111456-85-0Relevant academic research and scientific papers
ACID-SENSITIVE LINKERS FOR DRUG DELIVERY
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Page/Page column 12-13, (2011/04/14)
The invention is in general directed to acid-sensitive linkers, and methods of use thereof, such as, for example, in drug delivery methods.
Hydration of acylimidazoles: tetrahedral intermediates in acylimidazole hydrolysis and nucleophilic attack by imidazole on esters. The question of concerted mechanisms for acyl transfers
Guthrie, J. Peter,Pike, David C.
, p. 1951 - 1970 (2007/10/02)
Heats of hydrolysis have been measured for three acylimidazole acetals.From these results free energies of formation in aqueous solution have been calculated for the acetals and the corresponding tetrahedral intermediates.Having free energies of formation for the tetrahedral intermediates allows a detailed analysis of the energetics of both the unobservable nucleophilic reaction of imidazole with ethyl acetate and also the observable reaction of imidazole with p-nitropehnyl acetate. pKa values of 1-(3-aminopropyl)-imidazole and 1-(2-aminoethyl)-imidazole have been determined to allow calculation of the ?* value for the imidazolyl substituent .The dependence of imidazole pKa values on the electron-withdrawing properties of the 1-substituent was also determined.There is a linear free energy relation between the free energy change for replacement of OH in a carbonyl hydrate by imidazolyl and the sum of the ?* values for the other substituents.The implications of these results for the question of concerted versus stepwise mechanism for the reaction of imidazole with aryl acetates have been examined.An equilibrium constant has been calculated for the addition of imidazole to p-nitrophenyl acetate.A simple extension of Marcus theory allows the free energy surface for a three-dimensional reaction coordinate diagram to be calculated using the energy levels of the tetrahedral intermediate determined in this work, the energy level of the acylium ion derived from literature data, and intrinsic barriers for the edge reactions.It is shown, that the reaction of imidazole with p-nitrophenyl acetate probably follows a concerted path.General conclusions from this theory of concerted reaction are discussed.
