Ene-Reductases in Pharmaceutical Chemistry
Peter Grunwald in 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)).
Chemistry
Stephen P. Coburn in The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
We have had no direct experience with any of these syntheses for 3-deoxypyridoxine. The route used by Jones and Kornfeld is appealing in spite of its low yield because it involves only two steps. The starting material, 3-methylisoquinoline, used to be readily available and inexpensive. Unfortunately, it is now stocked by only a few suppliers, and its cost is currently about $2 per gram. After evaluating the various possibilities, it was our conclusion that the most inexpensive route would be to condense acetone and diethyloxalate to form ethyl acetopyruvate,299 which could then be condensed with cyanoacetamide,29,216 hydrolyzed with 50% sulfuric acid to 2-methyl-6-pyridone-4,5-dicarboxylate,71 chlorinated with thionyl chloride, hydrogenated to 2-methyl-pyridine-4,5-dicarboxylate, and reduced to 3-deoxypyridoxine. Sodium borohydride has been used.312 It seems likely that lithium aluminum hydride would also be useful. Under the proper conditions,216,408 the 2-chloro-group can be replaced without reducing the nitrile group to an amine. However, the need for such selectivity in the hydrogenation step could be eliminated by hydrolyzing the nitrile to a carboxyl group at an earlier stage as suggested. We are currently testing this proposed route.
Coupled Mass Spectrometic—Chromatographic Systems
Steven H. Y. Wong, Iraving Sunshine in Handbook of Analytical Therapeutic Drug Monitoring and Toxicology, 2017
The QIT has some unique advantages in CI relative to normal QMF techniques. When methane is used as a reagent gas, both CH5+ and C2H5+ are produced in approximately equal amounts. The C2H5+ can participate in both proton exchange and hydride abstraction reactions.25 Because the QIT can store or eject ions, selective storage of the CH5+ is, in principle, readily accomplished, simplifying the CI reaction chemistry. In addition to the selective storage of CI species, the relatively long reaction times available in the QIT relative to the dynamics of CI in an external source allow the use of very low concentrations of CI reagent gas. This, in turn, allows the use of less volatile compounds, as CI reagents. For example, acetonitrile (CH4CN+) can be used as the CI reagent for cocaine (Figure 10–4). A vial of liquid acetonitrile is attached to the vacuum system of the instrument, and sufficient reagent gas is available to produce analytically useful ion currents. Greater fragmentation is sometimes observed for CI on the QIT because of internal energy acquired from collisions with the bath gas. This could potentially be a positive finding for identification of drugs using CI, although no systematic studies have been done. Furthermore, electron capture negative CI cannot be conducted in an internal ionization QIT because of the elimination of the thermal electrons by the RF field. Selective storage of hydride abstraction systems may overcome this limitation.
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).
Arabian Primrose leaf extract mediated synthesis of silver nanoparticles: their industrial and biomedical applications
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Shruti Nindawat, Veena Agrawal
The smaller size of biosynthesized Ah-AgNPs having greater surface area and negative potential offered more catalytic sites for the reduction of dyes as it aids the adsorption of dye and BH4−. The nanocatalyst helps in relay of electrons in the redox reaction and transfer surface hydride ions (donor) to the dye (acceptor) [36]. Thus, a similar mechanism might have been followed by the Ah-AgNPs acting as potential catalysts as it was observed that the absorption peak and colour of the dyes vanished completely (Figure 7). The probable mechanism for catalytic degradation (decolourization) of dyes could be: (i) release of hydrogen by NaBH4 solution which gets adsorbed on catalytic surfaces (ii) adsorption of dyes on the surface of AgNPs activating the nanocatalytic surface (iii) simultaneously, the BH4− ions transfer electrons to AgNPs (iv) a negative charged layer develops around nanoparticles which are then transferred to dye molecules (v) finally the dyes get reduced and are released [13]. These dyes were selected due to their chromophoric nature making it easier to screen their degradation as they become colourless after reduction.