Cyclic tetrapeptide

One of the first HDAC inhibitors to be identified and characterized was sodium butyrate, where it was found to alter the histone acetylation state (Riggs et al, 1977), and further determined to inhibit HDAC activity both in vitro and in vivo (Candido et al, 1978). Almost a decade later trichostatin A (TSA), a fungistatic antibiotic, was found to induce murine erythroleukemia cell differentiation (Yoshida et al, 1987). To date, a wide range of molecules have been described that inhibit the activity of Class I and Class II HDAC enzymes, and with a few exceptions, can be divided into structural classes including (1) small-molecule hydroxamates, such as TSA, suberoylanilide hydroxamic acid (SAHA), scriptaid and oxamflatin (2) short-chain fatty-acids, such as sodium butyrate, sodium phenylbutyrate and valproic acid (VPA) (3) cyclic tetrapeptides, such as apicidin, trapoxin and the depsipeptide FK-228 and (4) benzamides, such as MS-275 and Cl-994 (for reviews see Remiszewski et al, 2002 Miller et al, 2003). Some of these molecules are represented in Fig. 4. 

Furumai R, Komatsu Y, Nishino N, Khochbin S, Yoshida M, Horinouchi S (2001) Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proc Natl Acad Sci U S A 98(l) 87-92... 

Fig. 12. Chemical structure of chlamydocin, a cyclic tetrapeptide inhibitor.

Nakao Y, Yoshida S, Matsunaga S, Shindoh N, Terada Y, Nagai K, Yamashita JK, Ganesan A, van Soest RWM, Fusetani N. (2006) Azumamides A-E Histone deacetylase inhibitory cyclic tetrapeptides from the marine spong Mycale izuensis. Angew Chem Int Ed 45 7553-7557. 

Kijima M, Yoshida M, Susita K, Horinouchi S, Beppu T. (1993) Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 30 22429-22435. 

Figure 1.6 Selected small molecule inhibitors of HDACs. Compounds 7 and 8 are short-chain fatty acids, compounds 9 and 10 are hydroxamic acids, compounds 11 and 12 are cyclic tetrapeptides, compound 13 is cyclic tetrapeptide analog and compound 14 is a benzamide.

Nishino, N., Jose, B., Okamura, S., Ebisusaki, S., Kato, T, Sumida, Y. et al. (2003) Cyclic tetrapeptides bearing a sulfhydryl group potently inhibit histone deacetylases. Organic Letters, 5,5079-5082. 

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]. 

Various classes of short-chain fatty acids, cyclic tetrapeptides and benza-mides have also been in chnical trials (Table 4). 

Other cyclic tetrapeptides have also been isolated by Japanese workers and AM toxins I, II, and III, isolated from Alternaria mail., are extremely toxic to certain plant species (9.10). These are constructed of L- i-hydroxyisovaleric acid, L-alanine, c-amino-acrylic acid and, in AM toxin I, L-6(-amino- -( .-methoxyphenyl)-valeric acid. The phenyl residue in AM toxin II is L-t(-amino-S-phenylvaleric acid, while in AM toxin III, it is L-ol-amino-( .-hydroxyphenyl)valeric acid (Figure 2), All the AM toxins produce leaf spot, or necrosis, in apple but as might he expected slight change in substitution (R-group) on the phenyl ring radically alters the specific activity of the molecule. Both AM toxin I and III induce interveinal necrosis in the "Indo" apple cultivar, which is also highly susceptible to A. mail. at concentrations as low as 0.1 pph within 18 h after treatment. In contrast, the resistant apple cultivar "Jonathan" is only affected by 1 ppm of AM toxin I and 10 ppm of AM toxin III. 

Contrary to the cyclic tripeptides, cyclic tetrapeptides are found as natural products such as chlamydocin,1208-2111 HC-toxin,1212-2131 WF 3161,1214,2151 or tentoxin,173,216-2191 which all exhibit interesting pharmacological properties, e.g. phytotoxic (HC-toxin and tentoxin) or can-cerostatic activities (chlamydocin) (Scheme 8). Correspondingly, this class of compounds has been studied extensively in terms of synthesis and conformational preferences. 

Scheme 8 Structures of the Cyclic Tetrapeptides Chlamydocinl208-2111 and Tentotoxin173 -1 219 ...

As an alternative, a rather unusual strategy for the synthesis of cyclic tetrapeptides utilizes the deprotonation of the backbone amides of cyclic tetrapeptides with LDA and subsequent alkylation to produce N-alkylated peptides, which can be achieved regio- and... 

Table 2 Examples for the Synthesis of Cyclic Tetrapeptides[1W3J7J4U10-233-243"247 ...

Biologically active cyclic tetrapeptides (4-7) showed (1) a conformational preference in the epoxyketone moiety (2) no n -+ jt peptide bond contribution to As near 288 nm and (3) anti-octant perturbation of oxirane ring. 

Oxamflatin (iii) cyclic tetrapeptides containing a 2-amino-8-oxo-9,10-epoxy-decanoyl (AOE) moiety such as trapoxin (iv) cyclic tetrapeptides without an AOE moiety such as apiddin and FR901228 (depsipeptide) (v) benzamides (Fig. 2 and Table 1). 

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

Cyclic tetrapeptide Apicidin Apoptosis and cell cycle arrest... 

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