Previous work has indicated an aziridinium ion mechanism in the hydrolysis of chlorambucil, and the present work on the alkylation of nucleophiles fully supports this mechanism. This mechanism forms the basis for understanding the kinetics of alkylation reactions because their rates are limited by the rate of formation of the aziridinium ion and the alkylation reaction competes with the hydrolytic reaction. We have measured alpha N, where alpha N(N) is the rate of reaction of the aziridinium ion with a nucleophile N relative to its reaction with water for several nucleophiles that are related to those found in proteins. The alpha values for hydroxide ion and some other bases are greater than 10(3), but the effective values at pH 7.5 are much smaller because there is little base present. The kinetic equations show that it is very difficult to alkylate a nucleophile extensively at pH 7.5 before chlorambucil has hydrolyzed. Therefore, it is not clear why angiotensin-converting enzyme is completely inhibited by low concentrations of chlorambucil. On the other hand, damage to DNA is easily understood.
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http://dx.doi.org/10.1016/0091-3057(94)90078-7 | DOI Listing |
ChemistryOpen
June 2024
Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 17, 35392, Giessen, Germany.
In previous works, we demonstrated that tertiary 3-chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3-chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N-chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination.
View Article and Find Full Text PDFJ Org Chem
August 2023
Institute for Information Technologies, Department of Science, University of Kragujevac, Jovana Cvijića bb, Kragujevac 34000, Serbia.
Fluorinated piperidines find wide applications, most notably in the development of novel therapies and agrochemicals. Cyclization of alkenyl -tosylamides promoted by BF-activated aryliodine(III) carboxylates is an attractive strategy to construct 3-fluoropiperidines, but it suffers from selectivity issues arising from competitive oxoaminations and the inability to easily modulate the reactions diastereoselectivity. Herein, we report an itemized optimization of the reaction conditions carried out on both cyclic and acyclic substrates and outline the origins of substrate- and reagent-based stereo-, regio-, and chemoselectivity.
View Article and Find Full Text PDFJ Org Chem
July 2023
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
The synthesis of a range of loline alkaloids is reported. The C(7) and C(7a) stereogenic centers for the targets were formed by the established conjugate addition of lithium ()--benzyl--(α-methylbenzyl)amide to -butyl 5-benzyloxypent-2-enoate, ensuing enolate oxidation to give an α-hydroxy-β-amino ester, and then formal exchange of the resultant amino and hydroxyl functionalities (via the intermediacy of the corresponding aziridinium ion) to give an α-amino-β-hydroxy ester. Subsequent transformation gave a 3-hydroxyprolinal derivative which was converted to the corresponding --butylsulfinylimine.
View Article and Find Full Text PDFInt J Mol Sci
May 2023
College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea.
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. In AD patients, amyloid-β (Aβ) peptide-mediated degeneration of the cholinergic system utilizing acetylcholine (ACh) for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without reversing disease progress, there is a need for effective therapies, and cell-based therapeutic approaches should fulfil this requirement.
View Article and Find Full Text PDFBull Exp Biol Med
December 2022
Institute of Experimental Medicine, V. A. Almazov National Medical Research Center, Ministry of Health of the Russian Federation, St. Petersburg, Russia.
We studied the role of both parts of the autonomic intracardiac nervous system in the pathogenesis of atrial fibrillation (AF). In 12 pigs weighing 39±3 kg, AF was induced by burst stimulation. Chemical inactivation of intrinsic cardiac neurons within the right atria was performed by transendocardial injections of liposomal neuromodulators into the dorsal part of the right atrial wall.
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