Apicidin

Final examples of applications of our results (91CPB1905, 99H1157) in 1-hydroxytryptophan chemistry come from the work of Boger and co-workers (99JA6197) on the synthesis of HUN 7293 (293, Scheme 46) (96MI69) and from Kitahara and co-workers (200 IHl) on the synthesis of apicidin (301) (96TL8077). 

No 1 -hydroxytryptamine or -tryptophan alkaloid that lacks a stabilizing group on the indole nucleus has been reported yet. However, isolation of37,38a, 38b, HUN-7293 (293) (96MI69), and apicidin (301) (96TL8077) offers indirect evidence for the existence of 1-hydroxytryptamines and/or 1-hydroxytryptophans in living organisms. We believe their isolation will be reported in the near future. 

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. 

Histones of Plasmodium falciparum represent a new target for antimalarials. Apicidin [Cyclo (N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-oxodecanoyl] is a potent, broad spectrum antiprotozoal agent. The target of apicidin is Histone deacetylases HDA (Darkin Rattray et al., 1996), evidenced as hyperacetylation of histones in treated parasites. 

Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, Cannova C, Meinke PT, Colletti SL, Bednarek MA, Singh SB, Goetz MA, Dombrowski AW, Polishook JD, Schmatz DM (1996) Apicidin A novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA 93(23) 13143-13147... 

Apicidins - coccidiostats and antimalarial peptides 8 Microsporin A - histone deacetyiase inhibitor 219... 

Apicidin (Fig. 10) was first isolated from fimgus Fusarium pallidoroseum ATCC 74289, MF6040, from Acacia sp. (collected from Santa Rosa National Park Costa Rica) as an antiprotozoal agent. It was found that apicidin was active against wide range of protozoans specially Apicomplexan parasites. The underlying mechanism for this cidal activity was found out to be HDAC inhibition of protozoas. It was also observed that they were very potent HDAC inhibitors when compared to similar cyclopeptide inhibitors known at that time (Table 5). 

Apicidin was the first HDAC inhibitor discovered without a classical zinc binding group. It was almost 30 times more active than HC toxin, which had a similar structure with keto-epoxide as the zinc... 

Fig. 10. Chemical structure of apicidin (left), the potency of the different apicidins on HeLa nuclear extract.

Table 5. Comparison of apicidin with other HD AC inhibitors.

Fig. 11. These two HDAC inhibitors developed by Jones and coworkers with apicidin structure as the inspiration.

Table 8. The EC50 values of FR23522 with HDAC-3 compared to apicidin. ...

The use of plants for medicinal purposes is an ancient practice. Nature, with its wealth of traditional knowledge has been the source of inspiration for numerous drugs currently used for the improvement of life as well as treatment for a cure. Considering the beneficial role of many plants and fruits, they were included in the human diets. In many instances, the knowledge of the underlying mechanism of action of a particular natural product is incomplete. Continuous investigation can lead to new mechanisms and new structures, which may open up entirely new windows and perspectives. For instance, before the discovery of apicidin and bispyri-dinium diene, it was believed that unless there is a classical chelator for zinc ion, it cannot be a HDAC inhibitor. SAHA has been approved by FDA, which is inspired from the natural product trichostatin. The natural product, romidepsin has also been approved by FDA and many are on clinical trials. Currently, isozyme-selective inhibition for HDAC is at its nascent stage. The invention of some novel molecules or invention of some novel natural product structures with synthetic modifications will solve the problem. 

Kwon SH, Ahn SH, Kim YK, Bae GU, Yoon JW, Hong S, Lee HY, Lee YW, Lee HW, Han JW. (2002) Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. J Biol Chem 111 2073-2080. 

Colletti SL, Myers RW, Darkin-Rattray SJ, Gumett AM, Dnlski PM, Galuska S, Allocco JJ, Ayer MB, Li C, Lim J, Crumley TM, Cannova C, Schmatz DM, Wyvratt MJ, Fisher MH, Meinke PT. (2001) Broad spectrum antiprotozoal agents that inhibit histone deacetylase Strnctnre-activity relationships of apicidin. Part 2. Bioorg Med Chem Lett 11 113-117. 

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

Myers, R.W., Dulski, P.M., Crumley, T.M., Allocco, J.J. et al. (1996) Apicidin A novel antiprotozoal agent that inhibits parasite HDAC. Proceedings ofthe National Academy of Sciences of the United States of America, 93, 13143-13147. 

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... 

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