Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
The classic examples of alcohol dehydrogenase-mediated bioactivation are in the toxicity of methanol and ethylene glycol. Formate, a metabolite of methanol, causes toxicity to the retina leading to blindness; and oxalate, a metabolite of ethylene glycol, forms a precipitant in kidney tubules leading to stone formation. Leading to hepatotoxicity, alcohol dehydrogenase converts allyl formate and allyl alcohol to the reactive aldehyde, acrolein (Rees and Tarlow, 1967; Reid, 1972). Since alcohol dehydrogenase has a periportal distribution in the liver, allyl formate and allyl alcohol induce periportal necrosis.
Manufacture of Glycerine from Petrochemical and Carbohydrate Raw Materials
Eric Jungermann, Norman O.V. Sonntag in Glycerine, 2018
The distilled allyl alcohol is oxidized with a 2 M aqueous solution of H2O2 containing 0.2% tungstic oxide. The glycerol water mixture, which is generated within 2 hr reaction time at 60–70°C is distilled to afford high-purity glycerol. The filtered catalyst is recycled. Yield of glycerol (based on allyl alcohol) is 80–90%; the overall yield of glycerol based on propylene is about 50%. Isopropanol and hydrogen peroxide auxiliary raw materials can be produced from propylene; acetone is highly marketable.
Linkers in fragment-based drug design: an overview of the literature
Published in Expert Opinion on Drug Discovery, 2023
Dylan Grenier, Solène Audebert, Jordane Preto, Jean-François Guichou, Isabelle Krimm
The ether function is also widely used in medicinal chemistry due to its high stability. Two main reactions give access to ether derivatives, the Mitsunobu and the Williamson reactions. Szczepankiewicz et al. [19] linked two fragments with amide and ether functions, leading to the discovery of protein PTP1B inhibitors. One of the fragments carried a carboxylic acid function while the second, a naphthoic acid, had to be functionalized. A Mitsunobu reaction was used to obtain the ether linker containing a primary amine. Finally, the combination of the acid and amine fragments resulted in a 22 nM PTP1B inhibitor. For the same target, Liu et al. [20] combined two fragments with a more rigid linker (allyl ether) than usual. One fragment was modified by a Still coupling reaction to introduce an allyl alcohol function. The modified fragment was linked to the second fragment containing a phenolic function using a Mitsunobu reaction. A lead compound with an IC50 of 6.9 µM was obtained.
Design, synthesis and characterization of enzyme-analogue-built polymer catalysts as artificial hydrolases
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Divya Mathew, Benny Thomas, Karakkattu Subrahmanian Devaky
We extended the investigation with the organic analogues -4-vinylimidazole, allyl alcohol, methacrylic acid - of methacrylated amino acid monomers [65]. The achiral monomers formed pre-polymer complex with both L- and D-TSAs from the rac-TSA and fabricated cavities with both L-and D configuration in the polymer matrix. The mimic exhibited reduced catalytic activity which may be expected due to the more rigid nature of organic monomers compared to the flexible amino acid monomers and the presence of both type of cavities. Due to the presence of both L- and D-cavities, these mimics exhibited selectivity towards L- and D-substrates and hence did not exhibit any enantioselectivity. The effect of crosslink density on the catalytic efficiencies of the polymer catalysts was also investigated. For the polymers derived from organic monomers, the rate enhancement and enzyme-like behaviour were observed, in the lower range of crosslink density (20 mol %). Replacement of allyl alcohol from the monomer triad by vinylpyridine afforded a catalyst with better enzymatic activity. The pyridine moiety was found to be capable of exerting H-bonding interaction with carboxyl group of methacrylic acid and p-nitroanilide (Figure 33) [66].
Identification of novel glutathione conjugates of terbinafine in liver microsomes and hepatocytes across species
Published in Xenobiotica, 2019
Amol Patil, Mayurbhai Kathadbhai Ladumor, Shyam H Kamble, Benjamin M. Johnson, Murali Subramanian, Michael W. Sinz, Dilip Kumar Singh, Sivaprasad Putlur, Priyadeep Bhutani, Deepak Suresh Ahire, Saranjit Singh
The third category includes metabolites formed by N-dealkylation, resulting in liberation of the conjugated side chain followed by reaction of the side chain with GSH. This category includes conjugates of the allylic aldehyde, which is the immediate product of N-dealkylation, as well as downstream products of redox reactions that convert the aldehyde to either alcohol or acid metabolites. The aldehyde (M11 and M17) and acid intermediates (M8 and M20) represent potential Michael acceptors that could undergo direct nucleophilic attack by the sulfhydryl residue of GSH via 1,4- or 1,6-addition. Interestingly, we have also identified metabolites formed by GSH conjugation to the allylic alcohol, which is not a Michael acceptor. The mechanism of the GSH conjugate formation to the allylic alcohol has not been defined. One could hypothesize about involvement of a GSH S-transferase in facilitating the reaction with the alcohol as a substrate, or about action of aldehyde dehydrogenase in reducing the aldehyde subsequent to GSH conjugate formation. It should be noted that the GSH conjugates of the allyl alcohol and allyl acids were of much lower abundance in these systems relative to the allyl aldehyde analog, reflecting the expected trend based on chemical reactivity.
Related Knowledge Centers
- Alcohol
- Allyl Group
- Glycerol
- Hydrolysis
- Organic Compound
- Precursor
- Propylene Oxide
- Preferred Iupac Name
- Allyl Iodide
- Allyl Chloride