Design and synthesis of small molecules based on a substructural analysis of the histone deacetylase inhibitors TSA and SAHA

Article abstract of DOI:10.1155/2011/403129

Inhibitors of histone deacetylases (HDACs) are patent inducers of differentiation and bear considerable potential as drugs for chemoprevention and treatment of cancer. In this paper, we have investigated three synthetic, inhibitors A1a,b, A2a. Analogue hybrid trichostatine A (TSA), suberoylanilide hydroxamic acid SAHA, in order to seek new histone deacetylases (HDACs) inhibitors.

Full text of DOI:10.1155/2011/403129

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(3), 1394-1400
http://www.e-journals.net
Design and Synthesis of Small Molecules
Based on a Substructural Analysis of the Histone
Deacetylase Inhibitors TSA and SAHA
LYNDA EKOU*, TCHIRIOUA EKOU, JAVIER GARCIA§,
ISABELLE OPALINSKI§ and JEAN PIERRE GESSON§
Université d’Abobo-Adjamé
Laboratoire de Thermodynamique et de Physico Chimie du Milieu
02 BP 801 Abidjan 02, Côte d’Ivoire
§Université de Poitiers, UMR-CNRS 6514,
Laboratoire de Synthèse et Réactivité des Substances Naturelles
40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
ekou_lynda@yahoo.fr
Received 30 June 2010; Revised 3 December 2010; Accepted 8 January 2011
Abstract: Inhibitors of histone deacetylases (HDACs) are patent inducers of
differentiation and bear considerable potential as drugs for chemoprevention
and treatment of cancer. In this paper, we have investigated three synthetic,
inhibitors A1a,b, A2a. Analogue hybrid trichostatine A (TSA), suberoylanilide
hydroxamic acid SAHA, in order to seek new histone deacetylases (HDACs)
inhibitors.
Keywords: Histone deacetylase, Hydroxamic acids, Enzyme inhibitors, Substructural analysis.
Introduction
Histone deacetylases (HDACs) and histone acetyl transferases (HATs) are known to play an
important role in the regulation of gene expression1,2. HATs mediate hyperacetylation of
positively charged lysine residues in the N-terminal tail of core histone and loosen the
histone-DNA binding. As a result, activation of genes transcription can occur. In contrast
HDACs catalyse deacetylation of the acetyl ε amino group residues and lead to the tight
histone-DNA binding3. In this case, the access to transcription factors is restricted. These
enzymes correlate with cell cycle progression, differentiation and apoptosis4 and their
deregulation is associated with tumorogenisis5.

1395
LYNDA EKOU et al.
HDACs inhibitors have demonstrated potential for the prevention and treatment of
cancer in numerous cell culture6,7 and animals models8. HDACs have emerged as an
attractive target for new anticancer drugs and there is a great demand for new inhibitors9,10
.
The well known histone deacetylase inhibitor trichostatine A (TSA)11,12 (1), a natural
product and other synthetic compounds such as suberoylanilide hydroxamic acid (SAHA)13-15
(2) and analogues16, oxamflatin17 (3), or MS-27518 (4) possess potent antitumor effect in vivo
in tumor-bearing animals19 and some of them are currently in phase I or phase I / phase II
clinical trials20-24 (Figure 1).
O
O
O
H
N
OH
N
H
N
H
OH
O
N
Trichostatine A (1)
SAHA (2)
O
O
S O
NH
N
N
H
H
N
O
NH2
O
H
N
OH
O
Oxamflatin (3)
MSM-2S-72755 ((44) )
Figure 1. Structures of known HDAC inhibitors
These compounds consist of a hydrophobic scaffold with a spacer that is attached to a
functional group which can interact with zinc ion present in the active site pocket25-26
.
Compounds containing hydroxamic acid as a functional group are reported as the most
potent inhibitors for HDACs 16.
Experimental
Nuclear magnetic resonance spectra (1H NMR and 13C NMR) were recorded on a Bruker
300 and 75 MHz. Flash column chromatography was performed using MACHEREY-
NAGEL silica gel 60 (15-40 µm) as the stationary phase. All reactions were run under a
positive pressure of nitrogen unless otherwise stated.
[1-(4-Methoxy-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (7a)
To a solution of N-(tert-butoxycarbonyl)-L-alanine 5 (32.5 mmol, 1 eq.) and aniline
6a (32.5 mmol, 1 eq.) in dimethylformamide (DMF) (80 mL) were added portion wise
of diphenylphosphorylazide (DPPA) (7.7 mL, 33.7 mmol) and triethylamine (TEA)
(9.70 mL, 69.8 mmol) at 0 °C. The stirring was continued at room temperature
overnight. dimethylformamide was removed under reduced pressure. The residue was
purified by flash chromatography (Ethyl acetate / Petroleum ether, 40/60) to give 7a
(90%, white solid). 1H NMR (CDCl3) δ ppm 1.44 (m, 12H), 3.77 (s, 3H), 4.38
(sl, 1H), 5.38 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H),
8.59 (s, 1H). 13C NMR (CDCl3) δ ppm 18.4, 28.7, 50.9, 55.8, 80.7, 114.3, 122.0,
131.3, 156.5, 171.3.

Design and Synthesis of Small Molecules
1396
[1-(4-Dimethylamino-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (7b)
White solid (yield 78%). 1H NMR (CDCl3) δ ppm 1.45 (m, 12H), 2.83 (s, 6H), 4.38 (sl, 1H),
5.15 (sl, 1H), 6.84 (d, J = 9.1 Hz, 2H), 7.40 (d, J = 9.1 Hz, 2H), 8.13 (sl, 1H). 13C NMR
(CDCl3) δ ppm 18.6, 28.7, 41.3, 50.9, 80.5, 113.3, 122.1, 128.0, 148.3, 156.3, 171.1.
2-Amino-N-(4-methoxy-phenyl)-propionamide (8a)
The protected compound 7a was dissolved in trifluoroacetic acid (TFA) (29 mL) at room
temperature and kept for 2 h. The mixture was evaporated under reduced pressure. The
residue was neutralised with Na2CO3 and consecutively extracted with ethyl acetate. The
organic layer was washed with water then brine, dried over Na2SO4 and concentrated
in vacuo. Purification by flash chromatography (CH2Cl2/MeOH, 90/10) gave 8a (white
1
solid). H NMR (CDCl3) δ ppm 1.33 (d, J = 7.0 Hz, 3H), 3.45 (sl, 2H), 3.77 (m, 4H), 6.89
(d, J = 9.1 Hz, 2H), 7.45 (d, J = 9.1 Hz, 2 H), 9.47 (s, 1H). 13C NMR (CDCl3) δ ppm 21.8,
51.2, 55.7, 114.4, 122.4, 131.7, 132.8, 157.6.
2-Amino-N-(4-dimethylamino-phenyl)-propionamide (8b)
White solid. 1H NMR (DMSO) δ ppm 1.41 (d, J = 7 Hz, 3H), 2.85 (s, 6H), 3.91 (q, J = 7 Hz,
1H), 6.73 (d, J = 9.1 Hz, 2H), 7.45 (d, J = 9.1 Hz, 2H), 8.00 (sl, 3H). 13C NMR (DMSO) δ
ppm 17.6, 40.7, 49.1, 112.9, 121.1, 128.0, 167.6.
4-[1-(4-Methoxy-phenylcarbamoyl)-ethylamino]-pent-4-enoic acid (9a)
To a solution of amine 8a in dimethylformamide (15 mL) were added succinic anhydride
(8.81 mmol, 1 eq.) and triethylamine (1.23 mL, 8.81 mmol). The mixture was stirred for 4 h
at room temperature. After evaporation of organic solvents, the residue was purified by flash
1
chromatography using (CH2Cl2/MeOH, 90/10) to give compound 9a (93%, white solid). H
NMR (DMSO) δ ppm 1.34 (d, J = 6.7 Hz, 3H), 2.49 (m, 4H), 3.79 (s, 3H), 4.44 (m, 1H),
6.95 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 8.30 (d, J = 6. 9 Hz, 1H), 10.00 (s, 1 H),
12.31 (sl, 1H). 13C NMR (DMSO) δ ppm 18.5, 29.4, 30.1, 49.2, 55.4, 114.1, 121.1, 130.4,
155.5, 171.1, 171.3, 174.3.
4-[1-(4-Dimethylamino-phenylcarbamoyl)-ethylamino]-pent-4-enoic acid (9b)
(61%, White solide). 1H NMR (DMSO) δ ppm 1. 41 (d, J = 7.0 Hz, 3H), 2.74 (m, 4H), 2.97
(s, 6H), 4.50 (m, 1H), 6.62 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 8.9 Hz, 2H), 8.35 (d, J = 7.32
Hz, 1H), 9.71 (s, 1H), 12. 20 (sl, 1H).
N-Hydroxy-N-[1-(4-methoxy-phenylcarbamoyl)-ethyl]-succinamide (A1-a)
To acid 9a (200 mg, 0.68 mmol), 1-[3(dimethylamino)propyl]-3-ethyl-carboimide
hydrochloride] (EDC) (196.1 mg, 1.02 mmol), N-hydroxybenzotriazole (HOBT) (119.9 mg,
0.89 mmol) was reacted in dimethylformamide for 1 h. NH2OBn.HCl (108.9 mg, 0.68
mmol), triethylamine (0.10 mL, 0.68 mmol) were added and the mixture was stirred for 2
days. DMF was removed under reduced pressure. The residue was purified by flash
chromatography using CH2Cl2/ MeOH, 95/5 to give N-benzyloxy-N`-[1-4-metoxy-
phenylcarbamoyl)-ethyl]-succinamide (white solid, 48%).
1H NMR (DMSO-d6) δ ppm 1.47 (d, J = 7.1 Hz, 3H), 2.43 (t, J = 6.4 Hz, 2H), 2.62
(t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 4.56 (m, 3H), 4.96 (s, 2H), 7.02 (d, J = 9.0 Hz, 2H ), 7.56
(m, 5H), 7.75 (d, J = 9.0 Hz, 2H), 8.46 (d, J = 7.3 Hz, 1H), 9.90 (s, 1H), 11.28 (s, 1H). 13C
NMR (DMSO-d6) δ ppm 18.4, 30.5, 28.0, 49.2, 55.4, 77.1, 114.0, 121.1, 128.5, 129.0,
132.4, 155.5, 169.3, 171.2.

1397
LYNDA EKOU et al.
The N-benzyl precursor (0.66 mmol) was dissolved in MeOH (10 mL), 10% Pd-C was
added and the solution was shaken under H2. After 4h the mixture was filtered through celite
and the filtrate was evaporated. The hydroxamic acid A1-a was isolated after purification of
1
small sample on preparative plates (qt, withe solid). H NMR (DMSO-d6) δ ppm 1.35
(d, J = 7.1 Hz, 3H), 2.29 (t, J = 6.7 Hz, 2H), 2.45 (t, J = 6.7 Hz, 2H), 3.87 (s, 3H), 4.45
(m, 1H), 6.95 (d, 2H, J = 9.0 Hz, 2H), 7.63 (d, J = 9.0 Hz, 2H), 8.30 (d, J = 7.3 Hz, 1H),
9.18 (s, 1H), 9.83 (s, 1H), 10.50 (s, 1H). 13C NMR (DMSO-d6) δ ppm 18.4, 30.8, 28.0, 49.1,
55.4, 114.0, 121.1, 136.4, 155.5, 168.9, 171.2.
N-[1-(4-Dimethylamino-phenylcarbamoyl)-ethyl]-N`-hydroxy-succinamide (A1-b)
To a solution of acid 9b (0.5 mmol, 1 eq.) and NH2OBn.HCl (0.159 g, 1 eq.) in
dimethylformamide (2 mL) diphenylphosphorylazide (0.12 mL, 0.55 mmol) and
triethylamine (0.14 mL, 1 mmol) were added portion wise at 0 °C. The stirring was
continued at room temperature for 1 h and 30 min. Dimethylformamide was removed under
reduced pressure. The residue was purified by flash chromatography using CH2Cl2/ MeOH,
90/10 to obtain N-benzyl-N`-[1-(4-dimethylamino-phenylcarbamoyl)-ethyl]-succinamide
(white solid, 50%). 1H NMR (DMSO-d6) δ ppm 1.27 (m, 3H), 2.31 (m, 2H), 2.42 (m, 2H),
2.88 (s, 6H), 4.37 (m, 1H), 4.83 (s, 2H), 6.71 (d, J = 8.9 Hz, 2H), 7.06 (m, 7H), 8.37 (d, J =
7.3 Hz, 1H ), 9.51 (s, 1H), 11.23 (s, 1H).
The N-benzyl derivative was subjected to hydrogenolysis with 10% Pd-C in MeOH in
the same way as for A1-a to give A1-b (73%, white solid). 1H NMR (DMSO-d6) δ ppm 1.10
(m, 3H), 2.05 (m, 2H), 2.21 (m, 2H), 2.66 (s, 6H), 4.16 (m, 1H), 6.51 (d, J = 9 Hz, 2H), 7.28
(d, J = 9 Hz, 2H), 8.04 (d, J = 7.32 Hz, 1H), 8.56 (sl, 1H), 9.43 (s,1H), 10.26 (s, 1H).
4-Oxo-pent-2enoic acid [1-(4-methoxy-phenylcarbamoyl)-ethyl]-amide (10)
To a solution of mono ethyl ester fumaric acid (373 mg, 2,6 mmol) in DMF (7 mL) 1-
[3(dimethylamino)propyl]-3-ethyl-carboimide hydrochloride (743.8 mg, 3.9 mmol) and N-
hydroxybenzotriazole (455 mg, 3.37 mmol) were added. The mixture was stirred at room
temperature for 1 h. Amine 8a (500 mg, 2.57 mmol) was added followed by triethylamine
(0.36 mL, 2.57 mmoL). The mixture was stirred overnight, then the solvent was evaporated.
The residue was purified by flash chromatography using EtOAc/EP, 50/50 to obtain
compound 10 (white solid, 49%). 1H NMR (DMSO-d6) δ ppm 1.41 (t, J = 7.1 Hz, 3H), 1.50
(d, J = 7.0 Hz, 3H), 3.89 (s, 3H,), 4.35 (q, J = 7.1 Hz, 2H), 4.67 (m, 1H), 6.75 (d, J = 15.5
Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 15.5 Hz, 1H), 7.67 (d, J = 9 Hz, 2H), 9.06 (d,
J = 7.3 Hz, 1H), 10.12 (s, 1H). 13C NMR (DMSO-d6) δ ppm 14.3, 18.5, 49.6, 55.4, 61.0,
114.1, 121.1, 128.9, 132.3, 137.6, 155.6, 162.8, 165.3, 170.5.
But-2-enodioic acid hydroxyamide[1-(4-methoxy-phenylcarbamoyl)-ethyl]-amide
(A2-a)
The ester 10 (130 mg, 0. 41 mmol) was dissolved in MeOH (40 mL) and an aqueous
solution of LiOH (16.24 mL, 1 M) was added. The mixture was stirred for 2 h at the room
temperature. The solution was neutralised with the amberlite resine IRN-77 then, the product
was filtered and evaporated to give 3-[1-(4-methoxy-phenylcarbamoyl)-ethylcarbamoyl]-
1
acrylic acid (white solid, 57%), which was used without further purification. H NMR
(DMSO-d6) δ ppm 1.38 (d, J = 7 Hz, 3H), 3.78 (s, 3H), 4.56 (m, 1H), 6.59 (d, J = 15.5 Hz, 1H ),
6.90 (d, J = 9.0 Hz, 2H ), 7.16 (d, J = 15.5 Hz, 1H), 7.56 (d, J = 9 Hz, 2H), 8.9 (d, J = 7.3
Hz, 1H), 10.00 (s, 1H), 12.94 (sl, 1H). 13C NMR (DMSO-d6) δ ppm 18.5, 49.6, 55.5, 114.1,

Design and Synthesis of Small Molecules
1398
121.1, 130.2, 132.3, 137.1, 155.6, 163.1, 166.7, 170.5. To a solution of acid (50 mg,
0.17 mmol) in DMF (0.5 mL) were added O-(bentriazol-1-yl-1, 3, 3)-tetraméthyl-uronium
tétrafluoroborate (TBTU) (54 mg, 0.17 mmol) and triethylamine (0.05 mL, 0.34 mmol).
The mixture was stirred for 2 h and then NH2OTHP (0.17 mmol, 22 mg) was added. The
mixture was stirred for 5 days at room temperature. dimethylformamide was removed
under low pressure, then the crude product was purified using the preparative plate
1
(CH2Cl2/ MeOH, 92/8) to give compound A2-a (66%, withe solid). H NMR (DMSO-d6)
δ ppm 1.26 (d, J = 7.0 Hz, 3H), 3.65 (s, 3H), 4.43 (m, 1H), 6.47 (d, J = 15.5 Hz, 1H), 6.82
(d, J = 9.0 Hz, 2H), 6.99 (d, J = 15.5 Hz, 1H), 7.47 (d, J = 9.0 Hz, 2H), 8.76 (d, J = 7.3
Hz, 1H), 9.86 (s, 1H). 13C NMR (DMSO-d6) δ ppm 18.4, 49.6, 55.5, 114.2, 121.2, 130.2,
132.3, 137.0, 155.6, 170.5.
Results and Discussion
As part of our efforts to search for novel HDACs inhibitors, we investigated a series of
new hydroxamate analogues (A) which were designed as hybrides of TSA/SAHA
(Figure 2).
H
H
N
CH3
O
O
O
R
O
O
O
OH
H
N
H
N
N
H
X
N
H
Y
NHOH
N
H
OH
N
O
O
TSA
TSA
SAHA
SAHA
envisaged analogues
envisaged analogues
A1: X=CH2, Y=CH3, A2: X=CH1, Y=CH
Figure 2. Analogues hybrides TSA/SAHA
The rationale for the structure relied on the following parameters. The presence of the
amide function on the lateral chain instead of substituted alkene on the TSA, is one common
feature shared by these analogues. We can then consider these analogues as TSA isosters.
The presence of the carbonyl function on the lateral chain instead of the methyl one,
introduces a new hydrophilic feature which can allow the formation of hydrogen binding in
the tubular pocket of the enzyme. Such a modification could have an impact on the affinity
toward HDACs. These analogues have an aryl recognition moiety which can be substituted
in different ways. The orientation of the methyl in the chain is identical to that of TSA. The
lateral chain comes from the acylation of an aromatic amine and leads to a pattern which is
identical to that of SAHA. This chain will be saturated or unsaturated. In this paper we
report the synthesis of these compounds. Scheme 1 shows a general synthetic route of the
desired analogues A1-a,b and A2-a.
R
R
i
i
O
O
NHBoc
+
NHBoc
HO
N
H
NH2
5
6a,b
6a,b
7a,b
7a,b
ii

1399
LYNDA EKOU et al.
MeO
O
O
R
H
N
O
vvii
R
iii
iii
O
O
N
H
OCH2CH3
NH2
H
N
N
H
O
a:R=OMe
N
H
OH
10
10
O
8a,b
8a,b
9a,b
9a, b
vii, viii
vii, viii
iv, v
iv, v
MeO
O
O
R
H
N
O
O
H
N
N
H
NHOH
a : R = OMe
b : R = N(CH3)2
N
H
NHOH
O
O
A2-a
A2-a
A1-a,b
A1-a,b
Scheme 1 General synthetic route analogues A1-a,b and A2-a
Reagents: (i) DPPA, TEA, DMF, 90% (R=OMe), 78% [R=N(CH3)2]. (ii) TFA qt [(R=OMe),
(R=N(CH3)2] (iii) anhydride succinic TEA, DMF, 93% (R=OMe), 61% [R=N(CH3)2] (iv) NH2OBn,
HCl EDC, HOBT, TEA, DMF,48% (R=OMe) or DPPA, TEA, DMF 50% [R=N(CH3)2] (v) H2, Pd/C,
MeOH, qt (R=OMe), 73% R=N(CH3)2 (vi) EDC, HOBT,TEA, DMF, mono-ethyl ester fumaric acid
49% (vii) LiOH, MeOH 57% (viii) NH2OTHP, DMF, TBTU, TEA.
The N-tert-butoxycarbonyl-L- alanine 5 was coupled with para substituted aniline 6a,b
in several conditions. The use of N,N-bis(2-oxo-3-oxazolidinyl)-phosphinique chloride
(BOP-Cl) as coupling reagent resulted in low yield 41%. Using DPPA to activate the
carboxylic acid gave a 90% and 78% yield for respectively 7a and 7b. The N protecting
group was removed after treatment with trifluoroacetic acid. The amine 8a,b reacted in
DMF with succinic anhydride in the presence of TEA to give carboxylic acid 9a: 93%, and
9b: 61%. The resulting acid was converted to the O-benzyl protected hydroxamate.
Subsequent catalytic hydrogenation of the protected group was used to generate the desired
hydroxamates A1-a (qt), A1-b (73%).
The synthesis of the analogue A2-a started with the coupling of amine 8a with the
monoethyl ester fumaric acid (Scheme 1). The ethyl ester 10 was cleaved under basic
conditions in the presence of LiOH-MeOH and generated the corresponding acid with 57%
yield. The acid was then converted to the O-THP (protected hydroxamate), using TBTU as
coupling agent. The hydroxamic acid A2-a was isolated after purification of a small sample
on the preparative plates with 66% yield.
Conclusion
We have synthesized three analogues hybrides of TSA/SAHA with good yields. From these
analogues, some novel synthetic inhibitors can be developed.
References
1.
Suzuki T, NaganoY, Matsuura A, Kohara A, Ninomiya S I, Kohda K and Miyata N,
Bioorg Med Chem Lett., 2003, 13(24), 4321-4326.
2.
Hanessian S, Auzzas L, Giannini G, Marzi M, Cabri W, Barbarino M, Vesci L and
Pisano C, Bioorg Med Chem Lett., 2007, 17(22), 6261-6265.
3.
4.
Desai D, Salli U, Vrana K E and Amin S, Bioorg Med Chem Lett., 2010, 20(6), 2044-2047.
Maeda T, Nagaoka Y, Kuwajima H, Seno C, Maruyama S, Kurotaki M and Uesato S,
Bioorg Med Chem., 2004, 12(16), 4351-4360.
5.
Nishino N, Jose B, Shinta R, Kato T, Komatsu Y and Yoshida M, Bioorg Med Chem.,
2004, 12(22), 5775-5784.

Design and Synthesis of Small Molecules
1400
6.
7.
Jung M, La Thangue N B and Bandara L R, Eds., Humana Press: Totowa, 2002, 123-144.
(a) Kelloff G J, Boone C W, Steel V E, Fay J R, Lubet R. A, Crowell J A and Sigman C C,
J Cell Biochem., 1995, Suppl. 20, 1-24; (b) Sartorelli A C, Br J Cancer, 1985, 52, 293-302.
Coffey D C, Kutko M C, Glick R D, Butler L, M Heller G, Rifkind R A, Marks, P A,
Richon V M and La Quaglia M P, Cancer Res., 2001, 61(9), 3591-3594.
Wittich S, Scherf H, Xie C, Brosch G, Loidl P, Gerhäuser C and Jung M, J Med
Chem., 2002, 45(15), 3296-3309.
8.
9.
10. Monneret C, Eur J Med Chem., 2005, 40, 1-13.
11. Tsuji N, Kobayashi M, Nagashima K, Wakisaka Y and Kiozumi K, Antibiot., 1976,
29(1), 1-6.
12. Yoshida M, Kijima M, Akita M and Beppu T, J Biol Chem., 1990, 265(28),
17174-17179.
13. (a) Richon V M, Emiliani S, Vedin E, Webb y, Bresloww R, Rifkind R A and Marks P A,
Proc Natl Acad Sci U S A, 1998, 95, 3003-3007; (b) Bulter L M, Agus D B, Scher H
I, Higgins B, Rose A, Cordon-Cordo P, Thaler H T, Rifkind R A, Marks PA and
Richon V M, Cancer Res., 2000, 60(18), 5165-5170.
14. Richon V M, Webb Y, Merger R., Sheppard T, Jursic B, Ngo L, Civoli F, Breslow R,
Rifkind R A and Marks P A, Proc Natl Acad Sci U S A, 1996, 93(12), 5705-5708.
15. Breslow R, Bel veder S and Gershell L, Helv Chim Acta, 2000, 83, 1685-1692.
16. (a) Remiszewski S W, Sambucetti L C, Atadja P, Bair K W, Cornell W D, Green M A,
Howell, K L, Jung M, Kwon P, Trogani N and Walker H, J Med Chem., 2002, 45(4), 753.
(b) Jung M, Brosh G, Kölle D, Schef H, Gerhouser C and Loidl P, J Med Chem.,
1999, 42, 4669-4679.
17
(a) Kim Y B, Lee K H, Sugita K, Yoshida M and Horinouchi S, Oncogene, 1999,
18(15), 2461-2470; (b) Ohtami, M, Takakaru M, Kazuhira S and Kenji S, J Med
Chem., 1996, 39(15), 2871-2873.
18. (a) Suzuki T, Ando T, Tsuchiya K, Fukazawa N, Saito A, Mariko Y, Yamashita T,
Nakanishi O, J Med Chem., 1999, 42(15), 3001-3003; (b) Saito A, Yamashita T,
Mariko Y, Nosaka Y, Tsuchiya K, Ando T, Suzuki T, Tsuruo T and Nakanishi O,
Proc Natl Acad Sci U S A, 1999, 96, 4592-4597.
19. Mai A, Massa S, Ragno R , Cerbara I, Jesacher F, Loidl P and Brosch G, J Med
Chem, 2003, 46(4), 512-524.
20. Johnston R W, Nature Rev Drug Discov., 2002, 1, 287-299.
21. Lavoie R, Bouchain G, Frechette S, Hyungwoo S, Abou Khalil E, Leit S, Fournel M,
Yan P T, Trachy-Bourget M C, Beaulieu C, Li Z, Besterman J and Delorme D,
Bioorg Med Chem Lett., 2001, 11, 2847-2850.
22. Bolden J E, Peart, M J and Johnstone R W, Nat Rev Drug Discov., 2006, 5, 769-784.
23. Saveria M and Pier G P, Nature Rev Cancer, 2006, 6, 38.
24. Glozak M A and Seto E, Oncogene, 2007, 26, 5420.
25. Jose B, Oniki Y, Kato T, Nishino N, Sumida Y and Yoshida M, Bioorg Med Chem
Lett., 2004, 4, 5343-5346.
26. Drummond D C, Noble C O, Kirpotin, D B, Guo Z, Scott G K and Benz C C, Annu
Rev Pharmacol Toxicol., 2005, 45, 495-528.

International Journal of
Advances in
Organic Chemistry
International
International Journal of
International Journal of
Photoenergy
Medicinal Chemistry
Analytical Chemistry
Physical Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Volume 2014
International Journal of
Carbohydrate
Chemistry
Journal of
Quantum Chemistry
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
http://www.hindawi.com
Volume 2014
Volume 2014
Submit your manuscripts at
http://www.hindawi.com
Journal of
The Scientific
Analytical Methods
in Chemistry
World Journal
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
http://www.hindawi.com
Volume 2014
Volume 2014
International Journal of
Journal of
Journal of
International Journal of
Bioinorganic Chemistry
Spectroscopy
Inorganic Chemistry
Electrochemistry
Applied Chemistry
and Applications
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Journal of
Journal of
International Journal of
Chromatography
Journal of
Theoretical Chemistry
Catalysts
Research International
Chemistry
Spectroscopy
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Volume 2014
Volume 2014
Volume 2014