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ACS Medicinal Chemistry Letters
Page 2 of 6
As a result of this clinical potential, the design of novel
HDACIs continues to attract the interest of medicinal chemꢀ
ists. The pharmacophore of a typical HDACI involves a cap
group that interacts with the surface of the enzyme, a linker
that occupies a hydrophobic channel, and a metal chelator that
coordinates with the zinc ion at the bottom of the catalytic
pocket.12,13 Many first generation HDACIs, like SAHA, are
panꢀinhibitory, i. e., they have little, if any, isoform selectivity.
Additionally, many HDACIs, such as trichostatin A (TSA,
Figure 1) and SAHA, contain a hydroxamic acid function as
the zincꢀbinding group (ZBG). Unfortunately, hydroxamates
are metabolically unstable (SAHA has a halfꢀlife of 1.5ꢀ2
hours in humans when administered orally), and their potent
metalꢀchelating ability can lead to offꢀtarget activity at other
zincꢀcontaining enzymes.14,15 In addition, many hydroxamic
acidꢀbased inhibitors have been shown to be Amesꢀpositive
and to cause chromosomal aberrations, thus linking them to
the potential for genotoxicity.16 Accordingly, alternative
ZBGs, such as mercaptoacetamides, may be preferable deꢀ
pending on the therapeutic goal.17,18 Certainly, the application
of an HDACI to chronic disorders such as certain CNS diseasꢀ
es would require that the compound does not cause genotoxiꢀ
city.
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Figure 2. Mercaptoacetamideꢀbased HDACIs presented in this
work, containing 8ꢀaminoquinoline and 1,2,3,4ꢀ
tetrahydroquinoline as the cap groups.
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One possible drawback of thiolꢀcontaining HDACIs is their
ability to undergo oxidative dimerization to form disulfides.
Thus, the rate of dimerization of the thiolꢀbased compounds
must be considered when profiling the activity of these inhibiꢀ
tors against the purified HDAC proteins. It is furthermore
possible that the disulfide bond of an oxidized HDACI could
be reduced by the high levels of glutathione present inside of
cells to restore the parent thiol.
Given these considerations, we carried out additional chemꢀ
istry and biology on mercaptoacetamides structurally related
to compound 1 (Figure 2). Herein we describe the synthesis,
HDAC inhibitory potency, and selectivity of these comꢀ
pounds.
In addition to their effects on histones, many HDACs, inꢀ
cluding HDAC6, act on nonꢀhistone proteins. Thus, HDAC6
participates in the deacetylation of αꢀtubulin, cortactin, and
HSP90, and thereby regulates important biological processes,
including microtubule stability and function, and cell motiliꢀ
ty.19 HDAC6 has emerged as an attractive target for drug deꢀ
velopment, as its inhibition is believed to offer potential theraꢀ
py for cancer and many neurodegenerative conditions, includꢀ
ing spinal cord injury.20 Only a few highly selective HDAC6
inhibitors have been reported to date. For instance, tubacin
(Figure 1) was developed over 10 years ago and has been exꢀ
tensively used in various disease models to validate HDAC6
as a therapeutic target.21 However, its high lipophilicity and
tedious synthesis limits its use as a drug. For this reason, we
developed tubastatin A (Figure 1), a more potent hydroxamic
acidꢀbased HDAC6 inhibitor.22 Despite the fact that these
small molecules are of great interest as chemical tools for
probing the biological function of HDAC6,22,23 it is now clear
that in order to minimize undesirable side effects, there is a
need to identify druggable, isoformꢀselective inhibitors that
are free of certain safety concerns associated with the hydroxꢀ
amate class of HDACIs.12
All new ligands prepared contain four to seven CH2 units
within the linker region, as this appears to be the optimal
length for small molecules to fit into the binding pocket of
HDAC6.26 The choice of cap groups was based on the strucꢀ
ture of compound 1 (Figure 2) and of other HDACIs previousꢀ
ly explored by us.
The mercaptoacetamides 2aꢀc were synthesized starting
from Nꢀprotected amino alcohols of varying lengths (5aꢀc,
Scheme 1). Their conversion into the corresponding alkyl halꢀ
ides (6aꢀc) took place under mild conditions in the presence of
triphenylphosphine (PPh3) and tetrabromomethane (CBr4). 8ꢀ
Aminoquinoline was alkylated with 6aꢀc under microwave
(µW) irradiation to give intermediates 7aꢀc, respectively. The
Boc protecting groups were removed with trifluoroacetic acid
(TFA), and then the free amines were subjected to a coupling
reaction with 2ꢀ(tritylthio)acetic acid in the presence of benꢀ
zotriazolꢀ1ꢀylꢀoxytripyrrolidinophosphonium hexafluorophosꢀ
phate (PyBOP). Removal of the trityl protecting groups in the
presence of TFA and triethylsylane (Et3SiH) afforded the final
mercaptoacetamides 2aꢀc.
Within this context, we considered it worthwhile to further
investigate the potency, isoform selectivity, and biological
effects of additional mercaptoacetamideꢀbased inhibitors. We
and others have previously reported on mercaptoacetamideꢀ
based HDACIs that exhibit HDAC6 selectivity combined with
promising therapeutic profiles compared to their respective
hydroxamic acid analogs.7,24 In particular, compound 1 (Figure
2) was found to regulate cell surface levels of the amyloid
precursor protein (APP) and to modulate the levels of Aβ synꢀ
thesis and Aβ degradation enzymes. Aβ peptides are neurotoxꢀ
ic products, mainly related to AD, that are released following
the cleavage of APP by βꢀ and γꢀsecretases. AD mice treated
with compound 1 had decreased brain Aβ levels, decreased tau
phosphorylation, and improved learning and memory.24 Addiꢀ
tionally, a related mercaptoacetamide was found to decrease
the inflammatory response in the brain of animals subjected to
traumatic brain injury.25
The mercaptoacetamide 3a, containing a tetrahydroquinoꢀ
line (THQ) cap, was obtained from coupling of NꢀBocꢀ7ꢀ
aminoheptanoic acid (10, Scheme 1) with N,Oꢀ
dimethylhydroxylamine hydrochloride to give the Weinreb
amide 11, which was reduced to aldehyde 12 with LiAlH4.
Subsequently, reductive amination of intermediate 12 with the
THQ cap afforded 13. Next, Boc deprotection, amide forꢀ
mation in the presence of PyBOP, and removal of the trityl
group gave mercaptoacetamide 3a.
Compound 3b was synthesized through coupling of the
THQ cap moiety with NꢀBocꢀ6ꢀaminohexanoic acid (16). The
resulting amide was then taken through the same three final
steps described above for analog 3a.
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