Trichostatin A (TSA) and trapoxin (TPX), inhibitors of the eukaryotic cell
cycle and inducers of morphological reversion of transformed cells, inhibit
histone deacetylase (HDAC) at nanomolar concentrations. Recently, FK228 (a
lso known as FR901228 and depsipeptide) and MS-275, antitumor agents struct
urally unrelated to TSA, have been shown to be potent HDAC inhibitors. Thes
e inhibitors activate the expression of p21Waf1 in a p53-independent manner
. Changes in the expression of regulators of the cell cycle, differentiatio
n, and apoptosis with increased histone acetylation may be responsible for
the cell cycle arrest and antitumor activity of HDAC inhibitors. TSA has be
en suggested to block the catalytic reaction by chelating a zinc ion in the
active site pocket through its hydroxamic acid group. On the other hand, a
n epoxyketone has been suggested to be the functional group of TPX capable
of alkylating the enzyme. We synthesized a novel TPX analogue containing a
hydroxamic acid instead of the epoxyketone. The hybrid compound, called cyc
lic hydroxamic-acid containing peptide I (CHAP1) inhibited HDAC at low nano
molar concentrations. The HDAC1 inhibition by CHAP1 was reversible, as is t
hat by TSA, in contrast to irreversible inhibition by TPX. Interestingly, H
DAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP I, while TSA in
hibited these HDACs to a similar degree. CHAP31, the strongest HDAC inhibit
or obtained from a variety of CHAP derivatives, exhibited antitumor activit
y in BDF1 mice bearing B16/BL6 tumor cells. These results suggest that CHAP
31 is promising as a novel therapeutic agent for cancer treatment, and that
CHAP may serve as a basis for new HDAC inhibitors and be useful for combin
atorial synthesis and high-throughput screening.