Cyclic hydroxamic acid-containing peptide

CHAP cyclic hydroxamic acid-containing peptide... 

Hydroxyamic acids/ cyclic tetrapeptide Cyclic hydroxamic acid-containing peptide (CHAP) Cell cycle arrest... 

Replacing the electrophilic epoxy ketone moiety in TPX by a reversible zinc chelator such as a hydroxamic acid was carried out by Yoshida et al. (Fig. 6) [51]. This modification led to a low nanomolar reversible inhibitor of the HDACl enzyme. Several other cyclic tetrapeptides containing the epoxyketone feature, such as chlamydocin, were converted into their hydroxamic acid coimterparts as well [52]. Additionally, the introduction of reversed hydroxamic acids (-N(OH)COR, with R = H or Me) onto the structure of Cyl-1 was reported to give potent HDAC inhibitors as illustrated in Fig. 6 [53]. Generally, the most potent inhibitors were the examples with R = H and m = 2. Apicidin, a cychc peptide more remotely related to TPX, exhibits potent antiprotozoal activity via HDAC inhibition in parasites [54]. 

Peptide antibiotics. Antibiotics with linear or cyclic oligopeptide structures containing not only L- amino acids but often also unusual, non-proteinogenic amino acids. Homopeptides are built up exclusively of amino acids (e.g., gramicidins), the so-called heteropeptides also contain other structural elements, e.g., hydroxamic acids. Macrocyclic Ra. containing one or more ester bonds in the ring are known as peptide lactones (e.g., hormaomycin) or depsipeptides (e.g., valinomycin). 

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). 

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