Apicidin cyclic tetrapeptide

HDAC inhibitors are potentially useful for the treatment of infectious diseases. This is most well documented with the malaria parasite. Merck and GlaxoSmithKline have reported [17] a series of inhibitors based on the apicidin cyclic tetrapeptide natural product scaffold with some selectivity for Plasmodium over human HDACs. In the antiviral field, HDAC inhibitors were recently shown [18] to drive the expression of latent reservoirs of HIV, thus facilitating their eradication. Outside the human therapeutic areas, there is an interesting recent patent [19] by Dow who has independently isolated FK228, a HDAC inhibitor, from a Madagascar plant and shown that it is an antiinsecticidal agent. 

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. 

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]. 

Cyclic tetrapeptide Apicidin Apoptosis and cell cycle arrest... 

Singh SB, Zink DL, Liesch JM, Mosley RT, Dombrowski AW, Bills GP, Darkin-Rattray SJ, Schmatz DM, Goetz MA. Structure and chemistry of apicidins, a class of novel cyclic tetrapeptides without a terminal alpha-keto epoxide as inhibitors of histone deacetylase with potent antiprotozoal activities. J. Org. Chem. 2002 67 815-825. 

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/ ... 

Like TPX, the microbially derived HDAC inhibitor depudecin 4 was also isolated based on its ability to reverse the transformed cellular phenotype of tumor cells. This diepoxide-containing natural product induced a flat phenotype in Kj-ras-transformed NIH 3T3 cells and was further characterized as an HDAC inhibitor by its ability to induce the accumulation of acetylated histones [13]. Apicidin (APC) 3, a cyclic tetrapeptide HDAC inhibitor with... 

Recently, Ghadiri has reported modified cyclic tetrapeptides with alterations in the peptide backbone. It was proposed that the most hioactive conformation of apicidin contains a cis amide rotamer and this was probed by incorporating a triazole isostere for the amide. The 1,5-triazole 33 (Figure 4.13) showed decreased isoform selectivity compared to apicidin, more potently inhibiting HDAC6 and HDAC8 than the natural product. 

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