, it possesses an inherent affinity toward PDAC cells and thus does not require conjugation to any targeting agent. The fluorescent probe can thus promote new strategies not only for precision image-guided surgery, but also for PC detection, monitoring of therapeutic outcomes, and basic research.

The very close structural similarities between cysteine and homocysteine present a great challenge to achieve their selective detection using regular fluorescent probes, limiting the biological and pathological studies of these two amino thiols. A coumarin-based fluorescent probe was designed featuring pH-promoted distinct turn-on followed by ratiometric fluorescence responses for Cys and turn-on fluorescence response for Hcy through two different reaction paths. These specific responses demonstrate the activity differences between Cys and Hcy qualitatively for the first time. The probe could also be used for Cys and Hcy imaging in living cells.

Cisplatin is widely used to treat a variety of cancers. However, ototoxicity and nephrotoxicity remain serious side effects of cisplatin-based chemotherapy. In order to inform the study of cisplatin’s off-target effects, a new drug-fluorophore conjugate was synthesized that exhibited utility as a tracer to determine the cellular uptake and in vivo distribution of cisplatin. This probe will serve as a useful tool to facilitate investigations into the kinetics and biodistribution of cisplatin and its associated side effects in preclinical models after systemic administration.

A series of geometrically well-defined cationic fluorophores were designed based on molecular mechanics. They contain biaryl linkers to impart rigidity preventing intramolecular folding between a conjugated biomolecule and fluorophore. All probes have absorption and emission maxima within 20 nm from Texas Red, as predicted by TDDFT calculations and validated experimentally.

Herein we utilize the similar though divergent nucleophilic properties of cysteine, homocysteine, and glutathione to achieve the selective detection of cysteine under mildly acidic conditions. This enables the specific in situ detection of lysosomal cysteine. Employing time-dependent fluorescent imaging of probe-labeled A549 cells, we demonstrate that dexamethasone-induced apoptosis is not dependent on lysosomal cysteine. This methodology can thus produce useful information about pathogenesis associated with cysteine and lysosomes.

E-cigarette aerosol emission studies typically focus on benchmarking toxicant levels versus those of cigarettes. However, such studies do not fully account for the distinct chemical makeup of e-liquids and their unique properties. These approaches often conclude that there are fewer and lower levels of toxins produced by e-cigarettes than by cigarettes. In 2015, we reported the discovery of new hemiacetals derived from the reaction of formaldehyde and the e-liquid solvents. The main finding was that they constituted a significant proportion of potentially undetected formaldehyde. Moreover, unlike gaseous formaldehyde, the hemiacetals reside in the aerosol particulate phase, and thus are capable of delivering formaldehyde more deeply into the lungs. However, the findings were criticized by those claiming that some of the results were obtained under conditions that are averse to vapers. A “reinvestigation” of our study was recently published addressing this latter issue. However, this reinvestigation ignored major details, including no mention of the formaldehyde hemiacetals. Herein, we isolated both gaseous formaldehyde and formaldehyde hemiacetals at an intermediate power level claimed, in the “reinvestigation”, to be relevant to “non-averse,” “normal” usage. The results were that both gaseous formaldehyde and formaldehyde from hemiacetals were produced at levels above OSHA workplace limits.

Multicolor microscopy tools necessary to localize and visualize the complexity of subcellular systems are limited by current fluorophore technology. While commercial fluorophores cover spectral space from the ultraviolet to the near infrared region and are optimized for conventional bandpass based fluorescence microscopy, they are not ideal for highly multiplexed fluorescence microscopy as they tend to have short Stokes shifts, restricting the number of fluorophores that can be detected in a single sample to four to five. Herein, we synthesized a library of 95 novel boron-dipyrromethene (BODIPY)-based fluorophores and screened their photophysical, optical and spectral properties for their utility in multicolor microscopy. A subset of our BODIPY-based fluorophores yielded varied length Stokes shifts probes, which were used to create a five-color image using a single excitation with confocal laser scanning microscopy for the first time. Combining these novel fluorophores with conventional fluorophores could facilitate imaging in up to nine to ten colors using linear unmixing based microscopy approaches.

A method for detecting glutathione selectively in whole blood deposited on filter paper is described. GSH is fractionated from proteins, hemoglobin and other potentially interfering components and determined using a resorufin-acrylate fluorescent probe. The relative standard deviation is lower than 5% (n = 5). Recoveries of GSH from whole blood are between 94% and 108.6%.

Direct determination of total lysophosphatidic acid (LPA) was accomplished using newly developed spiroguanidines derived from rhodamine B as universal fluorogenic probes. Optimum conditions for the quantitative analysis of total LPA were investigated. The linear range for the determination of total LPA is up to 5 μM with a limit of detection of 0.512 μM.

The electronic cigarette solvents propylene glycol and glycerol are known to produce toxic byproducts such as formaldehyde, acetaldehyde and acrolein. However, the aerosol toxin yield depends upon a variety of chemical and physical variables. The formaldehyde hemiacetals derived from these solvents were reported as major electronic cigarette aerosol components by us in 2015. In the study described herein, the formaldehyde hemiacetals were found at higher levels than those of free formaldehyde via an orthogonal sample collection protocol. In addition, the common aldehyde collection methods for electronic cigarettes, such as impingers and sorbent tubes containing DNPH, significantly underestimate the levels of formaldehyde. The reason for this is that formaldehyde hemiacetals follow other reaction pathways, such as the formation of a less reactive full cyclic acetal catalyzed by the acidity of the DNPH solution and the silica. We found that formaldehyde hemiacetals are a considerable fraction of the total formaldehyde produced in electronic cigarette that cannot be determined accurately by DNPH derivatization methods. Although the health effects of the hemiacetals are not yet known, they warrant further investigation.

The most common low molecular weight aminothiols are glutathione (GSH), cysteine (Cys), and homocysteine (Hcy). They each play major roles in biology and biomedicine in both enzymatic and nonenzymatic processes. In the latter regard, the distinctive redox and nucleophilic properties imparted by their sulfhydryl groups enable them to modulate a variety of physiological states. The traditional probes and abiotic sensors for the biothiols are mainly dye molecules functionalized with universal electrophile moieties to enable conjugation to all thiol-containing compounds. More recently, the field has focused on optical reagents that can selectivity differentiate GSH, Cys, and Hcy from each other, in addition to many other components in natural media, since each of the biothiol analytes is involved in distinct biological processes. Herein, examples are presented of how the covalent reactivity of electrophilic dyes toward biothiols can be modulated via supramolecular chemistry to attain highly selective probes and sensors for each of the biothiols. In addition, significant opportunities and needs in the field of biothiol sensing are presented, highlighting relatively under-investigated biomedical issues.

Due to the biological and industrial importance of hypochlorous acid, the development of optical probes for HOCl has been an active research area. Hypochlorous acid and hypochlorite can oxidize electron-rich analytes with accompanying changes in molecular sensor spectroscopic profiles. Probes for such processes may monitor HOCl levels in the environment or in an organism and via bio-labeling or bioimaging techniques. This review summarizes recent developments in the area of chromogenic and fluorogenic chemosensors for HOCl.

There is ongoing interest in near infrared (NIR) absorbing and emitting dyes for a variety of biomedical and materials applications. Simple and efficient synthetic procedures enable the judicious tuning of through-space polar (field) effects as well as low barrier hydrogen bonding to modulate the HOMO-LUMO gap in xanthene dyes. This affords unique NIR-absorbing xanthene chromophores.

Red-shifted and near-infrared (NIR)-active rhodamine analogs and their boronic acid derivatives were synthesized and studied. These latter compounds function as fluorogenic NIR active substrates for sugar sensing. The effects of benzannulation and boronic acid functionalization on fluorophore optical and sensing properties are described.

Elevated homocysteine levels are a well-known independent risk factor for cardiovascular disease. To date, relatively few selective fluorescent probes for homocysteine detection have been reported. The lack of sensing reagents and remaining challenges largely derive from issues of sensitivity and/or selectivity. For example, homocysteine is a structural homologue of the more abundant (ca, 20-25 fold) aminothiol cysteine, differing only by an additional methylene group side chain. Fluorescein tri-aldehyde, described herein, has been designed and synthesized as a sensitive and selective fluorophore for the detection of homocysteine in human plasma samples. It responds to analytes selectively via a photoinduced electron transfer (PET) inhibition process that is modulated by predictable analyte-dye product hybridization and ionization states. Mulliken population analysis of fluorescein tri-aldehyde and its reaction products reveals that the characteristic formation of multiple cationic of homocysteine-derived heterocycles leads to enhanced relative negative charge build up on the proximal phenolate oxygen of the fluorophore as a contributing factor to selective emission enhancement.

The first solid phase extraction materials for selective lysophosphatidic acid (LPA) enrichment from human plasma are described. Molecularly imprinted polymers were designed, synthesized and evaluated as cartridge fillings. They enabled a relatively rapid and simple extraction protocol for LPA without any need for multiple liquid–liquid extraction steps. The five major subspecies of lysophosphatidic acid are readily separated from all other native plasma phospholipids, including those well-known to interfere with LPA quantitation, such as phosphatidylcholine and lysophosphatidylcholine. Outstanding LPA purity is obtained via these solid phase materials in a tandem extraction setup.

New drugs with enhanced electron donor properties that target the ryanodine receptor from skeletal muscle sarcoplasmic reticulum (RyR1) are shown to be potent inhibitors of single-channel activity. In this article, we synthesize derivatives of the channel activator 4-chloro-3-methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor 4-[-3{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (K201, JTV519) with enhanced electron donor properties. Instead of activating channel activity (~100 μM), the 4-methoxy analog of 4-CmC [4-methoxy-3-methyl phenol (4-MmC)] inhibits channel activity at submicromolar concentrations (IC(50) = 0.34 ± 0.08 μM). Increasing the electron donor characteristics of K201 by synthesizing its dioxole congener results in an approximately 16 times more potent RyR1 inhibitor (IC(50) = 0.24 ± 0.05 μM) compared with K201 (IC(50) = 3.98 ± 0.79 μM). Inhibition is not caused by an increased closed time of the channel but seems to be caused by an open state block of RyR1. These alterations to chemical structure do not influence the ability of these drugs to affect Ca(2+)-dependent ATPase activity of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase type 1. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It seems as if FKBP12, K201, its dioxole derivative, and 4-MmC inhibit RyR1 channel activity by virtue of their electron donor characteristics. These results embody strong evidence that designing new drugs to target RyR1 with enhanced electron donor characteristics results in more potent channel inhibitors. This is a novel approach to the design of new, more potent drugs with the aim of functionally modifying RyR1 single-channel activity.

The photolytic formation of thiyl radicals allows for the selective detection of total homocysteine (tHcy) in plasma after reduction and filtering. The mechanism is based on the reduction of viologens by the α-amino carbon centred radical of Hcy generated by intramolecular hydrogen atom transfer (HAT) of its thiyl radical.

Fluorescent dyes based on small organic molecules that function in the near infra red (NIR) region are of great current interest in chemical biology. They allow for imaging with minimal autofluorescence from biological samples, reduced light scattering and high tissue penetration. Herein, examples of ongoing NIR fluorophore design strategies as well as their properties and anticipated applications relevant to the bioimaging are presented.

A readily accessible new class of near infrared (NIR) molecular probes has been synthesized and evaluated. Specific fluorophores in this unique xanthene based regioisomeric seminaphthofluorone dye series exhibit a combination of desirable characteristics including ( i ) low molecular weight (339 amu), ( ii ) aqueous solubility, and ( iii ) dual excitation and emission from their fluorescent neutral and anionic forms. Importantly, systematic changes in the regiochemistry of benzannulation and the ionizable moieties afford ( iv ) tunable deep-red to NIR emission from anionic species and ( v ) enhanced Stokes shifts. Anionic SNAFR-6, exhibiting an unusually large Stokes shift of ≈200 nm (5,014 cm −1 ) in aqueous buffer, embodies an unprecedented fluorophore that emits NIR fluorescence when excited in the blue/green wavelength region. The successful use of SNAFR-6 in cellular imaging studies demonstrates proof-of-concept that this class of dyes possesses photophysical characteristics that allow their use in practical applications. Notably, each of the new fluorophores described is a minimal template structure for evaluation of their basic spectral properties, which may be further functionalized and optimized yielding concomitant improvements in their photophysical properties.

The synthesis of new benzo[a]- and [b]xanthene dye frameworks is described. A unique benzo-[a]xanthene, seminaphtho[a]fluorone (SNAFR-1), is studied in a variety of media. The optimization of solution parameters and excitation wavelengths allows SNAFR-1 to display red, green, and blue emission bands of approximately equal intensities and also to produce white light. Ratiometric red (anion) and green (neutral) emissions are observed upon varying solution pH. A pH-independent violet-blue emission band is due to the addition of nucleophiles to the benzylic carbon of SNAFR-1.

Several discreet sugar-boronate complexes exist in solution. This is due to the complex equilibria between isomeric species of even the simplest monosaccharides. In the current investigation, we determine the regio- and stereochemical features of the various equilibrating sugar isomers that induce signal transduction in boronic acid chemosensors such as 1 as well as 2 and 3. We present a unique example of a chemosensor (1) that is selective for ribose, adenosine, nucleotides, nucleosides, and congeners. As a result of this study, we are able to predict and achieve selective fluorescence and colorimetric responses to specific disaccharides as a consequence of their terminal sugar residue linkage patterns and configurations. We also find that the combined use of chemosensors exhibiting complementary reactivities may be used cooperatively to obtain enhanced selectivity for ribose and rare saccharides.

The fabrication of reliable non- or minimally invasive glucose sensors, including those that embody automated insulin-delivery systems, has been a long-term goal of researchers from a variety of disciplines. The foremost challenge is the attainment of materials that are selective for glucose in bodily fluids, wherein a vast number of potential interferences exist.[1]

A facile synthetic route utilizing readily available reagents affords a series of regioisomerically pure xanthene dye derivatives. Advantages include relatively mild conditions and good to excellent yields. Nonpolar, highly crystalline intermediates are isolable by standard chromatographic techniques. The intermediates are in the requisite xanthene oxidation state, thus avoiding the need for relatively inefficient oxidation chemistry and/or harsh conditions. During the course of this work, a new boron-mediated 1,2-aryl migration reaction was discovered.

[reaction: see text] A new method for the bioassay of concanavalin A is based on the interaction of saccharide-substituted oligopyrrolic macrocycles with lectins. A general sensing mechanism involves the interaction of aggregated and primarily nonfluorescent labels with the target protein, label deaggregation, site-specific binding, and fluorescence signaling. Addition of saccharides to the fluorescent lectin-macrocycle complex leads to the release of the label and partial quenching of fluorescence due to reaggregation. Specificity of the protein-probe binding is discussed.

As part of a broader program focusing on the detection of colorless biomolecules in the visible region, a simple and mild procedure for the visual detection of the most abundant sialic acid at room temperature and neutral pH is reported. The role of the interaction of the sialic acid amide with boron in a readily synthesized boronic acid-based receptor is an important feature of the signaling mechanism. Selectivity of reaction can be tuned by the judicious choice of solvents. This study embodies a departure from many of the author's earlier efforts in sugar solutions that are not heated, affording relatively more selective and milder detection.

Molecular structure of a Boc-protected piperidine-spiro-hydantoin has been studied by solution state NMR and X-ray crystallography. Complete assignments of the 1 H and 13 C spectra have been performed using homo- and heteronuclear 2D NMR techniques. The 1 H NMR indicates that the molecule is asymmetric at low temperature and exhibits a C–N bond rotational process of the carbamate fragment attached to the piperidine ring. Solution conformation of the molecule was derived from NOE constraints, in which the piperidine ring exhibits a single half-chair conformation. The crystal structure of the piperidine-spiro-hydantoin determined by X-ray crystallography showed that the piperidine ring adopts the same conformation as in solution state and the exocyclic carbamate group is twisted from the potential symmetrical plane of the piperidine ring.

Background/Objective The heating of the fluids used in electronic cigarettes (“e-cigarettes”) used to create “vaping” aerosols is capable of causing a wide range of degradation reaction products. We investigated formation of benzene (an important human carcinogen) from e-cigarette fluids containing propylene glycol (PG), glycerol (GL), benzoic acid, the flavor chemical benzaldehyde, and nicotine. Methods/Main results Three e-cigarette devices were used: the JUULTM “pod” system (provides no user accessible settings other than flavor cartridge choice), and two refill tank systems that allowed a range of user accessible power settings. Benzene in the e-cigarette aerosols was determined by gas chromatography/mass spectrometry. Benzene formation was ND (not detected) in the JUUL system. In the two tank systems benzene was found to form from propylene glycol (PG) and glycerol (GL), and from the additives benzoic acid and benzaldehyde, especially at high power settings. With 50:50 PG+GL, for tank device 1 at 6W and 13W, the formed benzene concentrations were 1.9 and 750 μg/m3. For tank device 2, at 6W and 25W, the formed concentrations were ND and 1.8 μg/m3. With benzoic acid and benzaldehyde at ~10 mg/mL, for tank device 1, values at 13W were as high as 5000 μg/m3. For tank device 2 at 25W, all values were ≤~100 μg/m3. These values may be compared with what can be expected in a conventional (tobacco) cigarette, namely 200,000 μg/m3. Thus, the risks from benzene will be lower from e-cigarettes than from conventional cigarettes. However, ambient benzene air concentrations in the U.S. have typically been 1 μg/m3, so that benzene has been named the largest single known cancer-risk air toxic in the U.S. For non-smokers, chronically repeated exposure to benzene from e-cigarettes at levels such as 100 or higher μg/m3 will not be of negligible risk.

We report the detection of homocysteine over cysteine based upon characteristic differences between 5- and 6-membered heterocyclic amines formed upon reaction with aldehyde-bearing compounds. Homocysteine-derived thiazinane-4-carboxylic acids are more basic than cysteine-derived thiazolidines-4-carboxylic acids. Fluorescence enhancement in response to homocysteine is achieved by tuning pH and excitation wavelength.

A simple and highly efficient technique for the analysis of lysophosphatidic acid (LPA) subspecies in human plasma is described. The streamlined sample preparation protocol furnishes the five major LPA subspecies with excellent recoveries. Extensive analysis of the enriched sample reveals only trace levels of other phospholipids. This level of purity not only improves MS analyses, but enables HPLC post-column detection in the visible region with a commercially available fluorescent phospholipids probe. Human plasma samples from different donors were analyzed using the above method and validated by LC-ESI/MS/MS.

Understanding cellular mechanisms of ototoxic and nephrotoxic drug uptake, intracellular distribution, and molecular trafficking across cellular barrier systems aids the study of potential uptake blockers that preserve sensory and renal function during critical life-saving therapy. Herein we report the design, synthesis characterization and evaluation of a fluorescent conjugate of the aminoglycoside antibiotic gentamicin. Live cell imaging results show the potential utility of this new material. Related gentamicin conjugates studied to date quench in live kindney cells, and have been largely restricted to use in fixed (delipidated) cells.

New drugs with enhanced electron donor properties that target the Ca2+ release channel (CRC) from sarcoplasmic reticulum are potent inhibitors of single channel activity. In this study we synthesize derivatives of the channel activator 4-chloro-3 methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor K201 (JTV519) with enhanced electron donor properties. Instead of activating channel activity (∼100 uM), 4-CmC's 4-methoxy analog (4-methoxy-3-methyl phenol) inhibits channel activity at sub-micromolar concentrations (IC50 = 0.34 ± 0.08 uM). Increasing the electron donor characteristics of K201, by synthesizing its dioxole congener, results in a new compound which is 16 times more potent an inhibitor of single channel activity (0.24 ± 0.05 uM) than K201(3.98 ± 0.79 uM). These alterations to chemical structure do not affect Ca2+ dependent ATPase activity of SERCA1. Both K201 and its dioxole derivate show a similar potency toward inhibiting ATPase activity (IC50 ∼50 uM), while 4-methoxy-3-methyl phenol does not inhibit ATPase activity at concentrations up to 1 mM. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It appears as if FKBP12, K201, its dioxole derivative, and 4-methoxy-3-methyl phenol inhibit the skeletal muscle SR CRC channel activity by virtue of their electron donor characteristics. We also show that the inhibitory action of K201 is independent of FKBP12 binding to RyR1. These results embody strong evidence that designing new drugs that target the CRC with enhanced electron donor characteristics results in more potent channel inhibitors. This represents a novel approach toward designing new more potent drugs aimed at functionally modifying the CRC from sarcoplasmic reticulum. Supported by PSU Faculty Development Award, University Venture Development Fund, ONAMI, and NIH (R01 AR48911) to JJA.

The reaction of [60]fullerene with 2-diazo-4,5-dicyanoimidazole affords new compound 4 which contains an electron poor aromatic heterocycle attached to the fullerene sphere.

[structure: see text] An X-ray crystallographic study of unique hydrogen-bonded supramolecular solid-state networks comprised of a tetraarylboronic acid resorcinarene is described. When 1 is recrystallized from 9:1 MeOH:EtOH, partial esterification takes place to give compound 2, the corresponding half methyl ester, which forms an infinite two-dimensional array. Each molecule participates in 12 hydrogen bonds with other macrocycles. These hydrogen bonds are both B-OH- - - OH (phenolic) and OH (phenolic)- - -OH (phenolic).

Fluorinated [2,2]paracyclophanes are useful precursors to poly( p -xylylene) polymers. The cyclophanes 1,1,9,9-tetrafluoro[2,2] p -cyclophane ( 3a ) and 1,1,10,10-tetrafluoro[2.2] p -cyclophane ( 3b ) can be readily prepared via a convenient two-step synthesis from the parent hydrocarbon [2,2] p -cyclophane ( 1) . The structures of 3a and 3b are confirmed via single crystal X-ray analysis.

The reaction of [60]fullerene with 2-diazo-4,5-dicyanoimidazole affords new compound 4 which contains an electron poor aromatic heterocycle attached to the fullerene sphere.

Elevated levels of homocysteine are associated with several major diseases. However, it is not clear whether homocysteine is a marker or a causative agent. The majority ( ca. 80%) of the homocysteine present in humans is protein bound. The study of the posttranslational modification of proteins by homocysteine and its cyclic congener, homocysteine thiolactone, is emerging as an area of great current interest for unraveling the ongoing “mediator/marker controversy” [Jacobsen DW (2009) Clin Chem 55:1–2]. Interestingly, many of the pathologies associated with homocysteine are also linked to oxidative stress. In the current study, chemical evidence for a causal relationship between homocysteine-bound proteins and oxidative damage is presented. For example, a reproducible increase in protein carbonyl functionality occurs as a consequence of the reaction of human serum albumin with homocysteine thiolactone. This occurs at physiological temperature upon exposure to air without any added oxidants or free-radical initiators. Alpha-amino acid carbon-centered radicals, well-known precursors of protein carbonyls, are shown to form via a hydrogen atom transfer process involving thiolactone-derived homocystamides. Model peptides in buffer as well as native proteins in human blood plasma additionally exhibit properties in keeping with the homocystamide-facilitated hydrogen atom transfer and resultant carbon-centered radicals.