The model drug clerocidin (CL) can form covalent adducts with both Tris and phosphate buffers with negative effects on biological activity, even though the latter is considered a largely inert physiological buffer. With the ultimate goal of learning how to control such reactivity and reduce undesired side reactions, we have investigated the influence of the different functionalities of CL on the formation of buffer adducts. For this reason, selected drug analogues were tested for their ability to react with the two buffers and comprehensive information was gained on both thermodynamics and kinetics aspects of these reactions. Two distinctive reactivity modes were readily observed. The first proved to be under kinetic control and involved the reaction of drug carbonyls (especially the aldehyde in C15) with the Tris amino group to form a Schiff base. The second was found to proceed under thermodynamic control through the attack at the oxirane ring of CL by the buffer's nucleophilic groups (amino nitrogen in Tris and oxygen in phosphate). Important relationships between the two modes were noted, thus providing further demonstration that drug reactivity toward buffers cannot be directly predicted from the functionalities that are potentially involved in the initial reaction. On the contrary, as true for almost any structure bearing potentially reactive functionalities, any solid prediction should be based on a deeper understanding of the mutual influence of vicinal groups.

Dissecting reactivity of Clerocidin towards common buffer systems by means of selected drug analogues

RICHTER, SARA;MORO, STEFANO;PALUMBO, MANLIO
2005

Abstract

The model drug clerocidin (CL) can form covalent adducts with both Tris and phosphate buffers with negative effects on biological activity, even though the latter is considered a largely inert physiological buffer. With the ultimate goal of learning how to control such reactivity and reduce undesired side reactions, we have investigated the influence of the different functionalities of CL on the formation of buffer adducts. For this reason, selected drug analogues were tested for their ability to react with the two buffers and comprehensive information was gained on both thermodynamics and kinetics aspects of these reactions. Two distinctive reactivity modes were readily observed. The first proved to be under kinetic control and involved the reaction of drug carbonyls (especially the aldehyde in C15) with the Tris amino group to form a Schiff base. The second was found to proceed under thermodynamic control through the attack at the oxirane ring of CL by the buffer's nucleophilic groups (amino nitrogen in Tris and oxygen in phosphate). Important relationships between the two modes were noted, thus providing further demonstration that drug reactivity toward buffers cannot be directly predicted from the functionalities that are potentially involved in the initial reaction. On the contrary, as true for almost any structure bearing potentially reactive functionalities, any solid prediction should be based on a deeper understanding of the mutual influence of vicinal groups.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/2465513
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