Trapoxins activity

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. 

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... 

Trapoxins were discovered by Itazaki et al. in 1990, from the flingas Helicoma ambiens RF-1023. These compounds exhibit detransformation activity against v-sis oncogene-transformed NIH3T3 cells. Trapoxin A has no effect on human red blood cells, even at a concentration of 250pg/ml and incubation at 37 °C for 2 days Trapoxins are known to inhibit histone deacetylase (HDACl) activity" and trapoxin B has no effect on the stability of HDAC6-PP1 complexes or on tubulin acetylation ... 

Antibacterial or antifungal activities of trapoxins and enamidonin was not reported. 

N. Uotani, H. Nakai, A. Terui, S. Yoshimatsu, Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents, /. Antibiot. 43 (1990) 1524. 

Identification of Molecular Target From a comparison with chlamydocin (3), Taunton et al. speculated that the benzyl side chain was not required for detransformation activity, and synthesized a bioactive trapoxin-Uke molecule, K-trap... 

They succeeded in isolating two nuclear proteins (55 and 50kDa) that co-purified with histone deacetylase activity by using trapoxin affinity matrix, which was created by cross-linking K-trap with Affi-GellO (5). Both proteins... 

Trichostatin A (35) is structurally related to suberoylanilide hydroxamic acid (SAHA), a molecule that has reached the market as a therapy for the treatment of cutaneous T-cell lymphoma (CTCL), marketed as vorinostat. ° Hybrid derivatives have been synthesized combining features of trichostatin A and fungal-derived cyclic tetrapeptides such as trapoxin and apicidin, which show subnanomolar activities/ ... 

The depsipeptide FK228 (originally called FR901,228) was isolated [28] by Fujisawa Pharmaceuticals from an extract of the bacteria Chromobacterium violaceum No. 968 on the basis of an assay for phenotypic reversal of ras-transformed tumor cells. The compound was shown to be active in a tumor xenograft animal model, and to have effects [29] similar to the known HDAC inhibitors, trichostatin A and trapoxin. Superficially, FK228 (Fig. 12-7) does not... 

A major challenge associated with the forward chemical genetic approach is the identification of the target of the small molecule probe.Affinity chromatography is a common approach to target identification. This approach requires the attachment of the small molecule probe to a solid support the site of the attachment of the linker must be chosen carefully to avoid the ablation of the probe s biological activity. Trapoxin, is a cyclic tetrapeptide whose... 

Trapoxin B 35 Helicoma amhiens [108] Inhibits en2ymatic activity, and histone deacetylase [109] Schreiber et al. [110]... 

Contemporaneously with the determination of the MOA of trapoxin, a novel cytotoxic microbial agent was reported by Ueda et al. in 1994 from the phytotoxic bacterium Chromobacterium violaceum, and its MOA was determined in 1998 by comparison to the activities of trichostatin This compound, known nowadays by a variety of names, FK-228, depsipeptide, romidepsin or Istodax (Figure 1.8, 72), can be thought of as the prototype structure for the cyclic agents (prodrugs) that contain a dithio bridge that when opened, will complex the zinc atom in the active site of the HDAC enzyme.FK228 was recommended for FDA approval in September of 2009 as a treatment for cutaneous T-cell lymphoma and was launched in the USA in March, 2010. 

The potent biological activity of the cyclic tetrapeptides coupled with their unusual structures has sparked extensive synthetic investigation into these compounds to establish SAR and identify analogues with improved biological profiles. Typically, these syntheses are carried out in solution-phase as in Schreiber s approach to trapoxin (Scheme 4.1). An exception is the total synthesis of microsporin A by Silverman using a solid-phase approach (Scheme 4.2). The Kenner safety-catch sulfonamide resin was used to assemble the linear tetrapeptide 17, followed by resin activation towards nucleophilic attack by alleviation of the sulfonamide with iodoacetonitrile. Boc deprotection of the N-terminus then induced macrocyclization to cleave the natural product from the resin. 

Compounds were titrated in a 1 5 dilution series (10 pM, 2 pM, 400 nM, 80 nM, and 16 nM) averages from duplicate trials are shown, except for known HDAC inhibitors, trichostatin A and trapoxin A. Concentration of compound required to produce 50% p21 promoter activity by psammaphn A (152). 

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