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Inhalation Toxicity of Metal Particles and Vapors
Published in Jacob Loke, Pathophysiology and Treatment of Inhalation Injuries, 2020
The toxicity of tin after inhalation is low. In exposed workers, chronic inhalation of tin oxide dust or fumes leads to “stannosis,” a benign pneumoconiosis without tissue reaction or pulmonary dysfunction (Barnes and Stoner, 1959). There are no data from animal experiments or from studies on human beings on deposition or absorption of inhaled inorganic tin or organotin compounds. The majority of inhaled tin or its salts remains in the lungs, most extracellularly, with some in the macrophages, in the form of SnO2. The organic tins, particularly triethyltin, may be somewhat better absorbed and are considerably more toxic when taken orally (Piscator, 1977). Stannic hydride, an unstable gas, is more toxic than arsine and primarily affects the central nervous system.
Ene-Reductases in Pharmaceutical Chemistry
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Going beyond the biocatalytic reduction of amines and carbonyls, a reaction of particular industrial interest is the stereospecific addition of hydrogen to C=C double bonds. A multitude of chemical approaches has been developed to carry out this reaction enantioselectively (Faber and Hall, 2015) including the use of hydride reagent like NaBH4, precious metal catalysts or organocatalysts such as Hantzsch esters. Drawbacks of these methods are the problematic evolution of flammable hydrogen gas (hydride reagent, metal catalyst), the limited chemoselectivity (hydride reagent), or high cost (metal catalyst, organocatalysts). In contrast to the chemical methods discussed above, the biocatalytic reduction of double bonds can be carried out with high chemo- and stereoselectivity under mild aqueous conditions by multiple enzyme families collectively called ene-reductases (EREDs) (Toogood and Scrutton, 2018). The use of EREDs in the production of chemicals avoids the need for protection and deprotection steps, heavy metal catalysts and difficult-to-handle hydrogen gas thus potentially reducing operating costs (waste reduction, low fixed-cost infrastructure, reusable biocatalyst) and improving eco-efficiency (“On advances and challenges in biocatalysis” (Editorial: Nature Catalysis 2018)).
Aldehyde Oxidases as Enzymes in Phase I Drug Metabolism
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Cristiano Mota, Teresa Santos-Silva, Mineko Terao, Enrico Garattini, Maria João Romão, Silke Leimkühler
The reaction mechanism that has been proposed for AOXs is a base-catalyzed mechanism starting with the initial attack of the deprotonated Glu1270 to the –OH ligand of the Mo-atom, thereby generating a nucleophilic –O− group (Fig. 13.4). The activated Mo–O− ligand then attacks the carbon atom of the substrate, adjacent to an aromatic nitrogen atom in the case of N-heterocycles oxidation. Concomitantly, hydride transfer occurs to the sulfido ligand and an intermediate species is formed (Fig. 13.4). This intermediate is stabilized by hydrogen bonding interactions with residues of the active site, namely Val811, Met889, and Lys885. This concerted mechanism is favored by experimental evidence of a variety of substituted N-heterocycles (Lepri et al., 2017) as well as by DFT calculations (Alfaro and Jones, 2008). In the following step, the product is released from the reduced Mo site and a water molecule replenishes the vacant coordination position (Fig. 13.4). The reaction cycle is completed once Mo is re-oxidized and the two reducing equivalents are transferred to molecular oxygen via the two [2Fe-2S] and the FAD cofactor.
Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary in vitro evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Loredana Salerno, Luca Vanella, Valeria Sorrenti, Valeria Consoli, Valeria Ciaffaglione, Antonino N. Fallica, Vittorio Canale, Paweł Zajdel, Rosario Pignatello, Sebastiano Intagliata
Inhibition activity assay for HO-1 was performed by extracting the enzyme from the rat spleen microsomal fraction. HO-1 activity was determined by measuring the formation of BR using the difference in absorbance at 464–530 nm, according to the protocol described in the experimental section. Results are expressed as enzyme inhibition activity (IC50) in μM (Table S2, Supplemental material). As expected, the hydride 3 exhibited a lower inhibitory potency towards HO-1 than the parent compound 1 (82 ± 2.1 μM vs. 0.4 ± 0.01 μM, respectively). Compound 2, a possible metabolite of 3 showed even lower inhibitory activity towards HO-1 (104.6 ± 5.8 μM). These results were consistent with previous structure-activity relationship (SAR) studies performed on azole-based analogs 44,45, stressing that changes at the ethanolic chain are detrimental to the HO-1 inhibitory activity. Although compound 3 displayed a lower inhibitory potency towards the HO-1 with respect to parent derivative 1, this aspect does not represent an issue since hybrid 3 acts as a mutual prodrug by releasing the parent drugs (i.e. 5-FU and 1, respectively).
Utility of boron in dermatology
Published in Journal of Dermatological Treatment, 2020
David G. Jackson, Leah A. Cardwell, Elias Oussedik, Steven R. Feldman
Boron is an essential nutrient with a variety of beneficial roles, including promotion of wound healing, bone growth, and boosting antioxidant enzymes (1). Unique properties of boron make it a promising new element in drug design (2). Boron-containing compounds are approximately the same size as carbon-containing compounds, their small size allows them to occupy the active sites of various enzyme targets. Carbon hydrides are compounds which contain carbon and hydrogen forming chains and rings. Boron hydrides, the boron-based equivalent of carbon hydrides, form cages and clusters. The unique structure of boron hydrides provide flexibility, enabling them to occupy an enzyme’s active site with more ease than rigid carbon compounds (2). Boron is electron-deficient, its outer shell carries three electrons though it has the capacity to hold four pairs of electrons. This characteristic of electron deficiency makes the atom a strong electrophile (Figure 1). Boron bonds with nucleophiles, allowing its electrons to reorganize and create an anionic, tetrahedral structure (3).
Effects of boron-containing compounds on immune responses: review and patenting trends
Published in Expert Opinion on Therapeutic Patents, 2019
Karla S. Romero-Aguilar, Ivonne M. Arciniega-Martínez, Eunice D. Farfán-García, Rafael Campos-Rodríguez, Aldo A. Reséndiz-Albor, Marvin A. Soriano-Ursúa
In a study conducted in mice with induced edema and chronic arthritis, amino carboxyboranes (7) in the form of boron hydrides were administered at doses of 8 mg/kg/day, with a reduction of the inflammation induced by indomethacin greater than 60%. Indeed, these boron compounds are potent inhibitors of lysosomal hydrolytic enzymes, and their carboxyborane derivatives effectively inhibit the release of the chemical mediators TNF-α and IL-1β from macrophages [42]. Other BCCs, such as benzimidazole, indole and benzolactam boronic (9) acid compounds, inhibit inflammatory cytokines [102].