The alkylating warhead of the pancreatic cancer drug streptozotocin (SZN) contains an N-nitrosourea moiety constructed from N ω -methyl-L-arginine (L-NMA) by the multidomain metalloenzyme SznF. The enzyme's central heme-oxygenase-like (HO-like) domain sequentially hydroxylates N δ and N ω ′ of L-NMA. Its C-terminal cupin domain then rearranges the triply modified arginine to N δ -hydroxy-N ω -methyl-N ω -nitroso-L-citrulline, the proposed donor of the functional pharmacophore. Here we show that the HO-like domain of SznF can bind Fe(II) and use it to capture O 2 , forming a peroxo-Fe 2 (III/III) intermediate. This intermediate has absorption-and Mossbauer-spectroscopic features similar to those of complexes previously trapped in ferritin-like diiron oxidases and oxygenases (FDOs) and, more recently, the HO-like fatty acid oxidase UndA. The SznF peroxo-Fe 2 (III/III) complex is an intermediate in both hydroxylation steps, as shown by the concentration-dependent acceleration of its decay upon exposure to either L-NMA or N δ -hydroxy-N ω -methyl-L-Arg (L-HMA). The Fe 2 (III/III) cluster produced upon decay of the intermediate has a small Mossbauer quadrupole splitting parameter, implying that, unlike the corresponding product states of many FDOs, it lacks an oxo-bridge. The subsequent decomposition of the product cluster to one or more paramagnetic Fe(III) species over several hours explains why SznF was previously purified and crystallographically characterized without its cofactor. Programmed instability of the oxidized form of the cofactor appears to be a unifying characteristic of the emerging superfamily of HO-like diiron oxidases and oxygenases (HDOs).

A combined Lewis acid/photoredox catalyst system enabled the intramolecular umpolung addition of ketyl radicals to vinylogous carbonates in the synthesis of 2,6-dioxabicyclo[3.3.0]octan-3-ones. This reaction proceeded on a variety of aromatic ketones to provide THF rings in good yield (up to 95%). Although diastereoselectivity was found to be modest (1.4-5:1) for the C-C bond forming reaction, the minor diastereomers were converted to 2,6-dioxabicyclo[3.3.0]octan-3-ones by an efficient Lewis acid-mediated epimerization cascade in up to 90% yield.

Photoredox catalysis has become a powerful method to generate free radical intermediates in organic synthesis. This report describes the use of photoredox catalysis to directly oxidize common nucleophilic anions to access electrophilic 1,3-dicarbonyl and amidyl radical intermediates. First, conjugate bases of 1,3-dicarbonyls were oxidized to neutral radical species for intramolecular hydro-and dialkylation of alkenes. This overall redox-neutral process provided cyclopentanone products in excellent yields (up to 96%). The scope included a variety of styrene radical acceptors and products with newly formed vicinal quaternary carbons. This process was then extended to the synthesis of pyrrolidinones by alkene amidoalkylation that proceeded via N-aryl amidyl radical intermediates in good yield (up to 85%). These reactions were characterized by their mild conditions, high atom economy, and the absence of stoichiometric byproducts. Mechanistic and computational studies supported a stepwise proton-coupled electron transfer mechanism, where an "electron borrowing" photocatalyst oxidizes an anion and reduces a benzylic radical after bond formation.

Mucus‐secreting epithelia protect marine gastropods from abrasive particles and microbes in seawater. We studied the morphology and function of the epithelium in the giant keyhole limpet Megathura crenulata. All exposed surfaces of the limpets were covered by a mucus‐secreting, simple columnar epithelium, in which most cells on the sole of the foot bore cilia, while the majority of cells on the side of the foot and three mantle regions bore microvilli. None of the coatings had antibacterial properties. The epithelium of the foot was distinct from that of other regions, in that the mucus secreted was used for locomotion and was left behind as the limpet moved. The glycocalyx bound to the microvilli of the mantle cells appeared to be clean in visual and SEM examinations, and attempts to enhance the binding of inert particles and bacteria were unsuccessful. Because studies have shown that standard tissue processing may cause artifactual shrinkage of mucous layers, cryostat sections and additives to standard fixatives were tested, but we found no change in the thickness of the mucous layers of the limpets compared to routinely processed tissues. Sloughing of the glycocalyx in vertebrate systems removes bound microbes, and alterations of the glycocalyx layers are associated with disease conditions. Sloughing of the glycocalyx on limpets was rarely observed. In one case, the outer mantle of the limpet was covered with silt and the glycocalyx appeared to be detaching. This process could be experimentally induced by dousing the outer mantle with talc particles. The types of secretory cells producing the mucus in each region of the skin were characterized using standard histological stains and lectin staining. Because analysis was hampered by their small size, classification of the types of secretory cells was based on TEM descriptions of granule morphology, which allowed for comparison to the secretory cells described from skin of the abalone. The possible roles of the numerous secretions, and the mechanisms of mucus production and loss, are compared to what is known in vertebrate systems and to our relative lack of knowledge regarding invertebrate systems.