Peptide hydroxamic acids

Peptide hydroxamates or hydroxamic adds have been shown to be potent enzyme inhibitors. Their target enzymes, the matrix metalloproteinases (MMPs), are a family of endopeptidases with a catalytic domain that houses a zinc atom as a coenzyme. The ability of the hydroxamate functionality to chelate such metal ions (25) and thus disrupt coenzyme activity is believed to be the reason for inhibitory activity. 

Much of the research carried out on peptide hydroxamates has involved their isolation from micro-organisms or biological tissues, but to isolate sufficient quantities of pure material for biological testing by this method can involve manipulating large volumes of solvent and can be difficult and time-consuming. 

RgureS. Generation of a peptidyl hydroxamic acid from a succinimide ester. 

Rgure7. Strategy for the generation of resin-bound hydroxylamine. 

Protocol 8. /V-Fmoc-aminooxy-2-chlorotrityl polystyrene resin for the synthesis of peptide hydroxamic acids 

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Peptide a-oxo acids, a-oxo esters, and a-oxoamides are also potent inhibitors of cysteine and serine proteases. Oxidation of peptide a-substituted carboxylic acid derivatives provides a general route to these compounds (Section 15.1.5). Peptide hydroxamic acids have been shown to be inhibitors of metalloproteinase and some have been reported to have antibiotic, anticarcinogenic, and antiviral activities. Peptide hydroxamic adds may be prepared by solution and solid-phase methods using a variety of resins (Section 15.1.6). a-Aminoboronic acids may be prepared by several routes and are reported to be inhibitors of aminopepti-dases. Procedures have been developed for their incorporation into peptides (Section 15.1.7). 

Independently, simple peptide hydroxamic acids (Z-Gly-L-Leu-NHOH and others) were first observed to inhibit the metalloprotease thermolysin in 1977 9,101 The structure was then further improved to the hydroxamidoalkylmalonyl-peptide moiety by considering the substrate specificity of thermolysin and other metalloproteases 10-121 A summary of hydroxamic acids reported to be inhibitors of various metalloenzymes up to 1983 has been published 131 In 1985 hydroxamido-benzylsuccinyl-L-alanine (kelatorphan) was synthesized and found to be one of the best enkephalinase inhibitors 141... 

Synthesis of Peptide Hydroxamic Acids by Solution-Phase Methods... 

In an early report on peptide hydroxamic acids as metalloprotease inhibitors, the peptide acid (Z-Gly-L-Leu-OH) was converted into the V-hydroxysuccinimide ester using DCC, which was subsequently reacted with hydroxylamineJ10 More reactive condensing reagents such as BOP can form the hydroxamic acid directly from the carboxylic acid and hydroxylamine via an intermediate HOBt ester. A number of hydroxamic acids has been synthesized by the treatment of the corresponding methyl esters with hydroxylamine in the presence of KOH 122 this reaction requires careful choice of reagent concentrations and ratios. In addition, the precursor carboxylic acid is treated with diazomethane to make the methyl ester. The use of diazomethane makes the procedure hazardous, but should be useful in special cases that require a better cost performance. 

Table 1 Selected Peptide Hydroxamic Acids Synthesized via the Hydrogenolysis of O-Benzy I hydroxamates in the Presence of Pd/BaSOj471...

Combinatorial Synthesis Of Peptide Hydroxamic Acids with Hydroxylamine-Linked Resin... 

Scheme 9 Preparation of a Hydroxylamine-Linked Wang Resin and Its Use for Peptide Hydroxamic Acid...

Recover the peptide hydroxamic acid using standard procedures. 

Che 1997 Chen, J.J. and Spatola, A.F., Solid Phase Synthesis of Peptide Hydroxamic Acids, Tetrahedron Lett., 38 (1997) 1511-1514. 

Relatively few heteroaromatic N-oxides occur in nature. The chemistry of compounds that contain the oxidized peptide bond (the so-called hydroxamic acids) and their role in iron metabolism have been reviewed (67SC1443). Another review deals with the natural occurrence of N-oxides (68MI1). 

Knobler Y, Bittner S, Frankel M (1964) Reaction of N-carboxy-alpha-amino-acid anhydrides with hydrochlorides of hydroxylamine O-alkylhydroxylamines + amines syntheses of amino-hydroxamic acids amido-oxy-peptides + alpha-amino-acid amides. J Chem Soc 3941... 

Pseudopeptidic Hydroxamic Acids and N-formyl-N-hydroxylamines Non-peptidic Templates... 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

TR Govindachari, S Rajappa, AS Akerkar, VS Iyer. Hydroxamic acids and their derivatives IV. Further studies on the use of esters of pivalohydroxamic acid for peptide synthesis. Tetrahedron 23, 4811, 1967. 

Hydroxamates have been observed in the water in the Bay of Quinte, a eutrophic bay of Lake Ontario, and are believed to be produced by blue-green algae (76). Simpson and Neilands (77) have identified schizokinen, a hydroxamic acid derivative of citric acid as an extracellular product of the blue-green algae, Anabaena sp. However, not all Anabaena produce hydroxamates, Walsby (78) has shown that Anabaena cylindrica releases a large pigmented, peptide-containing material which complexes iron. As yet these peptides have not been examined for ability to complex the actinides. 

Exochelins (322,323) are peptidic siderophores imm Mycobacterium spp. (see also below mycobactins). Exochelin MS (16) from M. smegmatis comprises (3-Ala and three W -OHOm units, which are linked by their atoms to acyl groups thus forming hydroxamic acids. 

CHAP cyclic hydroxamic acid-containing peptide... 

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