Cychc peptide

Fig. 3. (a) Chemical stmcture of a synthetic cycHc peptide composed of an alternating sequence of D- and L-amino acids. The side chains of the amino acids have been chosen such that the peripheral functional groups of the dat rings are hydrophobic and allow insertion into Hpid bilayers, (b) Proposed stmcture of a self-assembled transmembrane pore comprised of hydrogen bonded cycHc peptides. The channel is stabilized by hydrogen bonds between the peptide backbones of the individual molecules. These synthetic pores have been demonstrated to form ion channels in Hpid bilayers (71). 

Bacitracin. Bacitracin, a cycHc peptide active against gram-positive bacteria, was discovered in 1943. Bacitracin received dmg certification in 1949 (60—62). Whereas human usage of bacitracin is almost exclusively topical, the vast majority of bacitracin manufactured worldwide is used as an animal feed additive. Reviews of work on bacitracin include its chemistry (63—67), comprehensive aspects (62), medical aspects (62,68), biosynthesis on large enzyme complexes and genetics (69—71), and production (71,72). 

Since then this method has been used for the development of synthetic strategies for many kinds of heterocycles, such as hydantoins [173, 174] or diketopipera-zines [175] as well as natural products [120] cychc peptides [176] and macrocycUc lactones [108]. 

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]. 

Depsipeptide is the leading compound in the cychc peptide class, and is currently in Phase 11 trials in CTCL, with a response rate (RR) of 38% in this disease. MS-275 and tacedinahne (CI-994) have undergone Phase I trials and are now in Phase 11 trials. Other drugs hke MGCD0103, a class-I isotype selective HDACi are in Phase 1 trials [123]. 

As discussed in Section 2.2.1, metalloporphyrins or cychc peptides have been used as a template for synthesis of topologically predetermined metallopeptides and proteins. 

Yamashita T, Kojima Y, Hirotsu K, Ohsuka A. Macrocyclic peptides. Synthesis and structure of a novel dipeptide, (2S, 3 S)-2-(2 -oxo-3 -methylpiperazin- l -oxyl)-propanoic acid, and its use as the unit of cychc peptides. Int. J. Pept. Protein Res. 1989 33 110-114. 

To illustrate the complex behaviour, the ESl-MS spectra of gramicidin S (1141 Da) and cyclosporin A (1202 Da), two cychc peptides of similar size, were stndied as a function of analyte concentration [23]. Over the concentration range studied, the abundance ratio was higher for gramicidin than for cyclosporin. This can be... 

The Uemura system found appHcation in an approach by Hutton towards members of the ustiloxin family of cycHc peptides. While the oxidation employing DET as ligand showed only Httle selectivity, the desired sulfoxide was obtained with a diastereomeric ratio of greater than 50 1 by changing to the (R)-BINOL ligand [23]. 

Ghadiri, M.R., Granja, J.R., Milligan, R.A., McRee, D., Khazanovich, N. Self-assembled organic nanotubes based on a cychc peptide. Nature 366, 324—327, 1993. 

At Hofmann-La Roche the work of K. Vogler and R.O. Studer on cyclic peptide antibiotics, for instance the polymyxins, is particularly noteworthy. At SANDOZ, R.A. Boissonnas was the primary mover of peptide studies. His work on mixed anhydrides (cf. p. 81) was the starting point of a continued research effort in which S. Guttmann, J. Pless. E. Sandrin, R. Huguenin, P.A. Jaquenoud, H. Bossert, W. Bauer and several younger associates participated. After early syntheses of the hormones of the neurohypophysis they became leaders in the synthesis of biologically active peptides on an industrial scale and first made oxytocin, then more complex molecules such as salmon calcitonin or more recently a cychc peptide with somatostatin activity, commercially available. 

The destruxins, cychc peptides containing five amide bonds and one ester bond, were first isolated hyKodaira in 1961 from Oospora destructor 760), hence the naming of these compounds. Well-documented biological effects are insecticidal and phytotoxic activities 758). Furthermore, also antitumor, inotropic, or enzyme inhibitory effects are reported. Destruxin E, for example, was synthesized in 2010 761). 

Koivunen E, Wang B, Ruoslahti E. Phage hhraries displaying cychc peptides with different ring sizes hgand specificities of the RGD-directed integrins. Biotechnol (NY) 1995 13 265-70. 

Use of l-(4-Methoxyphenyl)-2-(4 -methylben lthio)ethyl-amine. Auxiliary 3 has been applied to the formation of cychc peptides and in the synthesis of cytochrome b562. ... 

Cyclocitropsides A and B (133a,b, Figure 8.6), 21-membered homodetic cycHc peptides and cyclocitropside C (133c, Figure 8.6), were recently isolated from... 

Antitnmor componnds, among them cychc peptides, terpenoids, and alkaloids isolated from higher plants 99YZ529. 

Example II MS" on a QTT was used for the identification of beauverolides, cychc peptides from the fermentation broth of Beauveria bassiana, a pathogenic fungus of insects [114]. All MS (ESI-CID-QIT) experiments started from singly charged [M+Hj precursor ions (Fig. 9.22). 

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