The lethal and sublethal impacts of two tire rubber-derived chemicals on brook trout (Salvelinus fontinalis) fry and fingerlings.

Recent toxicity studies of stormwater runoff implicated N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-quinone) as the contaminant responsible for the mass mortality of coho salmon (Oncorhynchus kisutch). In the wake of this discovery, 6PPD-quinone has been measured in waterways around urban centers, along with other tire wear leachates like hexamethoxymethylmelamine (HMMM). The limited data available for 6PPD-quinone have shown toxicity can vary depending on the species.

Reactive Oxygen Species and Chromophoric Dissolved Organic Matter Drive the Aquatic Photochemical Pathways and Photoproducts of 6PPD-quinone under Simulated High-Latitude Conditions.

The photochemical degradation pathways of 6PPD-quinone (6PPDQ, 6PPD-Q), a toxic transformation product of the tire antiozonant 6PPD, were determined under simulated sunlight conditions typical of high-latitude surface waters. Direct photochemical degradation resulted in 6PPDQ half-lives ranging from 17.5 h at 20 °C to no observable degradation over 48 h at 4 °C.

Concentrations of Tire Additive Chemicals and Tire Road Wear Particles in an Australian Urban Tributary.

Tire road wear particles (TRWPs) are one of the largest sources of microplastics to the urban environment with recent concerns as they also provide a pathway for additive chemicals to leach into the environment. Stormwater is a major source of TRWPs and associated additives to urban surface water, with additives including the antioxidant derivative -(1,3-dimethylbutyl)-'-phenyl--phenylenediamine-quinone (6PPD-quinone) demonstrating links to aquatic toxicity at environmentally relevant concentrations. The present study used complementary analysis methods to quantify both TRWPs and a suite of known tire additive chemicals (including 6PPD-quinone) to an urban tributary in Australia during severe storm events.

Syrbactin-class dual constitutive- and immuno-proteasome inhibitor TIR-199 impedes myeloma-mediated bone degeneration in vivo.

Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae.

A Direct Mass Spectrometry Method for the Rapid Analysis of Ubiquitous Tire-Derived Toxin -(1,3-Dimethylbutyl)-'-phenyl--phenylenediamine Quinone (6-PPDQ).

The oxidative transformation product of a common tire preservative, identified as -(1,3-dimethylbutyl)-'-phenyl--phenylenediamine quinone (6-PPDQ), has recently been found to contribute to "urban runoff mortality syndrome" in Coho salmon at nanogram per liter levels. Given the number of fish-bearing streams with multiple stormwater inputs, large-scale campaigns to identify 6-PPDQ sources and evaluate mitigation strategies will require sensitive, high-throughput analytical methods. We report the development and optimization of a direct sampling tandem mass spectrometry method for semiquantitative 6-PPDQ determinations using a thin polydimethylsiloxane membrane immersion probe.

Cannabichromene Racemization and Absolute Stereochemistry Based on a Cannabicyclol Analog.

Cannabichromene (CBC) is unusual among cannabinoids in having been described as both a racemic and a scalemic compound from natural sources. Several explanations are available for this circumstance, including facile racemization. Cannabichromene was resolved chromatographically, and the enantiomer matching CBC from local was identified.

Spider web biomonitoring: A cost-effective source apportionment approach for urban particulate matter.

Elevated levels of particulate matter (PM) in urban atmospheres are one of the major environmental challenges of the Anthropocene. To effectively lower those levels, identification and quantification of sources of PM is required. Biomonitoring methods are helpful tools to tackle this problem but have not been fully established yet.

Synthetic Access to Cannabidiol and Analogs as Active Pharmaceutical Ingredients.

Cannabinoids have surely been one of the most widely self-administered drugs other than caffeine. The U.S.

Syrbactin proteasome inhibitor TIR-199 overcomes bortezomib chemoresistance and inhibits multiple myeloma tumor growth in vivo.

Multiple myeloma (MM) and mantle cell lymphoma (MCL) are blood cancers that respond to proteasome inhibitors. Three FDA-approved drugs that block the proteasome are currently on the market, bortezomib, carfilzomib, and ixazomib. While these proteasome inhibitors have demonstrated clinical efficacy against refractory and relapsed MM and MCL, they are also associated with considerable adverse effects including peripheral neuropathy and cardiotoxicity, and tumor cells often acquire drug resistance.

Synthesis and bioluminescence of thioluciferin.

The firefly luciferin analog thioluciferin (S-luc) was synthesised as a key element of bioluminescent reporters for oxidation state and thiol/disulfide equilibria. It shows blue-shifts in absorption and fluorescence compared to luciferin, and is a modest luciferase substrate. These features are attributed to a π-system that is less conjugated than luciferin.

Thiasyrbactins Induce Cell Death Proteasome Inhibition in Multiple Myeloma Cells.

Background/aim: Proteasome inhibition is a validated therapeutic strategy for the treatment of refractory and relapsed multiple myeloma (MM) and mantle cell lymphoma. We previously showed that thiasyrbactins (NAM compounds) are inhibitors with an affinity for the trypsin-like (T-L, β2) site of the constitutive proteasome, and more profoundly for the T-L site of the immunoproteasome.

Materials And Methods: In this study, the biological activity of three NAM compounds was evaluated using four MM cell lines (ARD, U266, MM1R, and MM1S).

β-Deuterium Isotope Effects on Firefly Luciferase Bioluminescence.

A 5,5- -luciferin was prepared to measure isotope effects on reactions of two intermediates in firefly bioluminescence: emission by oxyluciferin and elimination of a putative luciferyl adenylate hydroperoxide to dehydroluciferin. A negligible isotope effect on bioluminescence provides further support for the belief that the emitting species is the keto-phenolate of oxyluciferin and rules out its excited-state tautomerization, one potential contribution to a bioluminescence quantum yield less than unity. A small isotope effect on dehydroluciferin formation supports a single-electron-transfer mechanism for reaction of the luciferyl adenylate enolate with oxygen to form the hydroperoxide or dehydroluciferin.

Native Serine Peptide Assembly: Scope and Utility.

This work develops serine peptide assembly (SPA), which complements and contrasts with classic native chemical ligation (NCL). Advances in reagent-less peptide bond formation have been applied to serine (and serine models) and a range of -terminal amino acids, including bulky residues that are not amenable to NCL. The particular appeal of SPA is preparative-scale segment condensations with zero racemization risk and favourable process mass intensity (PMI).

Correction: Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation.

Correction for 'Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation' by Michael C. Pirrung, et al.

Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation.

Solution-phase syntheses of three bioactive natural products of mixed polypeptide-polyketide biogenesis, fellutamides A, B, and C, have been achieved. Three peptide bonds are generated without the use of coupling reagents in each synthesis of the fellutamides, which act against proteasomes.

Syrbactin Structural Analog TIR-199 Blocks Proteasome Activity and Induces Tumor Cell Death.

Multiple myeloma is an aggressive hematopoietic cancer of plasma cells. The recent emergence of three effective FDA-approved proteasome-inhibiting drugs, bortezomib (Velcade®), carfilzomib (Kyprolis®), and ixazomib (Ninlaro®), confirms that proteasome inhibitors are therapeutically useful against neoplastic disease, in particular refractory multiple myeloma and mantle cell lymphoma. This study describes the synthesis, computational affinity assessment, and preclinical evaluation of TIR-199, a natural product-derived syrbactin structural analog.

Synthesis and bioluminescence of difluoroluciferin.

A new synthesis route to firefly luciferin analogs was developed via the synthesis of 5',7'-difluoroluciferin. As a luciferase substrate, it produces maximal bioluminescence at a much lower pH than is optimal for native luciferin, and at lower pH it gives much more of the red-shifted emission that is characteristic of the phenolate. These features are attributed to the enhanced acidity of the o,o-difluorophenol.

The genesis of microarrays.

This review provides a perspective on the initial development of microarray technologies by two independent groups in the late 1980s.

Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential.

A fluorescent amino acid probe to monitor efficiency of peptide conjugation to glass surfaces for high density microarrays.

Using a fluorescent NBD amino acid, new protease substrates were developed that are attractive because of the excellent chemical stability and long wavelength of excitation (480 nm) of the NBD fluorophore. The fluorescent peptides are synthesized by Fmoc solid-phase peptide synthesis. An example peptide was efficiently immobilized onto a microarray surface using click chemistry, and its proteolysis was monitored by fluorescence imaging.

Syringolin B-inspired proteasome inhibitor analogue TIR-203 exhibits enhanced biological activity in multiple myeloma and neuroblastoma.

Context: The bacterium Pseudomonas syringae pv. syringae (Pss) is a pathogen of many plant species and causes, for example, brown spot disease in bean plants (Phaseolus vulgaris). Pss excretes the syringolins, natural product molecules that act as a virulence factors and inhibit the proteasome of the host plants.

Novel proteasome-inhibitory syrbactin analogs inducing endoplasmic reticulum stress and apoptosis in hematological tumor cell lines.

The proteasome has been recognized as a druggable target in cancer cells, and this has led to searches for pharmacologic agents that target this cellular organelle for cancer therapeutic purposes. Syrbactins are a group of microbial metabolites consisting of two related families, the glidobactins and the syringolins. Some members of this group have revealed cytotoxic efficacy in tumor cells, and more recently it was discovered that they exert proteasome-inhibitory function.