Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Several general classes of xenobiotics are biotransformed by P450. Generic reactions include aliphatic hydroxylation at ω-1 carbons of straightchain alkanes or alkyl functional groups, aromatic hydrocarbon hydroxylation at carbon-hydrogen bonds, alkene epoxidation at carbon-carbon double bonds, dealkylation via hydroxylation of carbon atoms alpha to nitrogen, oxygen, or sulfur atoms, deamination via hydroxylation of carbons alpha to primary amino groups, oxidation of sulfur- and nitrogen-containing groups by insertion of oxygen to a free-electron pair, and dehalogenation of alkyl halides by insertion of an oxygen atom at the carbon-halogen bonds. Reduction reactions are catalyzed by the P450 system, but are rare relative to oxidations. These readily occur only under conditions of low oxygen tension in which substrates compete with oxygen for electron transfer from NADPH-cytochrome P450 reductase. Reduction reactions are important biotransformation/bioactivation pathways for xenobiotics containing nitrogen functional groups such as nitro, azo, arene oxides, N-oxides, and alkyl halides, however. Other enzymes for catalysis of nitrogen group reduction include xanthine oxidase, aldehyde oxidase, and DT-diaphorase of liver cytosol and bacteria reductases of the intestinal microflora.
Chemical Causes of Cancer
Peter G. Shields in Cancer Risk Assessment, 2005
Some adducts are repaired better than others, as noted above. For example, N-7 and O6–alkylation of guanine are better repaired than O4–alkyl thymine, which is therefore more persistent (290). The basis for the efficient repair of O6–alkylation is that it is a substrate for the AGAT repair process. The dealkylation by AGAT is stoichiometric and the repair molecule is inactivated by transferring the alkyl group to one of its cysteine residues (315). AGAT is also inactivated by reaction with nitric oxide (316).
General toxicology
Timbrell John in Study Toxicology Through Questions, 2017
A9. (a) Dealkylation is the removal of an alkyl (usually a methyl or ethyl group) from a molecule. The alkyl group may be attached to a nitrogen, sulphur or oxygen atom as indicated below. The dealkylation reaction is catalysed by the microsomal monooxygenase enzyme cytochrome P450 and involves an initial oxidation of the alkyl carbon atom followed by a rearrangement with loss of the oxidised alkyl group as an aldehyde (e.g. methanal or ethanal as indicated below). The other product is either an alcohol, thiol or amine as shown below:
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.
Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ivana Šagud, Nikolina Maček Hrvat, Ana Grgičević, Tena Čadež, Josipa Hodak, Milena Dragojević, Kornelija Lasić, Zrinka Kovarik, Irena Škorić
Using the reaction of N-alkylation on the previously synthesised trans-chloro-arylethenyloxazole 120, new trans-amino-5-arylethenyl-oxazole derivatives trans-2–18 were synthesised (Scheme 1) with an aim to add a new functional group at the end of the oxazole derivative that resembles acetylcholine, the substrate of cholinesterase. The Buchwald-Hartwig reaction21 was utilised with two catalysts and the reaction was optimised for best conditions to enhance the yield. Change of base was crucial for the optimisation of this reaction. Sodium tert-butoxide was previously used as a base but the dehalogenation of the starting material was observed. Caesium carbonate improved yield and conversion. Temperature, solvent and catalyst used were independently varied to give the best conversion. The best conditions found are given in Scheme 1. The catalysed N-alkylation reaction is a complex coupling reaction and it gave a vast array of yields. Some of the substrates were optimised to excellent yields, while in the example of others only moderate to low yields were obtained. There is still some room for optimisation in the future with additional catalysts but at this time this was sufficient.
Bioanalytical strategies in drug discovery and development
Published in Drug Metabolism Reviews, 2021
Aarzoo Thakur, Zhiyuan Tan, Tsubasa Kameyama, Eman El-Khateeb, Shakti Nagpal, Stephanie Malone, Rohitash Jamwal, Chukwunonso K. Nwabufo
Enrichment/immunocapture is followed by a reduction step, wherein a reducing agent, such as DTT (dithiothreitol) or TCEP (tris(2-carboxyethyl) phosphine) is used to break up disulfide bonds. Thereafter, alkylating agents, such as iodoacetamide or iodoacetic acid are then added to prevent the broken bonds from reforming (DelGuidice et al. 2020). Challenges with alkylation are that the molecular weight can change. Often with reduction, extracts must be cleaned up either before or after with additional sample extraction procedures, such as SPE, PPT, or MWCO filtration. Clean-up is shown in a case study of insulin, where a PPT procedure was used followed by reduction with DTT and incubation before being further subjected to digestion (Chen et al. 2013).