Novel inhibitors of human histone deacetylases: Design, synthesis and bioactivity of 3-alkenoylcoumarines

Article abstract of DOI:10.1016/j.bmcl.2014.06.067

Histone deacetylases (HDACs) are well-established, promising targets for anticancer therapy due to their critical role in cancer development. Accordingly, an increasing number of HDAC inhibitors displaying cytotoxic effects against cancer cells have been reported. Among them, a large panel of chemical structures was described including coumarin-containing molecules. In this study, we described synthesis and biological activity of new coumarin-based derivatives as HDAC inhibitors. Among eight derivatives, three compounds showed HDAC inhibitory activities and antitumor activities against leukemia cell lines without affecting the viability of peripheral blood mononuclear cells from healthy donors.

Full text of DOI:10.1016/j.bmcl.2014.06.067

Accepted Manuscript
Novel inhibitors of human histone deacetylases: design, synthesis and bioac-
tivity of 3-alkenoylcoumarines
Carole Seidel, Michael Schnekenburger, Clemens Zwergel, François Gaascht,
Antonello Mai, Mario Dicato, Gilbert Kirsch, Sergio Valente, Marc Diederich
PII:
S0960-894X(14)00695-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.06.067
BMCL 21786
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 May 2014
19 June 2014
21 June 2014
Please cite this article as: Seidel, C., Schnekenburger, M., Zwergel, C., Gaascht, F., Mai, A., Dicato, M., Kirsch,
G., Valente, S., Diederich, M., Novel inhibitors of human histone deacetylases: design, synthesis and bioactivity of
3-alkenoylcoumarines, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.
2014.06.067
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Leave this area blank for abstract info.
Novel inhibitors of human histone
deacetylases: design, synthesis and
bioactivity of 3-alkenoylcoumarines
Cancer cell
proliferation
Carole Seidel, Michael Schnekenburger,
Clemens Zwergel, François Gaascht,
Antonello Mai, Mario Dicato, Gilbert Kirsch,
Sergio Valente, Marc Diederich
7a-g
Cancer cell
viability
HDAC
Normal cell
viability
7h

Bioorganic & Medicinal Chemistry Letters
jou rn al h om ep a ge : www .e ls e v ie r .c om
Novel inhibitors of human histone deacetylases: design, synthesis and bioactivity
of 3-alkenoylcoumarines
Carole Seidela, Michael Schnekenburgera, Clemens Zwergelb, François Gaaschta, Antonello Maic, Mario
Dicatoa, Gilbert Kirschb, Sergio Valenteb,c*, Marc Diederichd*
a Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, L-2540 Luxembourg, Luxembourg
b UMR CNRS 7565 SRSMC, Université de Lorraine, 57070 Metz, France
c Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P.le Aldo Moro 5, 00185 Roma, Italy
d College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Histone deacetylases (HDACs) are well-established, promising targets for anticancer therapy
due to their critical role in cancer development. Accordingly, an increasing number of HDAC
inhibitors displaying cytotoxic effects against cancer cells have been reported. Among them, a
large panel of chemical structures was described including coumarin-containing molecules. In
this study, we described synthesis and biological activity of new coumarin-based derivatives as
HDAC inhibitors. Among eight derivatives, three compounds showed HDAC inhibitory
activities and antitumor activities against leukemia cell lines without affecting the viability of
peripheral blood mononuclear cells from healthy donors.
Revised
Accepted
Available online
Keywords:
Chalcone
Coumarin
2009 Elsevier Ltd. All rights reserved
.
Histone deacetylase inhibitors
Anti-proliferative activity
Cancer
Histone deacetylases (HDACs) are enzymes that catalyze
removal of acetyl groups from lysine residues. Beyond their
originally identified histone substrates, HDACs target non-
histone proteins including α-tubulin, heat shock protein 90 or p53
[1]. The HDAC family comprises 18 members subdivided into
four classes based on sequence similarity and catalytic activity
[2]. HDACs play a critical role in epigenetic gene regulation and
therefore control multiple cellular processes [1, 3].
Since expression and/or activity of HDACs are deregulated in
various cancer subtypes, they became an interesting target for
anticancer therapy [4, 5]. Accordingly, numerous compounds
from natural sources as well as synthetic derivatives were
identified and further developed as HDAC inhibitors (HDACi)
and some of them are already undergoing clinical trials for
anticancer therapy [6-8]. Among HDACi, chalcone-based
compounds (1,3-diaryl-2-propen-1-ones) are a group of aromatic
natural or synthetic unsaturated ketones with anti-inflammatory
and anticancer activities [9, 10]. Ease of preparation, oral
administration and safety also support the feasibility of chalcone-
based compounds as therapeutic agents [11-13].
Additionally, their simple and efficient synthesis makes them
attractive for industrial production [14].
Curcumin is a promising molecule that also modulates the
acetylation status of proteins [15]. In vitro studies demonstrated
that it possesses potent cytotoxic and chemotherapeutic
properties in different models [16-24]. Whilst curcumin itself has
limited efficacy due to its low bioavailability and stability in
physiological media [25], analogs including N-methylpiperidone
were generated [26]. Natural products bearing 2H-1-benzopyran-
2-one (coumarin) possess cytotoxic antitumor potential [27, 28].
Coumarin-based compounds were previously described as Cdc25
phosphatase and HDAC inhibitors [27, 29-32].
So far only two molecules, FK228 (Romidepsin) and
suberoylanilide hydroxamic acid (SAHA, Vorinostat), gained
Food and Drug Administration approval for cutaneous T-cell
lymphoma [8]. In this context, development of novel HDACi
with good anticancer properties and low toxicity remains a
challenge. Here we designed novel coumarin-containing analogs
7a-h and we assessed their HDACi potential and effects on cell
proliferation and viability in K-562 and U-937 leukemia cell
lines compared to peripheral blood mononuclear cells (PBMCs)
of healthy donors.
*Corresponding authors:
Marc Diederich. Tel: +82-2-880-8919; e-mail: marcdiederich@snu.ac.kr;
Department of Pharmacy, College of Pharmacy, Seoul National University,
Building 20 Room 303, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Korea.
Sergio Valente. Tel: +39 06 49913891; fax +39 06 491491; e-mail:
sergio.valente@uniroma1.it; Dipartimento di Chimica e Tecnologie del
Farmaco, Sapienza Università di Roma, P.le Aldo Moro 5, 00185 Roma, Italy
The new series of coumarin-based analogues (7a-h) bearing an
α,β-(mono- or bis)-unsaturated ketone at the C3 or C4 position
(Figure 1) were prepared carrying out aldolic condensation
between 3-acetylcoumarins (5a-b) or 4-acetyl coumarin (5c),
previously synthesized by us according to the literature [33-35]

and the appropriate aldehydes (6a-h) following an adapted
procedure of Cechinel-Filho et al. [36]. All the chemical-physical
data, elemental analyses, 1H NMR and 13C NMR of the
compounds as well as all the conditions for their biological
evaluation are described in the supporting information.
Figure 1: Synthesis of coumarin-based compounds 7a-h.
Reagent and conditions (1): pyrrolidine, ethanol, 80°C, 1-3 h.
Coumarin-based compounds were tested for their total HDAC
proliferation was accompanied by a marked decrease of cell
viability (Figure 2B). We noticed that compound 7d precipitated
at 100 µM in cell culture medium that could explain why this
compound was less effective at this concentration compared to 50
µM. Thus, we observed a close effect between compounds 7b
and 7d on leukemia cancer cell lines. Indeed, these two
compounds are structurally identical except a methoxy group
present in compound 7d. Interestingly, among compounds with
one unsaturation (7e-g), compound 7h, the more active
compound on cell viability and proliferation, was the only
structure inhibiting HDAC activities and corresponds to the C4
regioisomer of compound 7f, which was inactive. These
differential activities could result from 3D structure variations
depending on the position of the keto function. To assess for
differential toxicity, PBMCs from healthy donors [39] were
treated with compounds 7b, 7d and 7h under the same
conditions. Results showed no effect on PBMC viability (Figure
2C).
Since among newly synthetized compounds, 7d was the most
active compound on HDAC activity, we further tested whether
this hybrid compound possessed an HDAC inhibitory potential
superior to the two parent compounds, namely the 3-
acetylcoumarin 5b and the aldehyde 6d. First, 5b and 6d were
tested on in vitro total HDAC activity. Results demonstrated that
100 µM compound 5b inhibited only 20% of total HDAC
activity, whereas at the same concentration compound 6d
enhanced total HDAC activity by 80%. Compounds 5b and 6d
were further tested on cancer as well as on PBMCs from healthy
donors. Results demonstrated that both compounds slightly
decreased proliferation only in U-937 cells after 72 hours of
treatment without affecting viability of both cancer K-562 and U-
937 cell lines and healthy PBMCs (Figure 3). All together these
results clearly demonstrated that the newly synthetized hybrid
compound 7d possesses an inhibitor potential superior to both
parent compounds 5b and 6d.
inhibitory potential on K-562 nuclear extracts [37, 38]. 7b, 7d
and 7h showed a 20 to 50% of inhibition of total HDAC activity
at 100 µM (Table 1). In opposition to 7b, compound 7d, with a
methoxy group at R3, presented increased levels of inhibition.
Noteworthy, compound 7c with a hydroxyl group instead of the
methoxy group in R2 was inactive against HDACs further
demonstrating the importance of the methoxy group in this
position. Compound 7d was tested against seven HDAC
isoenzymes representing classes I, IIb and IV and acted as a pan-
HDACi (Table 2) with IC50s between 12 and 85 µM.
Interestingly, 7d inhibited HDAC3 with an IC50 at 12 µM and
may serve as a lead for targeting this nuclear isoenzyme.
Table 1: Effect of compounds 7a-h on in vitro total HDAC activity. Values
represent the mean of the percentage of inhibition measured in two
independent experiments. Inactive means inhibition < 10% at 100 µM.
Compound
Effect on HDAC activity
Inactive
7a
7b
7c
7d
7e
7f
30% inhibition at 100 µM
Inactive
50% inhibition at 100 µM
Inactive
Inactive
7g
7h
Inactive
20% inhibition at 100 µM
Table 2: Effect of 7d on in vitro activity of HDAC isoenzymes.
Values represent the mean of the percentage of inhibition measured in two
independent experiments. Inactive means inhibition < 10% at 100 µM.
HDAC
Class
I
IC50 (µM)
Isoenzyme
HDAC1
HDAC2
HDAC3
HDAC8
59
33
12
28
IIb
IV
HDAC6
32
85
74
In this study, we have described three new coumarin-
based derivatives, 7b, 7d and 7h, endowed with HDAC
HDAC10
HDAC11
inhibitory and antitumor properties. Regarding differences in
their chemical structures and biological effects, these
compounds can support a new design of molecules to
increase their reactivity against HDAC activity and cancer
cells.
Compounds 7b and 7d showed moderate effects on proliferation
and viability of chronic myeloid leukemia K-562 and histiocytic
lymphoma U-937 cell lines (Figure 2A). Compound 7h strongly
inhibited proliferation in both cell lines. In U-937 cells, loss of

A
K-562
15
10
5
*
*
*
*
***
*
*
***
***
***
*
*
***
***
*
*
*
***
***
0
U-937
20
*
***
**
15
10
5
***
***
***
***
***
*
**
***
***
***
*
***
*
*
***
*
***
***
***
***
***
***
***
***
0
Hours
24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72
0
10
25
50
100
10
25
50
100
10
25
50
7h (µM)
100
7b (µM)
7d (µM)
B
K-562
*
*
**
*
*
100
**
*
***
***
*
***
***
***
***
***
80
60
40
20
***
0
100
80
U-937
***
*
*
***
***
***
***
*** ***
***
*
***
***
***
***
***
***
***
***
***
***
***
***
60
***
***
***
40
20
0
Hours
24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72
10 25 50 100 10 25 50 100 10 25 50 100
7b (µM) 7d (µM) 7h (µM)
0
C
100
80
60
40
20
0
24 48 24 48 24 48 24 48 24 48 24 48 24 48 24 48 24 48 24 48 24 48 24 48 24 48
10 25 50 100 10 25 50 100 10 25 50 100
7b (µM) 7d (µM) 7h (µM)
Hours
0
Figure 2: Effect of 7b, 7d, 7h on cell proliferation and viability.
K-562 and U-937 cells were treated with the indicated concentration of compound. (A) Cell viability and (B) proliferation were assessed after 24, 48 and 72h. (C)
PBMCs from healthy donors were incubated with 7b, 7d, 7h and then cell viability was evaluated after 24 and 48h of treatment. Data are the mean SD of three
independent cultures. * p < 0.05, ** p < 0.01, *** p < 0.005 versus control.

A
K-562
20
15
10
5
0
U-937
20
*
*
*
*
*
*
***
***
15
10
5
*
0
Hours
24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72
0
10
25
50
100
10
25
50
100
5b (µM)
6d (µM)
B
K-562
100
80
60
40
20
0
U-937
100
80
60
40
20
0
Hours
24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72 24 48 72
10 25 50 100 10 25 50 100
0
5b (µM)
6d (µM)
C
100
80
60
40
20
0
Hours
24 48 24 48 24 48 24 48 24 48 24 48 24 48 24 48 24 48
10 25 50 100 10 25 50 100
5b (µM) 6d (µM)
0
Figure 3: Effect of 5b and 6d on cell proliferation and viability.
K-562 and U-937 cells were treated with the indicated concentration of compound. (A) Cell viability and (B) proliferation were assessed after 24, 48 and 72h. (C)
The viability of PBMCs from healthy donors was evaluated after 24 and 48h of treatment with compounds 5b and 6d. Data are the mean SD of three
independent cultures. * p < 0.05, *** p < 0.005 versus control.
the “Recherche Cancer et Sang” foundation, the “Recherches
Scientifiques Luxembourg” association, by the “Een Häerz fir
kriibskrank Kanner” association, by the Action LIONS “Vaincre
le Cancer” association and by Télévie Luxembourg. MD is
supported by the National Research Foundation of Korea (NRF)
grant for the Global Core Research Center (GCRC) funded by the
Korea government, Ministry of Science, ICT & Future Planning
(MSIP) (No.2011-0030001).
Acknowledgments
The research leading to these results has received funding from
the [European Community's] Seventh Framework Programme
([FP7/2007-2013] under grant agreement n° 215009. CS is
recipient of a Télévie Luxembourg fellowship. MS is supported
by a “Waxweiler grant for cancer prevention research” from the
Action Lions “Vaincre le Cancer”. This work was supported by

[22] C.P. Prasad, G. Rath, S. Mathur, D. Bhatnagar, R. Ralhan, Potent growth
suppressive activity of curcumin in human breast cancer cells: Modulation of
Wnt/beta-catenin signaling, Chemico-biological interactions, 181 (2009) 263-
271.
Conflict of interest
The authors declare no conflict of interest.
[23] M.H. Teiten, S. Eifes, M. Dicato, M. Diederich, Curcumin-the paradigm
of a multi-target natural compound with applications in cancer prevention and
treatment, Toxins, 2 (2010) 128-162.
References and notes
[24] M.H. Teiten, F. Gaascht, M. Cronauer, E. Henry, M. Dicato, M.
Diederich, Anti-proliferative potential of curcumin in androgen-dependent
prostate cancer cells occurs through modulation of the Wingless signaling
pathway, International journal of oncology, 38 (2011) 603-611.
[25] A.L. Cheng, C.H. Hsu, J.K. Lin, M.M. Hsu, Y.F. Ho, T.S. Shen, J.Y. Ko,
J.T. Lin, B.R. Lin, W. Ming-Shiang, H.S. Yu, S.H. Jee, G.S. Chen, T.M.
Chen, C.A. Chen, M.K. Lai, Y.S. Pu, M.H. Pan, Y.J. Wang, C.C. Tsai, C.Y.
Hsieh, Phase I clinical trial of curcumin, a chemopreventive agent, in patients
with high-risk or pre-malignant lesions, Anticancer Res, 21 (2001) 2895-
2900.
[1] S. Spange, T. Wagner, T. Heinzel, O.H. Kramer, Acetylation of non-
histone proteins modulates cellular signalling at multiple levels, Int
Biochem Cell Biol, 41 (2009) 185-198.
J
[2] A.J. de Ruijter, A.H. van Gennip, H.N. Caron, S. Kemp, A.B. van
Kuilenburg, Histone deacetylases (HDACs): characterization of the classical
HDAC family, Biochem J, 370 (2003) 737-749.
[3] C. Hildmann, D. Riester, A. Schwienhorst, Histone deacetylases--an
important class of cellular regulators with a variety of functions, Appl
Microbiol Biotechnol, 75 (2007) 487-497.
[4] C. Florean, M. Schnekenburger, C. Grandjenette, M. Dicato, M.
Diederich, Epigenomics of leukemia: from mechanisms to therapeutic
applications, Epigenomics, 3 (2011) 581-609.
[26] B. Yadav, S. Taurin, R.J. Rosengren, M. Schumacher, M. Diederich, T.J.
Somers-Edgar, L. Larsen, Synthesis and cytotoxic potential of heterocyclic
cyclohexanone analogues of curcumin, Bioorganic & medicinal chemistry, 18
(2010) 6701-6707.
[5] M. Schnekenburger, M. Diederich, Epigenetics Offer New Horizons for
Colorectal Cancer Prevention, Current colorectal cancer reports, 8 (2012) 66-
81.
[27] I. Kostova, Synthetic and natural coumarins as cytotoxic agents, Curr
Med Chem Anticancer Agents, 5 (2005) 29-46.
[6] F. Folmer, B. Orlikova, M. Schnekenburger, M. Dicato, M. Diederich,
Naturally occurring regulators of histone acetylation/deacetylation, Current
Nutrition & Food Science, 6 (2010) 78-99.
[28] M.E. Riveiro, N. De Kimpe, A. Moglioni, R. Vazquez, F. Monczor, C.
Shayo, C. Davio, Coumarins: old compounds with novel promising
therapeutic perspectives, Curr Med Chem, 17 (2010) 1325-1338.
[29] A. Beillerot, J.-C.R. Domínguez, G. Kirsch, D. Bagrel, Synthesis and
protective effects of coumarin derivatives against oxidative stress induced by
doxorubicin, Bioorg Med Chem Lett, 18 (2008) 1102-1105.
[30] A.J. Olaharski, J. Rine, B.L. Marshall, J. Babiarz, L. Zhang, E. Verdin,
M.T. Smith, The flavoring agent dihydrocoumarin reverses epigenetic
silencing and inhibits sirtuin deacetylases, PLoS Genet, 1 (2005) e77.
[31] D. Rotili, V. Carafa, D. Tarantino, G. Botta, A. Nebbioso, L. Altucci, A.
Mai, Simplification of the tetracyclic SIRT1-selective inhibitor MC2141:
coumarin- and pyrimidine-based SIRT1/2 inhibitors with different selectivity
profile, Bioorganic & medicinal chemistry, 19 (2011) 3659-3668.
[32] S. Valente, E. Bana, E. Viry, D. Bagrel, G. Kirsch, Synthesis and
biological evaluation of novel coumarin-based inhibitors of Cdc25
phosphatases, Bioorg Med Chem Lett, 20 (2010) 5827-5830.
[7] C. Seidel, C. Florean, M. Schnekenburger, M. Dicato, M. Diederich,
Chromatin-modifying agents in anti-cancer therapy, Biochimie, (2012).
[8] C. Seidel, M. Schnekenburger, M. Dicato, M. Diederich, Histone
deacetylase modulators provided by Mother Nature, Genes Nutr, 7 (2012)
357-367.
[9] S.H. Lee, Y.Z. Zhao, E.J. Park, X.H. Che, G.S. Seo, D.H. Sohn, 2',4',6'-
Tris(methoxymethoxy) chalcone induces apoptosis by enhancing Fas-ligand
in activated hepatic stellate cells, Eur J Pharmacol, 658 (2011) 9-15.
[10] B. Orlikova, M. Schnekenburger, M. Zloh, F. Golais, M. Diederich, D.
Tasdemir, Natural chalcones as dual inhibitors of HDACs and NF-kappaB,
Oncol Rep, 28 (2012) 797-805.
[11] M. Baba, R. Asano, I. Takigami, T. Takahashi, M. Ohmura, Y. Okada,
H. Sugimoto, T. Arika, H. Nishino, T. Okuyama, Studies on Cancer
Chemoprevention by Traditional Folk Medicines XXV.&mdash;Inhibitory
Effect of Isoliquiritigenin on Azoxymethane-Induced Murine Colon Aberrant
Crypt Focus Formation and Carcinogenesis, Biological and Pharmaceutical
Bulletin, 25 (2002) 247-250.
[33] T. Hirai, H. Togo, Preparation and Synthetic Use of Polymer-Supported
Acetoacetate Reagent, Synthesis, 2005 (2005) 2664-2668.
[34] S.t. Starčević, P. Brožič, S. Turk, J.k. Cesar, T. Lanišnik Rižner, S.
Gobec, Synthesis and Biological Evaluation of (6- and 7-Phenyl) Coumarin
Derivatives as Selective Nonsteroidal Inhibitors of 17β-Hydroxysteroid
Dehydrogenase Type 1, J Med Chem, 54 (2010) 248-261.
[12] D.A. Israf, T.A. Khaizurin, A. Syahida, N.H. Lajis, S. Khozirah,
Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-
kappaB nuclear translocation and Ikappa-B phosphorylation in RAW 264.7
macrophage cells, Molecular immunology, 44 (2007) 673-679.
[13] L. Wattenberg, Chalcones, myo-inositol and other novel inhibitors of
pulmonary carcinogenesis, J Cell Biochem Suppl, 22 (1995) 162-168.
[14] B. Orlikova, D. Tasdemir, F. Golais, M. Dicato, M. Diederich, The
aromatic ketone 4'-hydroxychalcone inhibits TNFalpha-induced NF-kappaB
activation via proteasome inhibition, Biochem Pharmacol, 82 (2011) 620-
631.
[35] S. Valente, G. Kirsch, Facile synthesis of 4-acetyl-coumarins,
-
thiocoumarin and -quinolin-2(1H)-one via very high alpha-regioselective
Heck coupling on tosylates, Tetrahedron Lett, 52 (2011) 3429-3432.
[36] V. Cechinel-Filho, Z.R. Vaz, L. Zunino, J.B. Calixto, R.A. Yunes,
Synthesis of xanthoxyline derivatives with antinociceptive and
antioedematogenic activities, European journal of medicinal chemistry, 31
(1996) 833-839.
[37] C. Seidel, M. Schnekenburger, M. Dicato, M. Diederich,
Antiproliferative and proapoptotic activities of 4-hydroxybenzoic acid-based
inhibitors of histone deacetylases, Cancer letters, (2013).
[15] M.H. Teiten, M. Dicato, M. Diederich, Curcumin as a regulator of
epigenetic events, Molecular nutrition & food research, 57 (2013) 1619-1629.
[16] T.L. Chiu, C.C. Su, Curcumin inhibits proliferation and migration by
increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in
breast cancer MDA-MB-231 cells, International journal of molecular
medicine, 23 (2009) 469-475.
[38] M. El Amrani, D. Lai, A. Debbab, A.H. Aly, K. Siems, C. Seidel, M.
Schnekenburger, A. Gaigneaux, M. Diederich, D. Feger, W. Lin, P. Proksch,
Protein kinase and HDAC inhibitors from the endophytic fungus Epicoccum
nigrum, J Nat Prod, 77 (2014) 49-56.
[39] M. Schnekenburger, C. Grandjenette, J. Ghelfi, T. Karius, B. Foliguet,
M. Dicato, M. Diederich, Sustained exposure to the DNA demethylating
agent, 2'-deoxy-5-azacytidine, leads to apoptotic cell death in chronic
myeloid leukemia by promoting differentiation, senescence, and autophagy,
Biochem Pharmacol, 81 (2011) 364-378.
[17] A. Duvoix, R. Blasius, S. Delhalle, M. Schnekenburger, F. Morceau, E.
Henry, M. Dicato, M. Diederich, Chemopreventive and therapeutic effects of
curcumin, Cancer letters, 223 (2005) 181-190.
[18] A. Duvoix, F. Morceau, S. Delhalle, M. Schmitz, M. Schnekenburger,
M.M. Galteau, M. Dicato, M. Diederich, Induction of apoptosis by curcumin:
mediation by glutathione S-transferase P1-1 inhibition, Biochem Pharmacol,
66 (2003) 1475-1483.
[19] A. Duvoix, F. Morceau, M. Schnekenburger, S. Delhalle, M.M. Galteau,
M. Dicato, M. Diederich, Curcumin-induced cell death in two leukemia cell
lines: K562 and Jurkat, Annals of the New York Academy of Sciences, 1010
(2003) 389-392.
[20] H.J. Kang, S.H. Lee, J.E. Price, L.S. Kim, Curcumin suppresses the
paclitaxel-induced nuclear factor-kappaB in breast cancer cells and
potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude
mice model, The breast journal, 15 (2009) 223-229.
[21] Q. Liu, W.T. Loo, S.C. Sze, Y. Tong, Curcumin inhibits cell
proliferation of MDA-MB-231 and BT-483 breast cancer cells mediated by
down-regulation of NFkappaB, cyclinD and MMP-1 transcription,
Phytomedicine
phytopharmacology, 16 (2009) 916-922.
:
international
journal
of
phytotherapy
and