Cyclization activated prodrug

K. F. Thomsen, F. Strpm, B. V. Sforzini, M. Begtrup, N. Mprk, Evaluation of Phenyl Carbamates of Ethyl Diamines as Cyclization-Activated Prodrug Forms for Protecting Phenols against First-Pass Metabolism , Int. J. Pharm. 1994, 112, 143-152. 

A. Vigroux, M. Bergon, C. Zedde, Cyclization-Activated Prodrugs A-(Substituted 2-Hydroxyphenyl and 2-Hydroxypropyl)carbamates Based on Ring-Opened Derivatives of Active Benzoxazolones and Oxazohdinones as Mutual Prodrugs of Acetaminophen , J. Med. Chem. 1995, 38, 3983-3994. 

Thomsen, K.F. Strom, F. Sforzini, B.V. Begtrup, M. Mprk, N. Evaluation of phenyl carbamates of ethyl diamines as cyclization-activated prodrug forms for protecting phenols against first-pass metabolism. Int. J. Pharma. 1994, 112, 143-152. 

Cyclization-Activated Carboxylic Acid Ester Prodrugs... 

Cyclization-Activated Double Prodrugs of Amines and Peptides... 

CHEMICALLY ACTIVATED PRODRUGS REACTIONS OF CYCLIZATION-ELIMINATION... 

Aminoxypropionate as a novel linker system for cyclization activation in prodrug design... 

Prodrug activation occurs enzymatically, nonenzymatically, or, also, sequentially (an enzymatic step followed by a nonenzymatic rearrangement). As much as possible, it is desirable to reduce biological variability, hence the particular interest currently received by nonenzymatic reactions of hydrolysis or intramolecular catalysis [18][20], Reactions of cyclization-elimination appear quite promising and are being explored in a number of studies. 

Fig. 8.6. Two-step activation of pilocarpine prodrugs [123]. The prodrugs are diesters of pilocarpic acid (8.86). Enzymatic hydrolysis (Reaction a) cleaves the acyl carrier group. The product is a monoester of pilocarpic acid that undergoes cyclization to pilocarpine (8.87) upon intramolecular nucleophilic attack and loss of the alcohol carrier. 

A few examples of ester prodrugs that are activated by intramolecular reactions have been mentioned in Sect. 8.3.1, 8.5.1, and 8.5.2. Here, we discuss the special case of some carboxylic acid esters of active alcohols or phenols that are released following an intramolecular cyclization-elimination reaction [168], The general reaction scheme of such reactions is shown in Fig. 8.8. 

Fig. 8.8. General reaction for the intramolecular activation of prodrugs by cyclization-elimination [168] [169]...

Fig. 8.9. Activation of basic ester prodrugs of 5-bromo-2 -deoxyuridine (8.132) by cyclization of the pro-moiety (Reaction a) and by enzymatic hydrolysis (Reaction b) [170]...

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]). 

The prodrugs examined here undergo a common, two-step mechanism of activation (hence their designation as double prodrugs) first, hydrolysis of the carboxylate group occurs, followed by intramolecular nucleophilic substitution to liberate the active amine (for reviews see [168] [169] [237] [238]). Such reactions of cyclization-elimination are analogous to those discussed in Sect. 8.5.7. 

Fig. 8.22. 2-[(Acyloxy)methyl]benzamides (8.187) as double prodrugs of active amines. Activation is by cyclization-elimination in a two-step sequence, namely hydrolase-catalyzed hydrolysis of the carboxylate moiety followed by an intramolecular nucleophilic substitution with...

Fig. 8.24. Schematic representation of cyclic, double prodrugs of peptides and their mechanism of activation by enzymatic ester cleavage, followed by cyclization-elimination [168][169][238]...

A more complex pathway of activation is seen in N-amino acid derivative of phosphoramidic acid diesters of antiviral nucleosides, as exemplified by prodrugs of stavudine (9.79, Fig. 9.14) [153 -155], The activation begins with a carboxylesterase-mediated hydrolysis of the terminal carboxylate. This is followed by a spontaneous nucleophilic cyclization-elimination, which forms a mixed-anhydride pentacycle (9.80, Fig. 9.14). The latter hydrolyzes spontaneously and rapidly to the corresponding phosphoramidic acid monoester (9.81, Fig. 9.14), which can then be processed by phosphodiesterase to the nucleoside 5 -monophosphate, and by possible further hydrolysis to the nucleoside. 

The cellular effects of FTase inhibition with 3 were observed with concentrations 5000-50,000 higher than the in vitro IC50 for FTase inhibition by carboxylic acid Id. Incomplete hydrolysis of the lactone in vivo could be partially responsible for this discrepancy in activity. However, it was also found that the lactone prodrug used in the context of the doubly reduced peptide isostere, i.e. 3, was chemically unstable at physiological pH. Rapid cyclization to the diketopiperazine 5 significantly reduced FTase inhibitory activity.40 Simple N-alkylation of the reactive secondary amine to give 4 led to loss of activity vs. FTase. To simultaneously protect the compound from both metabolic inactivation (via peptidases) and chemical instability, isosteric replacements of the second amide bond other than methylene-amino were explored. Since the second amide bond in the tetrapeptide inhibitors could be reduced without loss of activity in vitro, peptide bond replacements which were both rigid (olefin) and flexible (alkyl, ether) were synthesized. 

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.. )...

Enol Esters Enol esters are rather stable, bioreversible derivatives of ketones and may be useful as prodrugs of agents containing enolizable carbonyl groups. As shown in Scheme 17, 6 -acetylpapaverine enol esters (107), prepared by acylation of the appropriate Li enolate with the respective anhydride, were hydrolyzed to 6 -acetylpapaverine (108) by esterases present in rat and human plasma, rat liver, and brain tissue supernatants. The intermediate 6 -acetylpapaver-ine cyclizes rapidly to coralyne (109), which has antitumor activity but has... 

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