ω-Alkoxy analogues of SAHA (vorinostat) as inhibitors of HDAC: A study of chain-length and stereochemical dependence

Article abstract of DOI:10.1016/j.bmcl.2007.09.014

A series of ω-alkoxy ethers were prepared with variation of the length of the aliphatic chain of suberoylanilide hydroxamic acid (SAHA, vorinostat). Eight carbon long chain analogues showed the best activity, among which several substituted benzyl ether d

Full text of DOI:10.1016/j.bmcl.2007.09.014

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6261–6265
x-Alkoxy analogues of SAHA (vorinostat) as inhibitors of HDAC:
A study of chain-length and stereochemical dependence
Stephen Hanessian,a,* Luciana Auzzas,a,b Giuseppe Giannini,c Mauro Marzi,c
Walter Cabri,c Marcella Barbarino,c Loredana Vescic and Claudio Pisanoc
aDepartment of Chemistry, Universite´ de Montre´al, PO Box 6128, Station Centre-ville, Montre´al, QC, Canada H3C 3J7
bIstituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca 3, I-07040 Sassari, Italy
cSigma-Tau Research & Development, Via Pontina Km 30.400, I-00040 Pomezia, Roma, Italy
Received 7 August 2007; revised 29 August 2007; accepted 4 September 2007
Available online 8 September 2007
Abstract—A series of x-alkoxy ethers were prepared with variation of the length of the aliphatic chain of suberoylanilide hydroxa-
mic acid (SAHA, vorinostat). Eight carbon long chain analogues showed the best activity, among which several substituted benzyl
ether derivatives exhibited inhibitory activity on HDAC comparable to SAHA, and antiproliferative activity on three human cell
lines (NB4, H460, and HCT-116) better than SAHA. However, no significant difference in antiproliferative activity was observed
between two enantiomers bearing the benzyl ether moiety.
Ó 2007 Published by Elsevier Ltd.
Metalloproteases are a superfamily of ubiquitous zinc-
dependent enzymes involved in a host of physiologically
important processes.1 Among two of the recently most
relevant enzymes are matrix metalloproteinases (MMPs)2
and histone deacetylases (HDACs).3 In either case the
most effective known inhibitors are hydroxamic acids that
bind a zinc atom in the respective enzymes.4
such as trichostatin A (TSA),7 and unnatural surrogates
such as the recently launched suberoylanilide hydroxa-
mic acid (SAHA)8 under the name vorinostat (Fig. 1).
A large body of work has been devoted to the synthesis
of hydroxamic acid analogues of acyclic and heterocy-
clic compounds.6
Fragments of natural products such as amamistatins A
and B (Fig. 2), containing an N-formyl-N-hydroxy
lysine moiety, have been reported as HDAC inhibitors.9
HDACs are nuclear enzymes that play a major role in
regulating gene expression. They catalyze the deacetyla-
tion of the N-acetyl lysine residues thereby changing the
accessibility of transcription factors to DNA, and conse-
quently affecting the chromatin remodeling process. Cell
specific patterns of gene expression depending on his-
tone acetylation result from a balance of the competing
activities of two classes of enzymes, the histone acetyl
transferases (HATs)5 and the histone deacetylases
(HDACs). Perturbations of this balance have been
linked to cancer, and inhibition of HDAC has been
shown to have antiproliferative effects on tumor cell
lines, resulting in considerable interest in this field.3,6
O
O
OH
OH
N
H
N
trichostatin A (TSA)
O
H
N
N
H
O
SAHA (vorinostat)
R2 OR3
N
O
The list of known inhibitors of HDACs covers a wide
cross-section of structures including natural products
OH
N
H
n
O
R1
n = 4, 5, 6
Keywords: Hydroxamic acid; HDAC; Anticancer activity.
*
Figure 1. Structures of known HDAC inhibitors and a proposed
prototype.
Corresponding author. Tel.: +1 514 343 6738; fax: +1 514 343
5728; e-mail: stephen.hanessian@umontreal.ca
0960-894X/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2007.09.014

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S. Hanessian et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6261–6265
acid was efficiently converted to anilide 3 by reaction
with N-sulfinylaniline.14 Alkylation with a variety of
alkyl halides, followed by treatment of the resulting
6-alkoxy esters with hydroxylamine in methanolic
NaOH, led to the corresponding hydroxamic acids
4b–g. The most effective base for the alkylations was
found to be Ag2O, although some yields were only mod-
est.15 Treatment of 3 under the same conditions gave race-
mic 6-hydroxy pimeloylanilide hydroxamic acid (4a).
R
O
O
O
O
H
N
N
N
O
N
N
OH
H
OH
O
O
H
OH
amamistatin A R = OMe
amamistatin B R = H
Analogues maintaining the original SAHA chain length
were prepared as shown in Scheme 2. Thus, using the
common intermediate 2, an Arndt–Eistert extension16
via the a-diazoketone 5, and subsequent manipulation
gave anilide 6 in excellent overall yield. Similar alkyla-
tions and subsequent treatment with hydroxylamine as
depicted in Scheme 1 led to the 7-alkoxy SAHA–
hydroxamic acids 7a–m, albeit in modest yields with
the exception of the methyl and allyl ethers 7b and 7c.
The reason for these modest yields of alkylation is not
clear.15 In one example, the O,N-bis 3-methoxybenzyl
analogue 7i was prepared along with the mono-alkyl-
ated analogue 7h.
Figure 2. Structures of amamistatin A and B.
De novo design and library approaches have also been
used in the search for novel HDAC inhibitors.10
The structural simplicity of SAHA as an effective inhib-
itor of HDACs has instigated the synthesis of closely
related analogues. In a recent patent11 Breslow and
coworkers have reported a series of 7-substituted amide
derivatives of SAHA with excellent inhibitory activities.
Although alkoxy analogues of SAHA are mentioned in
this patent, little if any detail on their inhibitory activity
is available.11 Efforts in the same general direction were
also ongoing in our laboratory, specifically to probe the
influence of the chain length of SAHA analogues
possessing x-alkoxy substituents on enzyme binding
and inhibition.12 A prototypical analogue is shown as
a generic structure in Figure 1.
The last series of inhibitors included nine carbon chain
analogues prepared from the common precursor 2
(Scheme 3). Thus, conversion to the aldehyde and olefin
extension led to the a,b-unsaturated ester 8. Reduction
of the double bond, followed by cleavage of the acetal
and anilide formation, gave 9 in excellent overall yield.
We first focused on SAHA analogues having a seven
carbon chain length and featuring a series of 6-alkoxy
substituents as shown in Scheme 1. Thus, racemic
aminopimelic acid 1 was subjected to diazotization13
and the resulting alcohol was protected as the lactone
acetal 2. After esterification as a methyl ester and cleav-
age of the acetonide protection, the resulting a-hydroxy
OH
O
O
H
N
a
b
O
N2
CO2Me
2
5
4
5
O
O
R1
6
R2 OR3
N
CONHOH
(70%)
c
5
O
R1
7a-m
NH2
O
O
a
b
R1 = R2 = H, R3 = H,
CO2H
OH
CO2H
7a
HO2C
R
R
1 = R2 = H, R3 = Me, 7b (59%)
4
4
O
1 = R2 = H, R3 = CH2=CHCH2,
(78%)
7c
1
2
R1 = R2 = H, R3 = 4-MeOC6H4CH2, 7d (39%)
R1 = R2 = H, R3 = 4-CF3C6H4CH2,
(37%)
OR
7e
H
N
H
N
c
R
1 = R2 = H, R3 = 4-BrC6H4CH2, 7f (51%)
CO2Me
CONHOH
R1 = R2 = H, R3 = 4-MeC6C4CH2, , (25%)
7g
4
4
O
O
R
1 = R2 = H, R3 = 3-MeOC6H4CH2, 7h (38%)
3
4a-g
R1 = H, R2 = R3 = 3-MeOC6H4CH2, (21%)
7i
R = H, 4a (77%)
R = Me, 4b (53%)
R = CH2=CHCH2, 4c (51%)
R = CH2=C(CH3)CH2, 4d (29%)
R = CH3CH2CH2, 4e (52%)
R
1 = R2 = H, R3 = 3,5-(MeO)2C6H3CH2, 7j (22%)
R1 = R2 = H, R3 = 3-C6H5OC6H4, 7k (24%)
1 = MeO, R2 = H, R3 = C6H5CH2, (33%)
7l
R
R
1 = MeO, R2 = H, R3 = 4-MeOC6H4CH2, 7m (35%)
4f
R = C6H5CH2, (26%)
Scheme 2. Eight carbon long chain x-alkoxy SAHA analogues 7a–m.
Reagents and conditions: (a) (i) SOCl2, cat. DMF, CH2Cl2, À10 °C to
rt; (ii) CH2N2, Et2O, À5 °C to rt (86%, two steps); (b) (i) AgOBz, Et3N,
MeOH, À25 °C to rt (99%); (ii) 70% aq AcOH, 60 °C (98%); (iii)
R1C6H4N@S@O, 1,2,4-triazole, CH2Cl2, 0 °C to rt (R1 = H, 84%;
R1 = OMe, 71%); (c) (i) R2Br or R2I, Ag2O, DMF or MeCN, rt or
4g
R = 4-MeOC6H4CH2,
(20%)
Scheme 1. Seven carbon long chain x-alkoxy SAHA analogues 4a–g.
Reagents and conditions: (a) (i) NaNO2, 2 N HCl, 0 °C to rt; (ii) 2,2-
DMP, PTSA (72%, two steps); (b) (i) CH2N2, Et2O, 0 °C to rt (99%);
(ii) 70% aq AcOH, 60 °C (85%); C6H5N@S@O, 1,2,4-triazole, DCM,
0 °C to rt (84%). (c) (i) RBr or RI, Ag2O, DMF or MeCN, rt or 40 °C
(30–80%); (ii) 50% aq HONH2, 1.0 N NaOH, MeOH, 0 °C to rt (75–
98%).
40 °C
(25–80%);
for
R2 = 4-MeOC6H4CH2,
4-MeOC6H4-
CH2O(C@NH)CCl3, cat. BF3 Æ OEt2, CH2Cl2 (39%); (ii) 50% aq
HONH2, 1.0 N NaOH, MeOH, 0 °C to rt (75–99%).

S. Hanessian et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6261–6265
6263
OH
OH
a
TBDPSO
b
O
TBDPSO
c
CO2Me
a
b
O
3
CO2Me
5
2
11
12
4
O
OAc
8
CO2Me
HO2C
OH
OR
O
5
H
N
H
N
c
CO2Me
CONHOH
13
6
6
O
O
9
10a-d
OH
O
10a
R = H,
(74%)
(63%)
H
H
N
N
CO2Me
10b
CONHOH
R = Me,
R = CH2=CHCH2,
R = 4-MeOC6H4CH2,
d
10c
(58%)
10d
5
5
O
O
(23%)
14
15
Scheme 3. Nine carbon long chain x-alkoxy SAHA analogues 10a–d.
Reagents and conditions: (a) (i) BH3 Æ DMS, THF, 0 °C to rt (87%); (ii)
(COCl)2, DMSO, DCM, À78 °C, then Et3N, À78 °C to rt (98%); (iii)
Ph3P@CHCO2Me, CH2Cl2 (96%); (b) (i) NaBH4, NiCl2 Æ 6H2O,
MeOH, 0 °C to rt (98%); (ii) 70% aq AcOH, 60 °C (94%); (iii)
PhN@S@O, 1,2,4-triazole, DCM, 0 °C to rt (96%); (c) (i) RBr or RI,
Ag2O, DMF or MeCN, rt or 40 °C (31–74%); (ii) 50% aq HONH2,
1.0 N NaOH, MeOH, 0 °C to rt (75–85%).
O
e
OH
O
H
N
H
N
CO2Me
CONHOH
d
5
5
O
O
16
17
Alkylation and treatment with hydroxylamine led to the
three 8-alkoxy and 8-hydroxy homo-SAHA analogues
10a–d.
Scheme 4. Enantiopure eight carbon long chain x-(p-methoxy)ben-
zyloxy SAHA analogues 15 and 17. Reagents and conditions: (a) (i)
CH2@CHCO2Me, Grubbs 2nd gen. catalyst, CH2Cl2 (95%); (ii) H2,
10% Pd–C, MeOH (86%); (b) (i) Ac2O, Py, DMAP (98%); (ii) TBAF-
AcOH, THF, 0 °C to rt (97%); (iii) TCCA, TEMPO, NaHCO3, NaBr,
acetone–H2O, 0 °C to rt (99%); (c) (i) PhNH2, EDCI, HOBt, DIEA,
CH2Cl2, 0 °C to rt (70%); (iv) KCN, MeOH, 0 °C to rt (99%); (d) (i) 4-
MeOC6H4O(CH@NH)CCl3, BF3 Æ OEt2, CH2Cl2 (39%); (ii) 50% aq
HONH2, 1.0 N NaOH, MeOH, 0 °C to rt (99%); (e) (i) DIEA, Ph3P, 4-
NO2BzOH, toluene, 0 °C to rt (83%); (ii) KCN, MeOH, 0 °C to rt
(99%).
In order to probe the effect of chirality of the inhibitory
activity of the original 6-alkoxy SAHA derivatives, we
chose the p-methoxybenzyl ether as a prototype based
on preliminary promising data on the racemate (Scheme
4). Cross metathesis of the known enantiomerically pure
alkenol 1117 with methyl acrylate in the presence of
Grubbs second generation catalyst,18 followed by cata-
lytic hydrogenation, gave 12 in excellent overall yield.
After acetylation of the alcohol function, cleavage of
the TBDPS ether, oxidation,19 anilide formation, and
deacetylation with KCN in MeOH20 gave 14, which
was alkylated, and the product treated with hydroxyl-
amine to give the 7-(S)-ether analogue 15. Mitsunobu
reaction21 of 14 followed by etherification of the result-
ing 16, and treatment with hydroxylamine gave the epi-
meric 7-(R)-ether 17.
porting Information) were inactive against HDAC-2 at
concentrations below 0.1 lM and they showed scarce
to moderate cytotoxicity, with the exception of the nine
carbon long x-O-allyl analogue 10c (Table 1) which
exhibited HDAC-2 and tumor growth inhibitory activity
similar to SAHA. On the other hand, the seven carbon
chain analogues 4b, 4e–f, and 7i (Table 1) were endowed
with moderate HDAC-2 inhibitory activity but low anti-
proliferative potency. Taking into account that several
factors could be involved, it is possible that HDAC-2
isoenzyme plays a marginal role in the growth of the cell
lines.
The pharmacological activities of the x-alkoxy SAHA
derivatives were investigated by measuring their potency
to inhibit HeLa immuno-purified HDAC-2 enzyme as
well as evaluating their antiproliferative activity on three
human tumor cell lines (NB4, H460, and HCT-116).
According to the literature data, a remarkable role in
HDAC-2 inhibition and antiproliferative activity was
played by the spacer group length in SAHA.6f In the
x-alkoxy series reported in the present study, the pre-
ferred chain length was found to be with CH2 = 5 (Table
1). Among the eight carbon long chain x-ethers, the
benzyloxy derivatives 7d, 15, 17, 7e–h, and 7j exhibited
HDAC-2 inhibitory activity comparable to SAHA, but
they had superior antiproliferative activity. Interest-
ingly, no significant difference in inhibitory activity
was found between the racemic O-(p-OMe) benzyl ana-
logue 7d and the single enantiomers (S-isomer, 15, or R-
isomer, 17). Simple alkyl ethers or x-hydroxy analogues
7a–c, 7k–m (Table 1), 4a, 4c–d, 4g, 10a–b, 10d (see Sup-
In conclusion, we have synthesized a series of x-alkoxy
analogues of SAHA and determined their inhibitory
activity on HDAC-2 as well as their cytotoxic activity
on three cancer cell lines. The x-benzyloxy analogues
of SAHA 7d, 15, 17, 7e–h, and 7j were more cytotoxic
and had a similar HDAC-2 inhibitor activity as com-
pared to SAHA. The racemic p-methoxybenzyl ether
analogue 7d showed the same biological profile as that
of the single enantiomers 15 and 17. Thus, in spite of
the very promising cytotoxic activity no stereochemical
preference was found in this series. Further work that
exploits the placement of hydrophobic ether appendage
on the original SAHA molecule is in progress.

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S. Hanessian et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6261–6265
Table 1. In vitro inhibitory activity against HDAC-2 and cytotoxic
activity of representative x-alkoxy SAHA analogues
162; (d) Wu, J.; Grunstein, M. Trends Biochem. Sci. 2005,
25, 619; (e) Archer, S. Y.; Hodin, R. A. Curr. Opin. Genet.
Dev. 1999, 9, 171.
HDAC-2 IC50
(lM) (range)
Growth inhibition IC50 (lM)
4. (a) Yang, K.; Lou, B. Mini-Rev. Med. Chem. 2003, 3, 349;
(b) Muri, E. M. F.; Nieto, M. I.; Sindelar, R. D.;
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0.5–0.1
P0.05
NB4
0.70
H460
HCT-116
SAHA
4b
4e
À
+
+
+
+
+
+
À
À
À
À
À
À
À
+
À
+
+
+
À
+
À
À
À
À
À
À
+
+
+
+
+
+
+
À
+
À
À
À
+
3.40
5.70
10.40
5.50
0.46
1.20
1.79
0.52
0.45
0.50
0.48
0.49
0.59
0.59
7.40
0.45
0.68
1.00
0.30
1.80
1.20
5.00
8.50
2.40
1.09
0.88
0.99
0.22
0.25
0.39
0.43
0.28
0.27
0.63
7.50
0.30
0.67
0.50
0.34
0.95
3.50
4.10
4f
>5
7a
7b
7c
0.34
0.52
0.45
0.12
0.11
0.07
0.17
0.06
0.12
0.16
4.00
0.05
0.23
0.25
0.15
0.62
7d
15
17
7e
7f
7g
7h
7i
7j
7k
7l
7m
10c
Values are means of a minimum of three experiments. HDAC-2
enzyme was obtained from HeLa cell lysate. Growth inhibition was
measured by SRB (sulforhodamine B) assay. See Supporting
Information.
Acknowledgments
We thank Consiglio Nazionale delle Ricerche, Istituto di
Chimica Biomolecolare, Italy, for a sabbatical leave to
L.A.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.09.014.
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