Phenol, hemiester prodrugs

Activation by intramolecular cyclization is not restricted to nucleophilic attack by acidic and basic N-atoms, but can also be catalyzed by carboxylate groups. This has been demonstrated with hemiester prodrugs of phenol and paracetamol (8.136, R=H and MeCONH, respectively, Fig. 8.12) [174]. In... 

Fig. 8.12. Activation of hemiester prodrugs of phenols by acid-catalyzed hydrolysis (Reaction a), base-catalyzed hydrolysis (Reaction b), and cyclization-elimination (Reaction c). Enzymatic hydrolysis not shown (adapted from [174]). 

Intramolecular cyclizations are not restricted to attack by a nucleophilic nitrogen (basic amino or acidic amido group). They can also be catalyzed by a nucleophilic oxygen as found in a carboxylate, phenolic, or alcoholic group. Illustration of the catalytic role of a carboxylate group can be found in hemiester prodrugs of phenol (taken as model compound) or paracetamol (Fig. 6 R = H or NHCOCH3, respectively). In addition to enzymatic hydrolysis, three mechanisms of chemical hydrolysis were seen, namely, acid-catalyzed, base-catalyzed, and an intramolecular nucleophilic attack. 

Fig. 6 Activation of hemiester prodrugs of phenols by proton-catalyzed hydrolysis (reaction a), hydroxyl-catalyzed hydrolysis (reaction b), or cyclization-elimination (reaction c). Enzymatic hydrolysis is not represented. (Adapted from Ref.. )...

K. Fredholt, N. Mprk, M. Begtrup, Hemiesters of Aliphatic Dicarboxylic Acids as Cyclization-Activated Prodrug Forms for Protecting Phenols against First-Pass Metabolism , Int. J. Pharm. 1995, 123, 209-216. 

Fredholt, K. Mprk, N. Begtrup, M. Hemiesters of aliphatic dicarboxylic acids as cyclization-activated prodrug forms for protecting phenols against first-pass metabolism. Int. J. Pharma. 1995, 123, 209-216. 

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See also in sourсe #XX -- [ ]

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