Synthesis and modeling of new benzofuranone histone deacetylase inhibitors that stimulate tumor suppressor gene expression

Article abstract of DOI:10.1021/jm9002439

New benzofuranones were synthesized and evaluated toward NCI-H661 non-small cell lung cancer cells. Benzamide derivatives possessed micromolar antiproliferative and histone deacetylase inhibitory activities and modulate histone H4 acetylation. Hydroxamic acids were found to be potent nanomolar antiproliferative agents and HDAC inhibitors. Computational analysis presented a rationale for the activities of the hydroxamate derivatives. Impact of the HDAC inhibition on the expression of E-cadherin and the SEMA3F tumor suppressor genes revealed new promising compounds for lung cancer treatments.

Full text of DOI:10.1021/jm9002439

3112
J. Med. Chem. 2009, 52, 3112–3115
Synthesis and Modeling of New Benzofuranone Histone Deacetylase Inhibitors that Stimulate
Tumor Suppressor Gene Expression
Ce´dric Charrier,† Jonathan Clarhaut,‡ Jean-Pierre Gesson,† Guillermina Estiu,§ Olaf Wiest,§ Joe¨lle Roche,‡ and
Philippe Bertrand*,†
Laboratoire Synthe`se et Re´actiVite´ des Substances Naturelles, UniVersite´ de Poitiers, CNRS-UMR 6514, 40 AVenue du Recteur Pineau,
Poitiers F-86022, France, Institut de Physiologie et de Biologie Cellulaires, UniVersite´ de Poitiers, CNRS-UMR 6187, 40 AVenue du Recteur
Pineau, Poitiers F-86022, France, Walther Cancer Research Center, Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556-5670
ReceiVed January 21, 2009
New benzofuranones were synthesized and evaluated toward NCI-H661 non-small cell lung cancer cells.
Benzamide derivatives possessed micromolar antiproliferative and histone deacetylase inhibitory activities
and modulate histone H4 acetylation. Hydroxamic acids were found to be potent nanomolar antiproliferative
agents and HDAC inhibitors. Computational analysis presented a rationale for the activities of the hydroxamate
derivatives. Impact of the HDAC inhibition on the expression of E-cadherin and the SEMA3F tumor
suppressor genes revealed new promising compounds for lung cancer treatments.
Introduction
interactions of large and lipophilic caps with residues sitting
outside the entry of the active site channel10 as in tubacin (5).
These interactions cannot be established in the class I isoforms.
Molecular modeling explained the mutation effects of key
residues of the channel11 and the selectivity of thiophenyl-biaryl
binders in HDAC1 vs HDAC3.
Chemical modifications of DNA and histones are eukaryotic
cellular events modulating DNA transcription and responsible
for altered epigenetic modifications during cancer progression.1
Histone modifications control chromatin remodeling, with
acetylation giving the inactive chromatin and DNA transcription
repression. The acetylation and deacetylation of histones are
mediated by histone acetyl transferases and histone deacetylases
(HDACa).2 Overexpression of HDAC has been reported in
cancers, and development of HDAC inhibitors (HDACi) is a
promising anticancer strategy.3 HDACi were isolated (tricho-
statin A (TSA) (1), apicidin (4), Chart 1) or synthesized, like
SAHA (2), FDA approved for treating cutaneous T-cell lym-
phoma,4 or benzamide MS-275 (3). The most important HDACi
are the hydroxamic acids group (1, 2), followed by the
benzamides (3), the cyclic tetrapeptides (4), the carboxylic acids,
and the electrophilic ketones.
From our previous work on TSA analogues, we planned to
produce more potent HDACi by replacing the methylene bridge
in compound 6b12a (Scheme 1) by an isosteric oxygen atom,
leading to a new family of compounds 7 with possible better
biological activities and selectivity for HDAC1 vs HDAC6.12
Representative ligands were modeled in homology models of
HDAC1 and HDAC6.10b The expression of E-cadherin and the
semaphorin 3F (SEMA3F) tumor suppressor gene, two known
HDACi targets in lung cancer, were evaluated. E-Cadherin plays
a major role in epithelial cell adhesion, and down regulation is
involved in several tumor progression mechanisms13 and
correlated to poor prognosis in lung cancer. SEMA3F is
expressed by multiple cell types, modulating the tumor angio-
genesis and progression.14 SEMA3F expression is lost or
reduced in lung cancers. Restoring SEMA3F and E-cadherin
expression could be a therapeutic strategy in lung cancer.
HDACi have a functional group, binding the zinc atom of
the active site, linked to a cap moiety by a spacer fitting the
geometry of the active site channel of HDAC. The cap can
produce specific interactions with the external surface of the
protein, leading to HDACi selectivity.5 In the protein p53, the
acetylated K382 amino group is close to the external Tyr100 and
Asp101 HDAC8 residues and stabilized by hydrogen bonding
contacts between the NH backbone of the substrate and the
Asp101.6 These pairs of residues conserved in classes I/II/IV7
were suggested to be important for selectivity.
Results and Discussion
Analogues 7 were prepared from furanones 13 (Scheme 1).12
Acid 8 gave the phenol 10b by esterification and N,N-
dimethylation. Etherification of phenols 10 afforded ethers 12,
cyclized in situ to the esters 14, heated to afford on decarboxy-
lation furanones 13. The decarboxylation of 14a was completed
by an additional stirring with HCl 6 N. Benzofuranones 13 were
reacted with 15 to give aldehydes 16. The unsuccessful initial
procedure was modified to use NaOMe/MeOH as a base.12
Acids 19 were obtained in good yields by a two-step
procedure from aldehydes 16.12a Hydroxamic acids 7a,b were
prepared by reacting acids 19 with the O-tetrahydropyranyl
protected hydroxylamine, followed by acidic methanolysis.
Coupling of acids 19 with 1,2-diaminobenzene gave the
benzamides 7c,d.
Benzamides are more active on class I,8 tetrapeptide 4 is more
active on HDAC2,3, and several alkylthiols are selective
HDAC8 inhibitors.9 Hydroxamic acids are nonselective. SAHA
is an inhibitor of most members of the class I/II but is a poor
HDAC8 ligand. HDAC6 selectivity can result from preferred
* To whom correspondence should be addressed. Phone: (33) 05 49 45
41 92. Fax: (33) 05 49 45 37 02. E-mail: philippe.bertrand@univ-poitiers.fr.
†
Laboratoire Synthe`se et Re´activite´ des Substances Naturelles, Universite´
de Poitiers.
‡
Institut de Physiologie et de Biologie Cellulaires, Universite´ de Poitiers.
Walther Cancer Research Center, Department of Chemistry and
§
Antiproliferative activities were evaluated against NCI-H661
non-small cell lung cancer cells (Figure S1 and Table 1,
Supporting Information). Compound 1 gave a 100 nM IC50
Biochemistry, University of Notre Dame.
a Abbreviations: HDAC, histone deacetylases; HDACi, HDAC inhibitors;
SEMA3F, semaphorin 3F; MD, molecular dynamics.
10.1021/jm9002439 CCC: $40.75
2009 American Chemical Society
Published on Web 04/22/2009

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3113
Chart 1. Examples of HDAC Inhibitors
Scheme 1. Preparation of Benzofuranonesa
a Reagents: (i) H2SO4, MeOH, 54%; (ii) CH2O, NaBH3CN, 65%; (iii) 11, K2CO3, DMF, 20 °C, overnight; (iv) K2CO3, DMF, reflux, 4 h; (v) HCl 6 N,
DMF, 4 h; (vi) MeONa, MeOH, 15, reflux; (vii) HCl 6 N, AcOEt, 80-81%; (viii) PhH, reflux, 17, 85%; (ix) LiOH aq, THF:MeOH, 95%; (x) H2N-OTHP,
TBTU, DMF, NEt3; (xi) Amberlyst resin H+, CH2Cl2, MeOH; (xii) H2N-Ph-NH2, EDC, THF.
value. Compound 7a was found less active (IC50 of 1 µM) and
7b more potent (IC50 of 45 nM). The benzamides 7c,d were
active at higher doses (IC50 3 and 4 µM, respectively), in
agreement with previous data.8,12 The HDAC inhibition
was analyzed for histone H4 and tubulin acetylation (Figure
1A).12 At 300 nM, 1 and 7b similarly induced histone H4 and
tubulin acetylation. Interestingly, 7a at 300 nM induced only
tubulin acetylation, while strong HDAC inhibition appeared at
3 µM for histone H4 acetylation. In contrast, benzamide
derivatives 7c,d were inactive at 300 nM and a moderate HDAC
inhibition was observed at 3 µM on histone H4 acetylation. We
tested E-cadherin and SEMA3F expressions by quantitative real-
time RT-PCR (Figure 1B). As expected, 1 (300 nM) stimulated
E-cadherin and SEMA3F expression, increasing their mRNA
levels of about 50- and 4-fold, respectively. The same efficiency
was obtained with 7b (300 nM). A 3 µM concentration was
necessary for 7a to reach the level of stimulation of TSA and
7b. Again, the benzamide derivatives were efficient only at 3
µM, without reaching the efficiency of 1 and 7b.
The most active compounds 6b and 7b were selected for
computational studies. The role of the oxygen bridge and the
spatial position of the dimethylamino group, shown to improve
the HDACi activities,12 were evaluated. In compounds 6 and
7, only the free rotating bond connecting the ketone rings to
the diene chain was expected to play a role in the resulting
conformations. In this respect, we selected only one stereoisomer
to perform molecular dynamics (MD) simulations. Compounds
6b and 7b bound to HDAC1 and HDAC6 were analyzed using
MD protocol to capture any specific interaction of the protein
with the oxygen atom of the benzofuranone moiety that may
explain the observed HDACi activities of compound 7b. In the
two isoforms, the hydroxamic group is bonded to the zinc ion
and the hydrocarbon chain (linker region) fills the narrow portion
of the pocket lined by hydrophobic groups (Phe205 and Phe150
in HDAC1). Compounds 6b and 7b in HDAC1 showed no
preferential orientation of the cap (Figure S2, Supporting
Information). The same orientation is favored at the end of the
dynamics for both ligands, which is only kept by lipophilic
interactions with Phe150 and the residues of a proline-rich
lipophilic pocket (Figure 2A). Similar interactions were found
for 6b and 7b in HDAC6, where Pro698 replaces Arg270
(Figure 2B), and proline residues also defined a lipophilic
pocket.
These results confirmed the low impact of the C2 stereochemistry.
Conclusion
In conclusion, the synthesis of new TSA analogues is
described, with antiproliferative activities and HDACi properties.
The hydroxamates 7a,b were found active on histone H4 and
tubulin acetylation, suggesting a class I/II inhibitory activity.
Compound 7b confirmed the key role of the dimethylamino
group for activity. Our benzamides 7c,d were found more potent
on class I HDAC at micromolar concentrations. The HDAC
inhibition was correlated with upregulation of two tumor
suppressor genes, SEMA3F and E-cadherin, demonstrating
potential therapeutic application for lung cancers. MD simula-
tions of 6b and 7b confirmed the interaction of the dimethy-

3114 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Brief Articles
Figure 1. (A) Analysis of histone H4 and tubulin acetylation. NCI-H661 cells were treated for 6 h with compounds 1 and 7a-d. Western blots
represent three independent experiments. Left: kDa, molecular weights; Ac-H4, acetylated histone H4; Ac-tubulin, acetylated tubulin. R-Tubulin:
loading control. (B) E-Cadherin (left) and SEMA3F (right) mRNA levels. Values obtained from duplicates are expressed in % of GAPDH expression.
Figure 2. Stick representations of the interactions of compounds 6b and 7b with residues lining the active site pocket of HDAC1 (A) and HDAC6
(B).
overnight. The solution was neutralized with saturated NaHCO3
and extracted with 3 × 50 mL EtOAc. The combined organic layers
were dried (MgSO4) and concentrated under vacuum. The protected
OTHP derivative was purified (flash chromatography on silica, PE:
EtOAc 60:40) and dissolved in 5 mL of MeOH. Then 150 mg of
Amberlyst were added and stirring at ambient temperature continued
3-6 h until the starting material was consumed. The resin was
filtered off and MeOH removed under vacuum. Purification (flash
chromatography on silica, EtOAc) was followed by recrystallization
in a refrigerator from PE:EtOAc to give 7a as a yellow solid (82
lamino moiety with the surface of the protein as well as several
hydrophobic contacts of the dihydrofuran ring at the entry of
the active site. The cap region does not have a preferred
orientation and rotates over the course of the simulation as found
for SAHA10b and typical for hydrophobic interactions. Com-
parison with the results found for tubacin analogues10b indicated
the potential for further development of isoform selectivity by
chemical modification of these regions. Work is in progress to
develop more hindered compounds as potential selective
HDACi.
1
mg, 50%). H NMR (300 MHz; CD3OD) δ ppm: 1.6 (s, 3H), 1.8
(s, 3H), 5.8 (d, 1H, J ) 15.4 Hz), 5.94 (s, 1H), 6.85-7.3 (m, 2H),
7.6 (m, 2H), 13C NMR (75 MHz; CD3OD) δ ppm: 14.1, 23.8, 88.8,
113.5, 116.6, 119.3, 122.1, 124.9, 134.8, 138.3, 138.4, 145.5, 171.0,
202.0. HRMS ESI: (M + H)+(C15H16NO4): calcd 274.10793, found
274.1084.
Experimental Section
General methods and analytical HPLC conditions, syntheses of
known compounds, and access to benzofuranones intermediates
13a-b, 16a-b, 18a-b, and 19a-b are reported in Supporting
Information. Compounds used for biological tests were at least 95%
pure as determined by HPLC methods (see Supporting Information).
5-(2-Methyl-3-oxo-2,3-dihydro-benzofuran-2-yl)-4-methyl-
penta-2,4-dienoic Acid Hydroxamide (7a). To a solution of acid
19a (155 mg, 0.6 mmol) in DMF (2 mL) were added TBTU (288
mg, 0.9 mmol) and NEt3 (0.165 mL, 1.2 mmol). After 2 h,
NH2-OTHP was added (106 mg, 0.9 mmol) and stirring continued
5-(6-Dimethylamino-2-methyl-3-oxo-2,3-dihydro-benzofuran-
2-yl)-4-methyl-penta-2,4-dienoic Acid Hydroxamide (7b). Pre-
pared as above from acid 19b (188 mg, 0.625 mmol), DMF
(2 mL), TBTU (300 mg, 0.937 mmol), and NEt3 (0.17 mL, 1.25
mmol). Recrystallization from PE:EtOAc in a refrigerator gave 7b
1
as a light-pink solid (60 mg, 30%, mp 131-132 °C). H NMR
(300 MHz; CD3OD) δ ppm: 1.45 (s, 3H), 1.9 (s, 3H), 3.1 (s, 6H),

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3115
deacetylase inhibitors: molecular mechanisms of action. Oncogene
2007, 26, 5541.
(2) Hodawadekar, S. C.; Marmorstein, R. Chemistry of acetyl transfer by
histone modifying enzymes: structure, mechanism and implications
for effector design. Oncogene 2007, 26, 5528.
5.8 (s, 1H), 5.80 (d, 1H, J ) 15.6 Hz), 6.16 (d, 1H, J ) 2.1 Hz),
6.45 (dd, 1H, J ) 2.1, 8.9 Hz), 7.05 (d, 1H, J ) 15.6 Hz), 7.30 (d,
1H, J ) 8.9 Hz). 13C NMR (75 MHz; CD3OD) δ ppm: 14.0, 25.0,
41.0, 90.8, 93.5, 108.5, 110.3, 119.1, 126.9, 136.9, 138.6, 146.1,
160.4, 166.6, 175.2, 200.7. IR neat: 3200, 2900, 1600, 1532, 1352,
1119. HRMS ESI: (M + Na)+ C17H20N2O4Na calcd 339.13208,
found 339.1320; (M + H)+ C17H21N2O4 calcd 317.15013, found
317.1510.
(3) Dokmanovic, M.; Clarke, C.; Marks, P. A. Histone deacetylase
inhibitors: overview and perspectives. Mol. Cancer Res. 2007, 5, 981.
(4) Duvic, M.; Talpur, R.; Ni, X.; Zhang, C.; Hazarika, P.; Kelly, C.;
Chiao, J. H.; Reilly, J. F.; Ricker, J. L.; Richon, V. M.; Frankel, S. R.
Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid,
SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood
2007, 109, 31.
(5) (a) Finnin, M. S.; Donigian, J. R.; Cohen, A.; Richon, V. M.; Rifkind,
R. A.; Marks, P. A.; Breslow, R.; Pavletich, N. P. Structures of a
histone deacetylase homologue bound to the TSA and SAHA
inhibitors. Nature (London) 1999, 401, 188. (b) Somoza, J. R.; Skene,
R. J.; Katz, B. A.; Mol, C.; Ho, J. D.; Jennings, A. J.; Luong, C.;
Arvai, A.; Buggy, J. J.; Chi, E.; Tang, J.; Sang, B. C.; Verner, E.;
Wynands, R.; Leahy, E. M.; Dougan, D. R.; Snell, G.; Navre, M.;
Knuth, M. W.; Swanson, R. V.; McRee, D. E.; Tari, L. W. Structural
snapshots of human HDAC8 provide insights into the class I histone
deacetylases. Structure 2004, 12, 1325.
(6) Vannini, A.; Volpari, C.; Gallinari, P.; Jones, P.; Mattu, M.; Carf´ı,
A.; De Francesco, R.; Steinku¨hler, C.; Di Marco, S. Substrate binding
to histone deacetylases as shown by the crystal structure of the
HDAC8-substrate complex. EMBO Rep. 2007, 8, 879.
(7) Nielsen, T. K.; Hildmann, C.; Dickmanns, A.; Schwienhorst, A.; Ficner,
R. Crystal structure of a bacterial class 2 histone deacetylase
homologue. J. Mol. Biol. 2005, 354, 107.
(8) Khan, N.; Jeffers, M.; Kumar, S.; Hackett, C.; Boldog, F.; Khramtsov,
N.; Qian, X.; Mills, E.; Berghs, S. C.; Carey, N.; Finn, P. W.; Collins,
L. S.; Tumber, A.; Ritchie, J. W.; Jensen, P. B.; Lichenstein, H. S.;
Sehested, M. Determination of the class and isoform selectivity of
small-molecule histone deacetylase inhibitors. Biochem. J. 2008, 409,
581.
(9) KrennHrubec, K.; Marshall, B. L.; Hedglin, M.; Verdin, E.; Ulrich,
S. M. Design and Evaluation of “Linkerness” Hydroxamic Acids as
Selective HDAC8 Inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 2874.
(10) (a) Kozikowski, A. P.; Tapadar, S.; Luchini, D. N.; Kim, K. H.;
Billadeau, D. D. Use of the Nitrile Oxide Cycloaddition (NOC)
Reaction for Molecular Probe Generation: A New Class of Enzyme
Selective Histone Deacetylase Inhibitors (HDACIs) Showing Pico-
molar Activity at HDAC6. J. Med. Chem. 2008, 51, 4370–4373. (b)
Estiu, G.; Greenberg, E.; Harrison, C. B.; Kwiatkowski, N. P.;
Mazitschek, R.; Bradner, J. E.; Wiest, O. Structural Origin of
Selectivity in Class II-Selective Histone Deacetylase Inhibitors. J. Med.
Chem. 2008, 51, 2898–2906.
(11) (a) Weerasinghe, S. V. W.; Estiu, G.; Wiest, O.; Pflum, M. K. H.
Residues in the 11 Å Channel of Histone Deacetylase 1 Promote
Catalytic Activity: Implications for Designing Isoform-Selective
Histone Deacetylase Inhibitors. J. Med. Chem. 2008, 51, 5542–5551.
(b) Witter, D.; Belvedere, S.; Chen, L.; Secrist, J.; Mosley, R.; Miller,
T. A. Benzo[b]thiophene-based histone deacetylase inhibitors. Bioorg.
Med. Chem. Lett. 2007, 17, 4562–4567.
(12) (a) Charrier, C.; Bertrand, P.; Gesson, J.-P.; Roche, J. Synthesis of
rigid trichostatin A analogs as HDAC inhibitors. Bioorg. Med. Chem.
Lett. 2006, 16, 5339. (b) Charrier, C.; Roche, J.; Gesson, J.-P.;
Bertrand, P. Antiproliferative activities of a library of hybrids between
indanones and HDAC inhibitor SAHA and MS-275 analogues. Bioorg.
Med. Chem. Lett. 2007, 17, 6142.
5-(2-Methyl-3-oxo-2,3-dihydro-benzofuran-2-yl)-4-methyl-
penta-2,4-dienoic Acid Benzamide (7c). To a solution of acid 19a
(134 mg, 0.52 mmol) in dry THF (5 mL) was added 1,2-
diaminobenzene (340 mg, 3.12 mmol) and EDC (145 mg, 0.68
mmol). After stirring overnight, the solution was concentrated under
vacuum. EtOAc was added (50 mL), and the resulting organic layer
was washed with H2O (30 mL) and then twice with aq 1 N NaOH
(20 mL). The organic layer was dried (MgSO4) and solvents
removed under vacuum. The resulting solid was purified (flash
chromatography EtOAc:PE 50:50) to give 7c as a pale-yellow
powder (127 mg, 70%, mp 174-175 °C). Rf: 0.8 (EtOAc:PE 50:
1
50). H NMR (300 MHz; CDCl3) δ ppm: 1.60 (s, 3H), 1.90 (s,
3H), 3.95 (s, 2H), 5.90 (s, 1H), 6.10 (d, 1H, J ) 15.3 Hz), 6.75
(m, 1H), 7.1 (m, 4H), 7.25 (d, 1H, J ) 15.3 Hz), 7.6 (m, 3H). 13
C
NMR (75 MHz; CDCl3) δ ppm: 13.7, 23.9, 88.8, 113.5, 118.1,
119.3, 119.4, 120.8, 122.1, 124.3, 124.9, 125.1, 127.1, 134.8, 137.3,
138.4, 140.7, 145.9, 164.3, 170.9, 201.8. IR neat: 3200, 2900, 1715,
1610, 1460, 1300, 1186. HRMS ESI: (M + Na)+ calcd 371.13716,
found 371.1378.
5-(6-Dimethylamino-2-methyl-3-oxo-2,3-dihydro-benzofuran-
2-yl)-4-methyl-penta-2,4-dienoic Acid Benzamide (7d). Prepared
as above from acid 19b (157 mg, 0.52 mmol), THF (5 mL), 1,2-
diaminobenzene (340 mg, 3.12 mmol), and EDC (145 mg, 0.68
mmol). Purification (flash chromatography EtOAc:PE 60:40) gave
7d as a pale-yellow powder (134 mg, 66%, mp: 136-140 °C). Rf:
1
0.8 (EtOAc:PE 60:40). H NMR (300 MHz; CDCl3) δ ppm: 1.6
(s, 3H), 1.9 (s, 3H), 3.1 (s, 6H), 3,6 (s, 2H), 5.9 (s, 1H), 6.0 (d,
1H, J) 15.2 Hz), 6.16 (s, 1H), 6.42 (dd, 1H, J ) 2.1, 8.9 Hz), 6.7
(m, 2H), 7.0 (t, 1H, J ) 7.5 Hz), 7.2 (m, 2H), 7.60 (d, 1H, J ) 8.8
Hz), 7.9 (s, 1H). 13C NMR (75 MHz; CDCl3) δ ppm: 13.6, 24.3,
40.5, 89.4, 92.4, 107.7, 108.1, 116.7, 118.1, 119.3, 120.5, 124.5,
125.2, 125.9, 127.0, 136.1, 136.7, 140.8, 146.3, 157.9, 164.6, 173.2,
198.3. IR neat: 3249, 2900, 1667, 1600, 1531, 1439, 1116. HRMS
ESI: (M + Na)+ C23H25N3O3Na calcd 414.17936, found 414.1777.
Acknowledgment. We thank MENRT, CNRS, and La Ligue
Contre le Cancer, Comite´ de Charente-Maritime for financial
support. G.E. and O.W. thank the Walther Cancer Institute at
the University of Notre Dame for continued financial support.
Supporting Information Available: Experimental details for
the synthesis of compounds 9, 10b, 13a,b, 16a,b, 18a,b, and 19a,b,
the analytical and spectral data for all compounds, the biological
evaluations of compounds 7a-d, and the molecular modeling
methods. This material is available free of charge via the Internet
at http://pubs.acs.org.
(13) Ohira, T.; Gemmill, R.; Ferguson, K.; Kusy, S.; Roche, J.; Brambilla,
E.; Zeng, C.; Baron, A.; Bemis, L.; Erickson, P.; Wilder, E.; Rustgi,
A.; Kitajewski, J.; Gabrielson, E.; Bremnes, R.; Franklin, W.; Drabkin,
H. WNT7a induces E-Cadherin in lung cancer cells. Proc. Natl. Acad.
Sci. U.S.A. 2003, 100, 10429.
(14) Potiron, V.; Roche, J.; Drabkin, H. Semaphorins and their receptors
in lung cancer. Cancer Lett. 2009, 273, 1.
References
(1) (a) Baylin, S. B.; Ohm, J. E. Epigenetic gene silencing in cancersa
mechanism for early oncogenic pathway addiction. Nat. ReV. Cancer
2006, 6, 107. (b) Xu, W. S.; Parmigiani, R. B.; Marks, P. A. Histone
JM9002439