Peptide hydroxamates, preparation

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). 

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

The properties of natural macrocycles, the cyclodextrins, has stimulated interest in the preparation of synthetic macrocycles. Three basic types have been made macrocyclic amines, cyclophanes, and cyclic peptides. Hersh-field and Bender (33) prepared a bicyclic amine with hydroxamate sub-... 

Application and Principle This procedure is used to determine transglutaminase activity in preparations derived from Streptoverticillium mobaraense var. The assay is based on the enzymatic formation of a glutamic acid y-hydroxamate in a glutaminyl residue in the substrate peptide with another substrate, hydroxylamine. The amount of the glutamic acid y-hydroxamate formed as a red complex with ferric ion in acidic conditions at 37° is measured spectrophotometrically. 

Rosse et al. described the oxidation of the resin-bound /3-sulfenyl hydroxamic acids A -sulfonyloxaziridines <2001SL538>. For example, oxidation of 143 with 33 afforded the corresponding sulfoxide 144 in 71% yield after cleavage of the resin with TFA. Apfel et al. in the preparation of some potent peptide deformylase inhibitors and antibacterial agents employed a similar transformation<2000JME2324>. 

Apart from the syntheses of peptides, the Nps group has found useful application in the preparation of aminopenicillins,t l of O-sulfated (3-lactam hydroxamic acids,t and of the (3-lactone antibiotic (-f)-obafluorin.t l... 

The first synthesis of a siderophore was the preparation of ferrioxamine B over 20 years ago in order to confirm the chemical structure of this natural product67). Synthesis of the other hydroxamate containing siderophores has as a central problem preparation of the constituent to-N-hydroxy amino acid in an optically pure form. The most important such subunit in hydroxamate siderophores is Ns-hydroxy ornithine. This is a chiral building block of the diketopiperazine-containing siderophores (rhodo-torulic acid 68), dimerum acid 69), coprogen 70) and coprogen B 69>), the cyclic hexa-peptides of the ferrichrome family27), the fusarinines 71 -73) and the antibiotic ferri-chrome derivatives albomycines Sl5 S2 and e 61-62). 

The THP-based hnker can be modified in such a way as to allow fhe synthesis of hydroxamic acids 49, as outlined in Scheme 24. Linker 48 has played a role in the solid-phase synfhesis of matrix metalloproteinase inhibitors [52], Alternative linkers that yield hydroxamic acids after release have been used in connection with peptide chemistry, as well as for the preparation of combinatorial compounds [53-58]. 

The method has been widely used and extended to the preparation of A-9-fluorenylmethoxycarbonyl (Fmoc)-o -amino aldehydes in good yields [83,92-94]. Fmoc- and Boc-/3-amino aldehydes, which are key intermediates in the synthesis of carba [16,17] and carbaza peptides [33] (see later), are also prepared in good yield from the corresponding hydroxamates [95]. In this case, the Weinreb amide can be obtained in high yield by direct Wolff rearrangement of a diazomethylketone with A,0-dimethylhydroxylamine. 

Primary peptide amides are prepared on the Rink linker 5. Although not covered in this chapter, secondary amides have been prepared on the linker described by Barany and co-workers (43). Peptide aldehydes have been prepared on the oxazolidine linker (44). The trityl linker (45) has also been used for the preparation of protected peptide fragments and other specialized C-terminal endings such as hydroxamic acids (46). 

Amidation. A number of other various amidation reactions have been conducted using BOP. Such preparations include A) O-dimethyl hydroxamates of amino acids and peptides (precursors of chiral peptidyl aldehydes), heterocyclic amide fragments in the synthesis of macrolide and porphyrin models, dan-sylglycine anhydride as a mixed sulfonic-carboxylic imide by dehydration-cyclization of dansylglycine, and selective monoacylation of heterocyclic diamine in carbohydrate series (eq 9). ... 

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