WF-3161,7 apicidin,8 and the recent depsipeptide FK228
(formerly FR901228)9 are naturally occurring HDAC inhibi-
tors (Figure 1). Inhibitors such as butyrate,10 valproate,11
suberoyl anilide hydroxamic acid,12 analogues of TSA,13 and
benzamide derivatives of MS-27514 were prepared through
synthetic methods.
revealed that the biological activity of these inhibitors can
be changed by the number of amino acids constituting the
ring structure, the pattern of the combination of amino acid
chirality, and the side chain structure of each amino acid.
Recently, we demonstrated that FK228 serves as a stable
natural prodrug that inhibits class I HDAC enzymes. FK228
is activated by the glutathione-mediated reduction of the
disulfide bond to sulfhydryl, and this sulfhydryl group is
coordinated to the zinc metal ion present in the HDAC
binding pocket.16 In this work, we report a new series of
HDAC inhibitors, sulfur-containing cyclic peptides (SCOPs),
by replacing the L-Aoe [(2S,9S)-2-amino-8-oxo-9,10-epoxy-
decanoic acid] moiety of natural cyclic tetrapeptides with
L-2-amino-7-mercaptoheptanoic acid (L-Am7). On the basis
of glutathione-mediated cellular reduction of disulfide bonds,
we synthesized SCOPs as homodimers (disulfide dimers) and
disulfide hybrids with several mercaptans.
Crystal structure studies on histone deacetylase-like protein
(HDLP) revealed the presence of a zinc metal ion at the
bottom of a narrow binding pocket, and the deacetylation
proceeds through an oxyanion intermediate (Figure 1a).17
Preliminary requirement for an effective inhibitor of HDAC
is an efficient zinc-coordinating ligand connected to a
hydrophobic scaffold by means of a spacer. The HDAC
activity is varied with the binding nature of the zinc-chelating
functionality, the length of the spacer, and the interactions
of the groups present in the scaffold to the rim of the active
site pocket. In our previous work, we found that the cyclic
tetrapeptide is effective as a scaffold for potent HDAC
inhibitors. CHAP 31, one of the several cyclic tetrapeptide
inhibitors we synthesized having the same scaffold as that
in natural cyclic tetrapeptide Cyl-1 and hydroxamic acid as
a functional group, is an excellent inhibitor of HDAC and
showed good selectivity during animal tests. Hydroxamic
acid can chelate with zinc ion in HDAC effectively (Figure
1b). Because of the high HDAC inhibitory activity of FK228
and the increased activity in the presence of dithiotritol
(DTT), which is known to reduce disulfide bonds, we
speculate that a synthetic compound with a tetrapeptide
scaffold and sulfhydryl zinc binding moiety can give better
results ascribed to the strong ligation of zinc ion to sulfide
ion (Figure 1c). Further, sulfhydryl-containing compounds
such as thermolysin and carboxypeptidases are known as
inhibitors of metalloproteases.18 For these reasons, we
proposed to synthesize new inhibitors for HDAC containing
a natural cyclic tetrapeptide scaffold and a sulfhydryl group
Figure 1. Structures of naturally occurring HDAC inhibitors and
CHAP31.
We have reported a group of synthetic HDAC inhibitors
(cyclic hydroxamic acid containing peptides; CHAPs) having
a cyclic tetrapeptide scaffold and hydroxamic acid as the
zinc-binding functional group.15 The SAR study on CHAPs
(4) Closse, A.; Hugenin, R. HelV. Chim. Acta 1974, 57, 533-545.
(5) Shute, R. E.; Dunlap. B.; Rich, D. H. J. Med. Chem. 1987, 30, 71-
78.
(6) Hirota, A.; Suzuki, A.; Aizawa, K.; Tamura, S. Biomed. Mass.
Specrom. 2974, 1, 15-19.
(7) Umehara, K.; Nahahara, K.; Kiyota, S.; Iwami, M.; Okamoto, M.;
Tanaka, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1983, 36,
478-483.
(8) (a) Darkin-Rattray, S. J.; Gurnett, A. M.; Myers, R. W.; Dulski, P.
M.; Crumley, T. M.; Allocco, J. J.; Cannova, C.; Meinke, P. T.; Colletti, S.
L.; Bednarek, M. A.; Singh, S. B.; Goetz, M. A.; Dombrowski, A. W.;
Polishook, J. D.; Schmatz, D. M. Proc. Natl. Acad. Sci. U. S. A. 1996, 93,
13143-13147. (b) Meinke, P. T.; Liberator, P. Curr. Med. Chem. 2001, 8,
211-235. (c) Han, J. W.; Ahn, S. H.; Park. S. H.; Wang, S. Y.; Bae, G.
U.; Seo, D. W.; Known, H. K.; Hong, S.; Lee, Y. W.; Lee, H. W. Cancer
Res. 2000, 60, 6068-6074.
(9) (a) Ueda, H.; Nakajima, H.; Hori, Y.; Fujita, T.; Nishimura, M.; Goto,
T.; Okuhara, M. J. Antibiot. 1994, 47, 301-310. (b) Ueda, H.; Manda, T.;
Matsumoto, S.; Mukumoto, S.; Nishigaki, F.; Kawamura, I.; Shimomura,
K. J. Antibiot. 1994, 47, 315-323.
(10) Gore, S. D.; Carducci, M. A. Exp. Opin. InVest. Drugs 2000, 9,
2923-2934.
(11) Phiel, C. J.; Zhang, F.; Huang, E. Y.; Guenther, M. G.; Lazar, M.
A.; Klein, P. S. J. Biol. Chem. 2001, 76, 36734-36741.
(12) Richon, V. M.; Emiliani, S.; Verdin, E.; Webb, Y.; Breslow, R.;
Rifkind, R. A.; Marks, P. A. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 3003-
3007.
(13) (a) Jung, M.; Brosch, G.; Ko¨lle, D.; Scherf, H.; Gerha¨user, C.; Loidi
P. J. Med. Chem. 1999, 42, 4669-4679. (b) Remiszewski, S. W.;
Sambucetti, L. C.; Atadja, P.; Bair, K. W.; Cornell, W. D.; Green, M. A.;
Howell, K. L.; Jung, M.; Known, P.; Trogani, N.; Walker, H. J. Med. Chem.
2002, 45, 753-757. (c) Woo, S. H.; Frechette, S.; Khalil, E. A.; Bouchain,
G.; Vaisburg, A.; Bernstein, N.; Moradei, O.; Leit, S.; Allan, M.; Fournel,
M.; Trachy-Bourget, M. C.; Li, Z.; Bestman, J. M.; Delorme, D. J. Med.
Chem. 2002, 45, 2877-2885.
(14) (a) Suzuki, T.; Ando, T.; Tsuchiya, K.; Fukazawa, N.; Saito, A.;
Mariko, Y.; Nakanishi, O. J. Med. Chem. 1999, 42, 3001-3003. (b) Saito,
A.; Yamashita, T.; Mariko, Y.; Nosaka, Y.; Tsuchiya, K.; Ando, T.; Suzuki,
T.; Tsuruo, T.; Nakanishi, O. Proc. Natl. Acad. Sci. U. S. A. 1999, 96,
4592-4597.
(15) (a) Furumai, R.; Komatsu, Y.; Nishino, N.; Khochbin, S.; Yoshida,
M.; Horinouchi, S. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 87-92. (b)
Komatsu, Y.; Tomizaki, K.; Tsukamoto, M.; Kato, T.; Nishino, N.; Sato,
S.; Yamori, T.; Tsuruo, T.; Furumai, R.; Yoshida, M.; Horinouchi S.;
Hayashi, H. Cancer Res. 2001, 61, 4459.
(16) Furumai, R.; Matsuyama, A.; Kobashi, M.; Lee, K.-H.; Nishiyama,
M.; Nakajima, H.; Tanaka, A.; Komatsu, Y.; Nishino, N.; Yoshida, M.;
Horinouchi S. Cancer Res. 2002, 62, 4916-4921.
(17) Finnin, M. S.; Donigian, J. R.; Cohen, A.; Richon, V. M.; Rifkind,
R. A.; Marks, P. A.; Breslow, R.; Pavletich, N. P. Nature 1999, 401, 188-
193.
5080
Org. Lett., Vol. 5, No. 26, 2003