Trapoxins

Like Class I HDACs, all Class II HDACS are inhibited by trichostatin A (TSA). However, unlike other family members, HDAC6 is uniquely resistant to the potent HDAC inhibitors trapoxin-B (Furumai et al, 2001) and sodium butyrate as a... 

HDACll lies at the boundary between these two classes. HDACll contains a catalytic domain situated at the N-terminus with proven HDAC activity that can be inhibited by trapoxin (a TSA analog). HDACll was found not to reside in any of the known HDAC complexes (Sin3, N-CoR/SMRT), possibly indicating a biochemically distinct function of HDACl 1 (Gao et al, 2002). 

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... 

KijimaM, YoshidaM, SugitaK, Horinouchi S, BeppuT(1993)Trapoxin, an antitumor cychc tetrapeptide, is an irreversible inhibitor of mammahan histone deacetylase. J Biol Chem 268(30) 22429—22435 Kim A, Dean A (2004) Developmental stage differences in chromatin subdomains of the P-globin locus. Proc Natl Acad Sci USA 101 7028-7033... 

Trapoxin (Fig. 16) is a fimgal metahohte isolated from Helicoma ambiens. It is an irreversihle HDAC inhihitor with nanomolar potency (Tahle 10) similar to chlamydocin and toxins. Trapoxin also has the ability to act on v-5 5-transformed N1H3T3 cells and reverse them into their normal cells. 

Fig. 16. Chemical structures of natural product (a) trapoxin A and (b) trapoxin B. Table 10. IC50 values of trapoxin A and trapoxin B against HDAC isoforms.

Taunton J, Collins JL, Schreiber SL. (1996) Synthesis of natural and modified trapoxins, useful reagents for exploring histone deacetylase function. JAm Chem Soc 118 10412-10422. 

Jung, M., Hoffmann, K., Brosch, G. and Loidl, P. (1997) Analogues of trichostatin A and trapoxin B as histone deacetylase inhibitors. Bioorganic Medicinal Chemistry Letters, 7, 1655-1658. 

Kijima, M., Yoshida, M., Sugita, K., Horinouchi, S. and Beppu, T. (1993) Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. The Journal of Biological Chemistry, 268, 22429-22435. 

In 1993, Yoshida et al. pubhshed trapoxin (TPX, Fig. 3), a fimgal product, which, in contrast to TSA, is an irreversible inhibitor of mammalian histone deacetylase [38]. When the epoxide moiety is reduced to the corresponding primary alcohol, HDAC inhibiting activity is completely lost. This observation emphasizes the importance of the oxirane ring, which most likely binds irreversibly via ring opening at the activated 2-position to a nucleophihc active site residue. 

Since the discovery of trapoxin (TPX), a niunber of related cyclic peptides have been found to also demonstrate HDAC inhibitory activity, explaining in part the phenotypic effects previously described for these compounds. One... 

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). 

Cyclic tetrapeptide with Trapoxin A Irreversible cell cycle arrest... 

Sternson SM, Wong JC, Grozinger CM, Schreiber SL, Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin, Org. Lett., 3 4239-4242, 2001. 

Structure of panobinostat 80 also based upon the fungal metabolite trapoxin A 92 and vorinostat 93. 

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