Reactivity of Asparagine and Glutamine Residues

Asparagine residues (and glutamine residues, see below) are sites of particular instability in peptides. As will be exemplified below, rates of degradation at asparagine residues are markedly faster (tenfold and even much more) than at aspartic acid residues. As reported, the t1 2 values for the internal asparagine in a large number of pentapeptides ranged from 6 to 507 d under physiological conditions of pH and temperature, while those of internal Gln ranged from 96 to 3409 d 6 . Degradation...

Eej

Chj-nh-ch2-cooh H Se CHj CH(NHj) COOH a) See www.chem.qmul.ac.uMupac AminoAcid . ) See Footnote e in Table 6.1.c) This name and the corresponding three-letter symbol are not recommended. d) Homoserine lactone can form only one peptide bond, namely with its amino group. Its only position in a peptide is therefore the C-termi-nus. e) Pyroglutamic acid can form only one peptide bond, namely with its carboxy group. Its only position in a peptide is therefore the N-terminus. f) One-letter symbol....

Prodrugs for Improved Solubility and Absorption

Preliminary information useful in prodrug design has been obtained with amino acids attached to model aromatic amines. Thus, N-(naphthalen-2-yl) amides of amino acids (6.1, R side chain of amino acid, R' H) proved to be of interest as test compounds to monitor peptidase activity such as ami-nopeptidase M (membrane alanyl aminopeptidase, microsomal aminopepti-dase, EC 3.4.11.2) 16 17 . In the presence of purified rabbit kidney amino-peptidase M or human cerebrospinal fluid (CSF) aminopeptidase...

Principles of Prodrug Design

Prodrugs will receive much attention in this book (Chapt. 4, 6, 8, 9, and 11 ). It is, therefore, appropriate in this introductory chapter to clarify some definitions and review various aspects of prodrug design and research 11- 22 . 1.2.1. Definition and Objectives Prodrugs are defined as therapeutic agents that are inactive per se but are predictably transformed into active metabolites. As such, prodrugs must be contrasted with soft drugs, which are active per se and yield inactive...

Info

Hydrolysis pathways in the metabolism of epicainide (4.29). Pathway a direct hydrolysis of the secondary amide function. Pathway b hydrolysis of the primary amide (4.30) formed by oxidative N-dealkylation. Pathway c hydrolysis of the intermediary metabolite (4.31) formed by N-deethylation and subsequent oxidation of the pyrrolidine moiety 17 . The biotransformation of clofexamide (4.33, Fig. 4.4), a compound with anti-inflammatory and antidepressant activities, was investigated in...

External Factors Influencing Stability

The stability of the -lactam ring is strongly influenced by the molecular factors discussed above and, obviously, also by external factors such as biological fluids or pharmaceutical matrices. Some of these factors are discussed below. 5.2.6.1. Buffer-Catalyzed Hydrolysis The presence of buffers often enhances the rate of hydrolysis of -lactam antibiotics, i.e., the rate constant of degradation increases linearly with an increase in buffer concentration at constant pH 86 125-130 . Acetate,...

Formation of Lactam Metabolites

Azaheterocycles can undergo oxidation at endocyclic a-C-atoms, forming metabolites with a lactam structure. In some cases, ring-opened metabolites (i.e., rn-amino acids) can also be detected. One might expect that these metabolites are the result of the hydrolytic cleavage of the lactam bond. However, comprehensive studies have revealed another mechanism for ring-cleavage (Fig. 5.23). A detailed discussion of this mechanism can be found elsewhere (Chapt. 6 in 184 ). Briefly, the first step is...

Pseudopeptides

As stated above, we define pseudopeptides as compounds having a modified peptide backbone, namely with at least one peptide bond replaced by a bioisosteric surrogate (summarized in Table 6.7) 139 181 234 . Such surrogate groups are nonhydrolyzable by nature, or hydrolyzable only under severe conditions in the case of the SO2-NH bond. In the vast majority of published pseudopeptides, only one or a very few peptide bonds had been replaced and most monomeric units are amino acids, meaning that...

Simple Lactam Derivatives

This section is devoted to the metabolic fate of lactam rings with five or more members but no additional heteroatoms, a group of structures we categorize as simple lactams. The simplest five-membered lactam is pyrrolidin-2-one (5.57), the cyclic form of y-aminobutyric acid (GABA (5.58)), an important inhibitory neurotransmitter in the central nervous system (CNS). Systemically administered GABA does not produce pharmacological effects since it does not cross the blood-brain barrier. In...

Imides 441 Linear Imides

Linear or acyclic imides are rarely found among drugs and agrochemicals because they are relatively unstable, being readily reduced, photolyzed, or hydrolyzed. The susceptibility of linear imides to undergo hydrolysis may be useful in the design of prodrugs of amides. For example, Kahns and Bundgaard 113 explored the potential usefulness of N-acylamides as prodrugs. For this, they examined the kinetics of hydrolysis and plasma-catalyzed degradation of a number...

References

Elander, 'The beta-Lactam Antibiotics Past, Present, and Future', Antonie van Leeuwenhoek 1999, 75, 5-19. 2 a J. H. C. Nayler, 'Early Discoveries in the Penicillin Series', Trends Biochem. Sci. 1991, 16, 195-197 b J. H. C. Nayler, 'Semi-Synthetic Approaches to Novel Penicillins', Trends Biochem. Sci. 1991, 16, 234-237. 3 W. D rckheimer, F. Adams, G. Fischer, R. Kirrstetter, 'Recent Developments in the Field of Cephem Antibiotics', in 'Advances in Drug Research', Vol. 17,...

Localization and Some Physiological Roles of Esterases

Localization of Carboxylesterases Carboxylesterases EC 3.1.1.1 can be detected in most mammalian tissues. Besides organs with high carboxylesterase activity such as liver, kidney, and small intestine, esterase activity is present, e.g., in the brain, nasal mucosa, lung, testicle, and saliva. Compared to rat plasma, human plasma contains little carboxylesterase, its esterase activity being essentially due to cholinesterase 61 73 79 89-91 . Most tissues have well-defined patterns of...

Aci Basw Catalyze Degradation Of Penicillin

Different mechanisms of hydrolysis of the b-lactam bond, namely a base-catalysis, b acid-catalysis, and c general base catalysis by H2O lyzed by different mechanisms. For amides, the rate-limiting step is the breakdown of the tetrahedral intermediate, whereas, for b-lactams, the rate-limiting step is the formation of the tetrahedral intermediate Fig. 5.6,a 76 . Since the rate-limiting step does not involve C-N bond fission, opening the ring does not lower the activation energy in the...

Amide Bonds That Link Two Aromatic Systems

Having discussed amides that carry an aromatic group on either the nitrogen or the carboxy side of the amide bond i.e., anilides or benzamides, respectively , we continue our presentation with compounds in which the amide bond links two aromatic systems. The simplest structure in this class is N-phenylbenzamide 4.154 . The influence of the nature and position of substitution on the rate of hydrolysis of a series of N-phenylbenzamides was investigated in mouse and sheep liver homogenates, with...

Cooh

Metabolism of the pyrrolidine ring according to the mechanism in Fig. 5.23. Nicotine 5.86 , tremorine 5.89 , and prolintane 5.90 are metabolized to both lactam and w-ami-no acid derivatives 185-187 . Due to steric hindrance next to the N-atom, piromidic acid 5.91 yields only the amino acid derivative 188 . known about the hydrolytic stability of the lactam metabolites in the examples given above. This may be due in part to the difficulty in separating and detecting the resulting...