Inhibitors of human histone deacetylase: Synthesis and enzyme and cellular activity of straight chain hydroxamates

Article abstract of DOI:10.1021/jm015568c

Inhibitors of histone deacetylase (HDAC) have been shown to induce terminal differentiation of human tumor cell lines and to have antitumor effects in vivo. We have prepared analogues of suberoylanilide hydroxamic acid (SAHA) and trichostatin A and have evaluated them in a human HDAC enzyme inhibition assay, a p21^waf1 (p21) promoter assay, and in monolayer growth inhibition assays. One compound, 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was found to affect the growth of a panel of eight human tumor cell lines differentially.

Full text of DOI:10.1021/jm015568c

© Copyright 2002 by the American Chemical Society
Volume 45, Number 4
February 14, 2002
Letters
of gene expression. Perturbation of this balance has
been linked to cancer.3 Natural product HDAC inhibi-
tors (HDAIs) such as trichostatin A (1) and trapoxin B
(2) have antiproliferative effects on tumor cells,4,5 and
reviews of synthetic and natural HDAIs as potential
anticancer agents have been published.6 The reports of
the discovery of scriptaid7 (3) as an HDAI and of the in
vivo antitumor efficacy of the HDAI suberoylanilide
hydroxamic acid8 (SAHA, 4) prompted us to report on
the synthesis and structure-activity relationship (SAR)
of analogous HDAIs in our p21waf1 (p21) promoter assay9
and in human tumor cell antiproliferation assays.
In h ibitor s of Hu m a n Histon e
Dea cetyla se: Syn th esis a n d En zym e a n d
Cellu la r Activity of Str a igh t Ch a in
Hyd r oxa m a tes
Stacy W. Remiszewski,*,§ Lidia C. Sambucetti,†
Peter Atadja,§ Kenneth W. Bair,§ Wendy D. Cornell,‡
Michael A. Green,§ Kobporn Lulu Howell,§
Manfred J ung, Paul Kwon,† Nancy Trogani,§ and
Heather Walker§
Oncology Research and Core Technology, Novartis Institute
for Biomedical Research, 556 Morris Avenue,
Summit, New J ersey 07901-1398, and Department of
Pharmaceutical Chemistry, Westfa¨lische
Wilhelms-Universita¨t Mu¨nster, Hittorfstrasse 58-62,
48149, Mu¨nster, Germany
Received September 5, 2001
Abstr a ct: Inhibitors of histone deacetylase (HDAC) have been
shown to induce terminal differentiation of human tumor cell
lines and to have antitumor effects in vivo. We have prepared
analogues of suberoylanilide hydroxamic acid (SAHA) and
trichostatin A and have evaluated them in a human HDAC
enzyme inhibition assay, a p21waf1 (p21) promoter assay, and
in monolayer growth inhibition assays. One compound, 4-(di-
methylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was
found to affect the growth of a panel of eight human tumor
cell lines differentially.
Ch em istr y. Scheme 1 outlines the preparation of
SAHA analogues. Monomethyl suberate (5) was treated
with i-butyl chloroformate followed by arylamines 6a -
d . The intermediate methyl esters were treated with
HONH2 in KOH/MeOH to afford hydroxamates 7a -d .
Synthesis of N-methyl amide 10 was accomplished by
methylation of amide 8,10 one-pot ester hydrolysis, and
coupling of the resulting acid with O-benzylhydroxy-
lamine followed by O-debenzylation (Scheme 2). O-
methyl hydroxylamine 11 was obtained via a similar
hydrolysis/coupling scheme. Hydrazide 12 was obtained
using the standard methods.
In tr od u ction . Reversible acetylation of nuclear hi-
stones is a major regulator of gene expression which
may act by altering accessibility of transcription factors
to DNA through conformational changes in the nucleo-
some1 or by altering interactions with protein bromo-
domains.2 A balance between histone acetyl transferase
(HAT) activity and histone deacetylase (HDAC) activity
exists in normal cells resulting in cell specific patterns
Amides 16a and 16b were obtained using standard
methodology (Scheme 3). Benzamide 15a was trans-
formed to hydroxamate 16a via the O-benzylhydroxam-
ate while 15b was converted to hydroxamate 16b using
NH2OH in MeOH/NaOMe. Hydrogenation of 15b fol-
lowed by hydroxamate formation afforded 17.
* To whom correspondence should be addressed. Tel: 908-277-3983.
Fax: 908-277-4374. E-mail: stacy.remiszewski@pharma.novartis.com.
§ Oncology Research, Novartis.
† Present address: Xenogen Corporation, 869 Atlantic Avenue,
Alameda, CA 94501.
‡ Core Technology, Novartis.
Westfa¨lische Wilhelms-Universita¨t.
10.1021/jm015568c CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/17/2002

754 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 4
Letters
Sch em e 1a
Ta ble 1. HDA Enzyme and p21 Promoter and Growth
Inhibition Data for SAHA Analogues, Trichostatin A and
Trapoxin Ba
enzyme
H1299
HCT116
cpd
IC50 (µM)
AC50 (µM)
IC50 (µM)
IC50 (µM)
4b
7a
7b
7c
7d
1
0.194 (0.068)
0.279 (0.019)
0.248 (0.032)
0.200 (0.056)
0.306 (0.040)
0.026 (0.010)
<0.005
3.1 (1.3)
2.4 (0.8)
2.9 (0.4)
7.9 (3.1)
8.9 (2.2)
0.4 (0.3)
7.2 (0.7)
>10
1.9 (0.6)
>10
2.0 (1.2)
6.5 (0.5)
5.4 (0.7)
>10
a
Reagents: (a) 6a f 7a : EDCI, HOBT, N-methylmorpholine
>10
>10
(NMM); all others: i-BuOCOCl, NMM, THF; (b) HONH3Cl, KOH,
MeOH.
0.10 (0.01) 0.013 (0.004)
2
0.010 (0.010) 0.004 (0.001) 0.002 (0.002)
Sch em e 2a
a
Values are the means of a minimum of six experiments.
b
Numbers in parentheses are standard deviations. Prepared as
described in ref 17.
are reported as AC50, the compound concentration that
results in 50% of the maximal promoter activation of a
reference compound, psammaplin A.16
The activity for 4 and its analogues 7a -d in the
enzyme assay is comparable (Table 1). The p21 promoter
activity of 4 and its 4-methoxy analogue, 7a , are similar,
but there is a difference in the monolayer growth
inhibition data for the analogues. The methoxy com-
pound 7a is inactive in both the H1299 and HCT116
cells, whereas 4 is a 7.27 µM inhibitor of H1299 cell
growth and a 1.91 µM inhibitor of HCT116 cell growth.
The 4-pyridyl isomer 7b is essentially equipotent to 4
in the promoter assay, 3-fold less potent in HCT116
growth inhibition, and >10 µM in H1299 growth inhibi-
tion. The 3- and 4-pyridyl isomers 7c and 7d are
approximately 2.5-fold less potent than 4 in promoter
induction, >10 µM in H1299 growth inhibition, and
approximately 8.5-fold less potent in HCT116 growth
inhibition. The reason for the difference in cellular
activity among these compounds is unclear, but may be
due to differences in cellular permeability or intracel-
lular metabolism of the compounds.
a
Reagents: (a) NaH, MeI, THF, 0 °C to reflux; (b) LiOH, H2O,
THF then BnONH3Cl, NMM, HOBT, EDCI (one pot); (c) 10% Pd/
C, H2; (d) LiOH, H2O, THF then MeONH3Cl, NMM, HOBT, EDCI
(one pot); (e) H4N2, EtOH, reflux.
Sch em e 3a
The enzyme potency of the amide analogues of 1 is
directly related to chain length, cf., Table 2, entries 1-4;
the most potent compound is 23 (entry 3), where n ) 6,
at 46 nM. A variety of substitution is tolerated at the
4-position of the aryl when n ) 5, cf., entries 6-10,
except for NO2, which resulted in a 6.4-fold loss of
enzyme potency when compared to the parent 4-di-
methylamino compound 22 (entry 2). Amide N-meth-
ylation (entry 5) resulted in a 1.8-fold loss of enzyme
potency. Changing the hydroxamate to O-methylhy-
droxamate (entry 12) or hydrazide (entry 13) resulted
in inactive compounds. In the homologous 6-carbon
chain series, replacement of 4-dimethylamino (entry 3)
by H (entry 11) resulted in 12-fold loss of enzyme
potency.
There is a distinct dependence of p21 promoter
activation on chain length within the 4-dimethylamino
compound series, with n < 5 resulting in inactive
compounds. However, 23, where n ) 6 (entry 3), and
24, where n ) 7 (entry 4), are essentially equipotent in
promoter activation, despite a 3-fold difference in en-
zyme activity. These compounds also have similar
potency in H1299 growth inhibition, ca. 1.9 µM, and are
sub-micromolar in HCT116 growth inhibition.
a
Reagents: (a) EDCI, HOBT, NMM; (b) LiOH, H2O, THF then
BnONH3Cl, NMM, HOBT, EDCI (one pot); (c) 10% Pd/C, H2; (d)
HONH3Cl, NaOMe/MeOH.
Sch em e 4a
a
Reagents: (a) i-BuOCOCl, NMM; (b) pyridine, HONH3Cl; (c)
EDCI, HOBT, O-tritylhydroxyl-amine resin; (d) 30% HCO2H/THF.
Starting from the known phthalimides 18a and 18b,11
hydroxamates 19a and 19b were prepared via the mixed
anhydride (Scheme 4). Hydroxamate 21 was synthesized
using O-tritylhydroxylamine resin.12
Resu lts a n d Discu ssion . We have profiled these
compounds using partially purified HDAC enzyme
obtained from H1299 cell lysate,13 in antiproliferative
assays14 and in a p21 promoter induction assay.9 Induc-
tion of p21 has been demonstrated using various HDAIs
in several cell types.15 The p21 promoter assay results
The 6-carbon chain phthalimide 19b is slightly more
potent in enzyme inhibition than its shorter homologue
19a , but these compounds are essentially equipotent in
promoter activation (Table 3). This is in contrast to 22

Letters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 4 755
Ta ble 2. HDA Enzyme and p21 Promoter and Growth Inhibition Data for Amidesa
entry
cpd
R1
R2
R3
n
enzyme IC50 (µM)
AC50 (µM)
H1299 IC50 (µM)
HCT116 IC50 (µM)
1
2
3
4
5
6
7
8
21b
22c
23b
24b
10
N(Me)2
N(Me)2
N(Me)2
N(Me)2
N(Me)2
Ph
BnO
OH
Cl
H
H
H
H
Me
H
H
H
H
H
H
H
H
NHOH
NHOH
NHOH
NHOH
NHOH
NHOH
NHOH
NHOH
NHOH
NHOH
NHOH
NHOMe
NHNH2
4
5
6
7
5
5
5
5
5
5
6
5
5
>10
>10
NT
NT
1.62 (0.03)
2.18 (0.031)
NT
NT
NT
NT
NT
NT
NT
0.21 (0.08)
0.50 (0.15)
NT
NT
NT
NT
NT
0.244 (0.038)
0.046 (0.009)
0.145 (0.061)
0.443 (0.193)
0.265 (0.021)
0.220 (0.075)
0.149 (0.064)
0.369 (0.027)
1.566 (0.250)
0.568 (0.240)
>10
>10
2.1 (0.7)
1.6 (0.6)
>10
25b
15b
16
>10
>10
>10
9
26b
27b
15a
11
>10
10
11
12
13
NO2
H
H
>10
NT
>10
NT
NT
1.04 (0.22)
NT
5.7 (3.4)
>10
12
H
>10
>10
NT
NT
a
b
Values are the means of a minimum of six experiments. Numbers in parentheses are standard deviations. NT ) not tested. Prepared
as described in ref 18. c Prepared as described in ref 10.
Ta ble 3. HDA Enzyme and p21 Promoter and Growth
Inhibition Data for Miscellaneous Compoundsa
enzyme
H1299
HCT116
cpd
IC50 (µM)
AC50 (µM)
IC50 (µM)
IC50 (µM)
19a
19b
20
0.515 (0.097)
0.357 (0.017)
0.270 (0.025)
7.5 (2.3)
6.9 (1.4)
4.1 (1.4)
NT
NT
>10
NT
NT
1.72 (0.89)
a
Values are the means of a minimum of six experiments.
Numbers in parentheses are standard deviations. NT ) not tested.
Ta ble 4. p53 Status, Tissue Type, and Growth Inhibition for
Cells Treated with 23a
cell line
HCT116
SW 620
A549
MDA-MB-435S
LS 174T
A431
tissue
colon
colon
lung
breast
colon
epidermoid
bladder
lung
p53 status
IC50 (µM)
F igu r e 1. Percent growth as compared to vehicle treated
control (% Growth) for cells treated with 23 for 72 h. Error
bars were omitted for clarity; see Table 4 for an indication of
reproducibility. Values below 0% cell growth indicate percent-
age of cell death.
wtb
mutant
wt
mutant
mutant
mutant
mutant
deleted
0.2 (0.08)
0.7 (0.05)
0.8 (0.02)
1.3 (0.04)
1.5 (0.17)
2.3 (0.12)
3.8 (0.18)
3.9 (0.51)
p53, these data do not rule out the activation of other
genes which lead to growth arrest or cell death, nor the
possibility that differential HDAC isoform expression
among the cell lines may contribute to the sensitivity
differences.
T24
H1299
a
Values are the means of a minimum of three experiments.
Numbers in parentheses are standard deviations. b wt ) wild type.
We have developed a homology model of human
HDAC-1 based on the crystal structure of a bacterial
HDAC homologue (PDB code 1C3R) and have docked
22, 23, and 24 into this model using the program QXP
(Figure 2).19 The hydroxamic acid and alkyl chain of
each molecule are essentially superimposed in the
binding pocket. Differences are observed in the interac-
tions of the substrates at the surface of the binding
pocket. Compounds 23 and 24 readily achieve confor-
mations where the amide proton of each compound
forms a H-bond with the terminal carboxy group of Asp-
92 (HDLP numbering) of the protein. A higher energy
conformation of 22 (cf., 23 and 24) is required for the
amide proton of compound 22 to form a H-bond to the
carboxy of Asp-92. Additionally, the phenyl groups of
23 and 24 have a lipophilic interaction with the alkyl
chain of Glu-91, while the phenyl group of 22 is more
solvent exposed. These differences may account for the
differences in enzyme potency among the compounds.
While the role of HDAC-1 has not been elucidated at
this time, the modeling illustrates one possible role
isoform specific inhibition may play in cell growth
and 23 (Table 2, entries 2 and 3), where the 5-carbon
chain homologue was inactive in promoter activation.
Hydroxamate 21, having an all-carbon spacer, is rela-
tively potent in enzyme inhibition, 0.270 µM, and in
promoter activation, 4.1 µM. It is 1.72 µM in HCT116
growth inhibition but >10 µM in H1299 cells.
The differential sensitivity of H1299 cells and HCT116
cells to the growth inhibitory effects of these compounds
led us to test the most potent enzyme inhibitor, 23, on
a panel of eight human tumor cell lines. Table 4 lists
the IC50s and p53 status of the cell lines used. The
effects range from growth inhibition for H1299 and
MDA-MB-435S cells to cell kill for HCT116 and A549
cells (Figure 1). Annexin V and propidium iodide stain-
ing of cells with % growth < 0 indicate the cells undergo
apoptosis (data not shown). These effects appear to be
p53 independent, since two cell lines having wild-type
p53, HCT116 and A549, undergo cell kill, as do two lines
having p53 mutations, SW 620 and MDA-MB-435S.
While this supports the hypothesis that p21 induction
plays a role in mediating the antiproliferative effects of
HDAC inhibition,15 since p21 functions downstream of

756 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 4
Letters
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