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  • Compounds and were outliers for this equation being

    2019-07-10

    Compounds and were outliers for this equation being the two most reactive compounds. The presence of outliers implies that other factors or specific mechanisms are involved in their chemical hydrolysis. Generally urea derivatives prove to be highly stable in aqueous solutions in vitro. Additionally, several works highlight the potential of increasing the stability and half-lives of -mustards prodrugs by introducing urea rather than carbamate linkages. A urea linker is able to lower the reactivity of the reactive -mustard pharmacophore. A comparison between the half-lives for several mustard urea derivatives () of glutamic Cisatracurium Besylate (), self-immolative derivatives (), -mustard–quinoline conjugates (), -mustard–tiramine conjugates () and urea derivatives of triazenes conjugated with tiramine and dopamine (), shows that some of these derivatives revealed an abnormally high chemical instability (– with <17min and with <4min), in PBS, a common feature with our and derivatives with 2.6 and 6.4min, respectively)., , , , , This fact raised the hypothesis of a mechanistic change in the chemical hydrolysis in physiological conditions, namely the occurrence of an intramolecular chemical catalysis ()., During this process there occurs a privileged initial cyclization, due to the close proximity of the carboxylate group. The observed rate is the result of two partitioning constants: the hydrolysis rate constant associated with nucleophilic attack by the solvent (b), and the neighboring-group promoted component (a). To recognize the occurrence of an intramolecular process, we synthesized a model structure that is structurally related to the derivatives, though incapable of reacting by the assisted route. When masking the carboxylate functions of these derivatives by esterification, chemically stable compounds are obtained () (). The dimethylester derivative presents a half-life value in PBS at 37°C of 101.9h, 34 times more stable than . This is evidence of the participation of the free COOH groups of prodrugs in the carbonyl displacement during the hydrolysis reaction that liberates the MMT. Intramolecular reactions are faster than the corresponding bimolecular processes, because of the close proximity of the reacting groups. So, this compound having a glutamic acid moiety show an extraordinary reactivity under conditions where ordinary ureas are very stable. Again, a comparison of the value for the compound (16.5h) with that of the compound (0.28h), or of the compound (364h) with (7.63h) reveals that urea derivatives with no carboxylic free groups are respectively 59 and 48 times more stable., , Another feature to consider is the presence of an abundant ion mass fragment / 84, for all the prodrugs in mass spectra (). This mass fragment results from the cyclization of the amino acid carrier, so it points out some easiness for intramolecular reactions involving the carboxylate functions of the glutamic acid moiety. These cyclic fragments are absent from the mass spectra of the compounds and which have the COOH group protected with an ester group. Blood serum and plasma contain a range of enzymes that could potentially catalyze the hydrolysis of urea derivatives. Therefore it is possible for the prodrugs to be prematurely hydrolyzed by the plasma enzymes leading to the release of triazenes before reaching the pre-localized CPG2. Consequently, we were interested in examining the stability of prodrugs in human plasma. Experimental procedure is detailed in .
    Introduction Alzheimer\'s disease (AD) is an irreversible neurodegenerative disease that is the most common cause of dementia and that is clinically characterized by progressive loss of the ability of learning and memory. In 2015, approximately 46.8 million people were diagnosed with AD in the world and this number is expected to increase to 131.5 million by 2050 (Prince et al., 2015). AD is histopathologically characterized by extracellular amyloid plaques that are primarily composed of amyloid beta (Aβ) peptides and intercellular neurofibrillary tangles, which result from accumulation of the hyper-phosphorylated microtubule-associated protein tau (Castellani et al., 2010). Previous reports indicated that extracellular deposits of Aβ peptides are the principal cause of AD onset (Hardy and Higgins, 1992, Tanzi, 2005, De Strooper, 2010) and that the innate immune function of microglia could prevent Aβ accumulation (Wang et al., 2015).