Synthesis and biological evaluation of a new series of N-ylides as protein farnesyltransferase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.08.088

A new family of 30 benzoylated N-ylides 4 and 5 was synthesized and evaluated for the inhibitory activity on human protein farnesyltransferase. Most of these novel compounds possessed in vitro inhibition potencies in the micromolar range. The nature of th

Full text of DOI:10.1016/j.bmcl.2013.08.088

Bioorganic & Medicinal Chemistry Letters 23 (2013) 5887–5892
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of a new series of N-ylides
as protein farnesyltransferase inhibitors
Cristina-Maria Abuhaie a,à, Alina Ghinet a,b,c,à, Amaury Farce b,d, Joëlle Dubois e, Benoît Rigo b,c
,
Elena Bîcu a,
⇑
a Department of Organic Chemistry, ‘Al. I. Cuza’ University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania
b Univ Lille Nord de France, F-59000 Lille, France
c UCLille, EA 4481 (GRIIOT), Laboratoire de Pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille, France
d Institut de Chimie Pharmaceutique Albert Lespagnol, EA GRIIOT (4481), IFR114, 3 Rue du Pr Laguesse, B.P. 83, F-59006 Lille, France
e Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new family of 30 benzoylated N-ylides 4 and 5 was synthesized and evaluated for the inhibitory activity
on human protein farnesyltransferase. Most of these novel compounds possessed in vitro inhibition
potencies in the micromolar range. The nature of the substituents on the pyridine and phenyl units
proved to be important in determining inhibitory activity and generally, the replacement of the
Received 25 June 2013
Revised 20 August 2013
Accepted 23 August 2013
Available online 3 September 2013
cyanoacrylonitrile function by
farnesyltransferase. These results completed our SAR study on this original class of N-ylides.
Ó 2013 Elsevier Ltd. All rights reserved.
a cyanoethylacrylate group decreased the biological potential on
Keywords:
Farnesyltransferase inhibitor
N-Ylide
Phenothiazine
Anticancer agent
The maturation of many proteins requires one or more post-
translational modifications including prenylation, proteolysis and
carboxymethylation.1 The prenyltransferases are a family of zinc
metalloenzymes that catalyze the addition of a prenyl unit to a cys-
teine thiol group of a set of proteins, causing their localization on
the plasma membrane.2–4 Many G-proteins, such as Ras, Rho, Rac
and CDC42, are located on the plasma membrane or
endomembranes. This superfamily is actively involved in many
important cellular signaling pathways, and plays an important role
in carcinogenesis. The G-protein superfamily is the most important
category of human CAAX proteins (A: aliphatic amino acids; X:
methionine, glutamine or serine for farnesyltransferase, leucine
or isoleucine for type I geranylgeranyltransferase). Since the dis-
covery of protein farnesyltransferase (FTase) in the late 1980s, its
inhibition has generated much attention as an important target
for the conception of new anticancer agents with reduced toxicity.5
As one of the most important G-proteins, Ras protein has a well-
established role in oncogenesis. Ras proteins function as switches
that control growth signals from cell surface receptors to nuclear
transcription factors. Human cancer studies show that gene muta-
tional activation of the Ras subfamily (K-Ras, N-Ras and H-Ras)
occurs in many type of cancers, such as adenocarcinomes,6a–e
melanomas, hepatocellular cancer, myelodysplastics syndrome
and acute myelogenous leukemia,6f–h thyroid follicular and papil-
lary carcinoma, bladder and renal cell cancer.6i,j
Inhibition of protein farnesyltransferase (FTase) prevents mem-
brane localization of Ras, and so constitutes a valid target for the
conception of new cytostatic anticancer drugs.7 Farnesyltransferase
inhibitors (FTIs) have thus been developed as a new class of prom-
ising drugs for cancer treatment.8 The main FTase inhibitors that
have undergone clinical development9 are non peptidic, heterocy-
clic compounds such as Tipifarnib (R-115777),10 L-778123,11
BMS-214662,12 Lonafarnib (SCH-66336)13 and SCH-226374.14
We recently described that bulky lipophilic groups such ferro-
cene15 (Compounds 1) or phenothiazine16 (Compounds 2) can be
placed in the A2 binding site of farnesyltransferase. During the syn-
thesis of other phenothiazine inhibitors,17 some N-ylides products
such as 3 were isolated which were observed to display farnesyl-
transferase inhibition properties. In this light, we were intrigued
by the fact that for the first time N-ylides compounds were encoun-
tered in the farnesyltransferase field (Ferrocenyl compounds are
generally not considered as ylides). Thus we decided to perform a
preliminary SAR study and some structural modifications of the
scaffold of 3, based mainly on replacement of the phenothiazine
group by conventional aromatic nucleus, and we described here
the results of this preliminary investigation (Fig. 1).
⇑
Corresponding author.
E-mail address: elena@uaic.ro (E. Bîcu).
à
These authors have made equal contributions.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.08.088

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C.-M. Abuhaie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5887–5892
Starting from the structure of compound 3, we were interested
The nature of the substitution of the pyridine ring, of the phenyl
group and the potential chelating bicyano or cyano ethylacetate
unit proved to be important for the biological potential. The best
results were obtained with 4-dimethylaminopyridinium deriva-
tives 4Ba, 4Da, 4Ea and 4Ka (Tables 1 and 2) exhibiting IC50 val-
in the synthesis of N-ylides 4 and 5 (Scheme 2) bearing complexing
groups (CN, CO2Et) that could potentially bind the zinc atom of
protein farnesyltransferase (Scheme 2). The initial reagents were
commercial bromo or chloroacetyl benzenes 6A–J (Scheme 2). As
for bromoacetyl-3,4,5-trimethoxybenzene 6K, it was obtained in
43% yield from the reaction of 3,4,5-trimethoxyacetophenone with
bromine in acetic acid.18 In this reaction, bromoacetyl-2-bromo-
3,4,5-trimethoxybenzene 6L was also isolated (Scheme 1). Now,
bromoacetyl or chloroacetyl substituted benzenes 6 were reacted
ues from 12.5 to 19.7 lM (Table 2). These ylides have also in
common a dicyano group. The replacement of one cyano unit
by an ethyl ester in compounds 5Ba, 5Da, 5Ea and 5Ka de-
creased the inhibitory activity (IC50 values from 31.9 to
48.0 lM). Next, the study of the influence of the pyridinium sub-
with pyridines
7
to give pyridinium salts 819 which were
stitution on the FTase activity revealed that, except 3,5-dim-
ethylpyridinium ylides 4Gd and 4Kd, that showed comparable
potential to that of corresponding 4-dimethylamino ylides 4Ga
and 4Ka, all other structural modifications (H, 4-OMe, 4-Me or
3,4-diOMe) of the pyridinium ring caused a slight reduction of
the inhibitory activity. Finally, the p-chloro and the p-bromo
substitutions of the phenyl ring proved to be favorable to bioac-
tivity. We then investigated the influence of different substitu-
ents (F, CN, OMe, NO2 or Me) at the para-position of the
phenyl ring. Except the p-methyl compound 4Ba which con-
reacted with 2-cyano-3-ethoxyacrylonitrile 9 or ethyl 2-cyano-3-
ethoxyacrylate 10 in the presence of DBU,17,20 leading to the new
ylides 4 and 5 (Table 1 and Scheme 2). In this reaction, indolizines
11 which could be generated from cyclization of salts 1221 were
not detected. The obtention of carbanion disubstituted N-ylides 4
and 5 could be due to the two cyano or cyanoester groups, linked
to the carbanion of the Michael addition intermediary 12, that pre-
vent positioning near the carbocation in the a-pyridinium position
of 12,17 or to the rapid elimination of ethoxy anion leading to the
new intermediate 13 (Scheme 2).
served similar activity (IC50 = 14.47 1.28 lM), all other struc-
As can be observed from Scheme 2, the reaction is quite general.
It is interesting to note that picolinium salt 8Ab only furnished cor-
responding ylides 4Ab and 5Ab and that pyridinylidene com-
pounds 14 and 15 were not observed. In contrast, under the
same conditions, the methyl group of phenothiazine derivative
16 reacted with acrylates 9 or 10 to give products 17 and 1817 as
it was reported for some other picolinium salts (Scheme 3).22 The
study of the generalization of the synthesis of pyridine-(1H)-
ylidene derivatives starting from 2- and 4-picolinium salts has
been realized and showed that an amide function was essential
for reaction effectiveness;22 this could perhaps result from stabil-
ization of intermediate charged species.
tural modifications caused a significant reduction in biological
activity (e.g. compound 4Da vs 4Ha, Table 2). A 3,4,5-triOMe
substitution of the same phenyl unit was also favorable to bioac-
tivity (ylide 4Ka: IC50 = 15.56 1.04 lM) while its replacement
by an unsubstituted phenyl moiety in ylide 4Aa caused an
important reduction of the biological potential (IC50 = 46.19
3.36 lM).
To further expand the understanding of the experimental re-
sults, molecular modeling studies for compound 4Aa and the phe-
nothiazine derivative 3 were carried out in the active site of protein
FTase. Farnesyltransferase structure was taken from the 1LD724 en-
try of the RCSB Protein Data Bank.25 The cocrystallized inhibitor
and water molecules were removed to permit docking of the stud-
ied compounds, built from the standard fragments library of Sybyl
The activity of the new series of synthesized N-ylides was
evaluated on human FTase.23 Results are summarized in Table 2.
Cl
N
Cl
N
NH2
N
N
H
N
N
O
N
N
N
S
N
SO2
N
O
NC
NC
Cl
Tipifarnib
L-778123
BMS-214662
Cl
S
O
Br
N
N
N
N
O
-
N
NH2
N
Fe2+
N
H
O
R
N
O
-
O
1
2
Br
Br
Lonafarnib
N
S
N
N
N
O
+
Me2N
3
Figure 1. Structure of FTIs.

C.-M. Abuhaie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5887–5892
5889
Br
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Me
O
Br
Br
(i)
+
O
O
MeO
6K 43%
6L 10%
Scheme 1. Reagents and conditions: (i) bromine (1.2 equiv), AcOH, rt, 2 h.
2
1
R
R
3
2
R
1
R
R
X
Y
-
3
(i)
Hal
N
R
+
O
N
Hal
+
X
z
O
8
Y
z
CN
W
7a-d
6A-K
Hal: Cl or Br
9 W = CN
10 W = CO2Et
(ii)
EtO
1
2
R
2
R
1
A R1,R2,R3 = H
R
R
EtO-
B R1,R3 = H, R2 = Me
C R1,R3 = H, R2 = F
3
R
3
NC
W
R
OEt
NC
- EtO-
H
-
D R1,R3 = H, R2 = Cl
E R1,R3 = H, R2 = Br
F R1,R3 = H, R2 = CN
G R1,R3 = H, R2 = OMe
H R1,R3 = H, R2 = NO2
I R1-R2 = NHCOCH2O, R3 = H
J R1,R2 = OMe, R3 = H
K R1,R2,R3 = OMe
W
O
N
O
N
+
+
X
X
Y
z
13
Y
z
12
1
2
1
R
R
2
R
R
a X,Z = H, Y = NMe2
3
R
3
NC
W
R
OEt
N
b X,Z = H, Y = Me
c X,Z = H, Y = OMe
d X,Z = Me, Y = H
NC
W
X
-
O
N
O
+
X
Y
Y
z
z
4 W = CN 47-89%
5 W = CO2Et 42-86%
11
O
N
14 W = CN
15 W = CO2Et
NC
W
CN
W
W
NC
9 W = CN
10 W = CO2Et
EtO
-
(i)
Cl
O
O
N
N
+
+
4Ab W = CN 78%
5Ab W = CO2Et 76%
8Ab
Me
Me
Scheme 2. Reagents and conditions: (i) pyridine derivative 7a–d (2–5 equiv), EtOAc or acetone, reflux, 24 h; (ii) DBU (1 equiv), DMF or acetonitrile, alkene (2-cyano-3-
ethoxyacrylonitrile (9) or ethyl 2-cyano-3-ethoxyacrylate (10)) (2 equiv), 70 °C, 24 h.
6.9.126 with GOLD 5.1.27 Thirty solutions were generated and
classed through an in-house scoring function based on GoldScore27
and X-Score functions.28
The phenothiazine derivative 3 adopts a single conformation
described in Fig. 2(a), where the cyano groups form two hydrogen
bonds with tyrosines 361b and 365b. The pyridine ring and the
phenothiazine unit of the same compound 3 are in a favorable po-
sition to establish stacking interactions with Tyr 361b and Tyr
166a, respectively. The p-chlorophenyl analogue 4Da displays dif-
ferent conformations. However, one conformation of ylide 4Da fits
into the binding site with the cyano units forming hydrogen bonds
with tyrosines 361b and 365b (Fig. 2(b)) in the same way as the
phenothiazine derivative 3. On the other hand, the chlorophenyl
ring of ylide 4Da is too small to occupy the hydrophobic cavity
compared to phenothiazine tricycle in compound 3 (Fig. 2(b)). This
highlights the importance of the phenothiazine moiety and

5890
C.-M. Abuhaie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5887–5892
Table 1
Table 2
Structure of synthesized N-ylides 4 and 5
Inhibitory activities of ylides 4 and 5 on human farnesyltransferase
a,b
Starting
salt no
Product
no
Ylide
R1
Yield
(%)
Compd No.
%
IC50
(
l
M
SDc)b
R2d
X
Y
Z
R2
R3
W
4Aa
5Aa
4Ba
5Ba
4Ca
5Ca
4Da
5Da
4Ea
5Ea
4Fa
5Fa
4Ga
5Ga
4Ha
5Ha
4Ka
5Ka
4Ia
79
68
89
65
81
64
95
100
91
100
77
69
99
64
88
N.D.e
93
73
92
62
29
45
83
51
77
88
75
49
82
90
46.19 3.36
30.94 1.77
14.47 1.28
43.64 2.63
23.57 0.91
62.3 3.50
12.49 0.79
31.89 8.94
19.69 0.88
36.37 10.39
23.85 2.24
46.19 3.36
22.19 2.58
62.67 4.11
28.23 2.21
N.D.
15.56 1.04
48.00 2.03
25.85 3.18
55.22 3.14
N.D.
N.D.
27.34 2.02
N.D.
0.972
0.970
0.980
0.952
0.991
0.976
0.992
0.806
0.995
0.830
0.976
0.977
0.965
0.972
0.985
—
0.990
0.988
0.962
0.967
—
—
0.973
—
8Aa
8Ba
8Ca
8Da
8Ea
8Fa
8Ga
8Ha
8Ka
8Ia
4Aa
5Aa
4Ba
5Ba
4Ca
5Ca
4Da
5Da
4Ea
5Ea
4Fa
5Fa
4Ga
5Ga
4Ha
5Ha
4Ka
5Ka
4Ia
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
F
F
Cl
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CN
82
CO2Et 86
CN 82
CO2Et 54
CN 72
CO2Et 76
CN 63
CO2Et 42
CN 51
CO2Et 77
CN 65
CO2Et 56
CN 68
CO2Et 54
CN 89
CO2Et 56
74
OMe OMe OMe CO2Et 69
Br
CN
CN
OMe
OMe
NO2
NO2
OMe OMe OMe CN
5Ia
–
H
CN
CO2Et 50
78
60
4Ab
5Ab
4Gc
5Gc
4Jc
NHCOCH2O–
–
NHCOCH2O–
5Ia
H
NMe2
H
H
8Ab
8Gc
8Jc
4Ab
5Ab
4Gc
5Gc
4Jc
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
OMe
OMe
H
H
H
H
H
H
H
H
CN
CO2Et 76
CN 47
CO2Et 68
CN 78
CO2Et 75
CN 75
CO2Et 68
78
Me OMe OMe OMe CO2Et 79
31.36 0.87
20.84 2.37
27.39 0.48
N.D.
20.13 0.59
43.48 5.00
0.997
0.897
0.998
—
0.994
0.938
5Jc
4Gd
5Gd
4Kd
5Kd
OMe OMe
OMe OMe
5Jc
8Gd
8Kd
4Gd
5Gd
4Kd
5Kd
H
H
OMe
OMe
a
b
c
Inhibition of protein farnesyltransferase at a 100
Values represent mean of two experiments.
SD: standard deviation.
lM concentration.
Me OMe OMe OMe CN
R2: regression factor.
Not determined.
d
e
explains the higher affinity towards human FTase obtained with
phenothiazine-containing ylides17 compared to benzoylated ylides
presented in this article (e.g. phenothiazine 3: (IC50 (FTase) =
The nature of the substituent on the pyridine group proved to
be important in determining inhibitory activity and generally, the
replacement of the cyanoacrylonitrile function by a cyanoethylac-
rylate group decreased the biological potential on FTase.
The study performed in the present work, based mainly on the
replacement of the phenothiazine group of a previously described
series of N-ylides17 by conventional aromatic nucleus, emphasizes
the importance of the phenothiazine unit in the structure of FTIs
and completes our structure–activity relationships on this original
class of N-ylides.
4.67 0.36
0.79 M)).
lM) vs compound 4Da: (IC50 (FTase) = 12.49
l
In summary, 30 new benzoylated N-ylides 4 and 5 have been
synthesized and evaluated for their inhibitory activity on human
farnesyltransferase. Most of these novel compounds were found
to possess in vitro inhibition potencies in the micromolar range.
However, given the modest inhibitory activity values obtained,
non-specific interactions are not excluded.
S
S
CN
9 W = CN
10 W = CO2Et
N
N
O
EtO
W
Cl
(i)
O
N
N
+
Me
16
17 W = CN
18 W = CO2Et
NC
W
S
N
NC
(i)
-
W
O
N
+
19 W = CN
20 W = CO2Et
Me
Scheme 3. Reagents and conditions: (i) DBU (1 equiv), DMF, 70 °C, 24 h.

C.-M. Abuhaie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5887–5892
5891
NC
CN
NC
-
CN
N
-
N
+
NMe2
NMe2
+
Tyr 365β
Tyr 365β
S
N
Cl
Zn
Zn
O
O
3
4Da
FPP
FPP
Tyr 361β
Tyr 361β
Trp 106β
Trp 106β
Arg 202β
Arg 202β
Trp 102β
Leu 196β
Trp 102β
Leu 196β
Tyr 166α
Tyr 166α
Cys 195β
Cys 195β
(a)
(b)
Figure 2. Docking of phenothiazine derivative 3 (a) and N-ylide 4Da (b) in the active site of protein FTase.
11. Lobell, R. B.; Liu, D.; Buser, C. A.; Davide, J. P.; DePuy, E.; Hamilton, K.; Koblan, K.
S.; Lee, Y.; Mosser, S.; Motzel, S. L.; Abbruzzese, J. L.; Fuchs, C. S.; Rowinsky, E.
K.; Rubin, E. H.; Sharma, S.; Deutsch, P. J.; Mazina, K. E.; Morrison, B. W.;
Wildonger, L.; Yao, S. L.; Kohl, N. E. Mol. Cancer Ther. 2002, 1, 747.
12. Hunt, J. T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide, R.; Cho, Y.; Chong, S.;
Chao, S.; Gullo-Brown, J.; Guo, P.; Kim, S. H.; Lee, F. Y. F.; Leftheris, K.; Miller, A.;
Mitt, T.; Patel, M.; Penhallow, B. A.; Ricca, C.; Rose, W. C.; Schmidt, R.;
Slusarchyk, W. A.; Vite, G.; Manne, V. J. Med. Chem. 2000, 43, 3587.
13. Khuri, F. R.; Glisson, B. S.; Kim, E. S.; Statkevich, P.; Thall, P. F.; Meyers, M. L.;
Herbst, R. S.; Munden, R. F.; Tendler, C.; Zhu, Y.; Bangert, S.; Thompson, E.; Lu,
C.; Wang, X. M.; Shin, D. M.; Kies, M. S.; Papadimitrakopoulou, V.; Fossella, F.
V.; Kirschmeier, P.; Bishop, W. R.; Hong, W. K. Clin. Cancer Res. 2004, 10, 2968.
14. Reyzer, M. L.; Hsieh, Y.; Ng, K.; Korfmacher, W. A.; Caprioli, R. M. J. Mass
Spectrom. 2003, 1081, 38.
15. Ghinet, A.; Rigo, B.; Dubois, J.; Farce, A.; Hénichart, J.-P.; Gautret, P. Med. Chem.
Commun. 2012, 3, 1147.
16. Belei, D.; Dumea, C.; Samson, A.; Farce, A.; Dubois, J.; Bîcu, E.; Ghinet, A. Bioorg.
Med. Chem. Lett. 2012, 22, 4517.
17. Abuhaie, C. M.; Ghinet, A.; Farce, A.; Dubois, J.; Gautret, P.; Rigo, B.; Belei, D.;
Bîcu, E. Eur. J. Med. Chem. 2013, 59, 101.
18. Lawrence, N. J.; Patterson, R. P.; Ooi, L.-L.; Cook, D.; Ducki, S. Bioorg. Med. Chem.
Lett. 2006, 16, 5844.
Acknowledgements
This work was supported by a grant of the Romanian Ministry
of Education, CNCS-UEFISCDI, project number PN-II-RU-PD-2012-
3-0426. The authors also acknowledge the ‘‘Programul Operational
Sectorial Dezvoltarea Resurselor Umane 2007-2013’’ (project POS-
DRU/88/1.5/S/47646) for a PhD scholarship (C.-M. A.).
Supplementary data
Supplementary data (synthesis details and physico-chemical
characterization for all new compounds) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.bmcl.2013.08.088.
References
1. Reid, T. S.; Terry, K. L.; Casey, P. J.; Beese, L. S. J. Mol. Biol. 2004, 343, 417.
2. Zhang, H. Handb. Metalloproteins 2004, 3, 37.
19. Szafran, M.; Szwajca, A.; Łe˛ska, B.; Schroder, G.; Dega-Szafran, Z. J. Mol. Struct.
2002, 643, 55.
3. Park, H. W.; Beese, L. S. Curr. Opin. Struct. Biol. 1997, 7, 873.
4. Casey, P. J. Lipid Res. 1992, 33, 1731.
20. (a) Szwajca, A.; Łe˛ska, B.; Schroeder, G.; Szafran, M. J. Mol. Struct. 2004, 708, 87;
(b) Sarkunam, K.; Nallu, M. J. Heterocycl. Chem. 2005, 42, 5.
5. Sebti, S. M.; Hamilton, A. D. In Farnesyltransferase Inhibitors in Cancer Therapy;
Sebti, S. M., Hamilton, A. D., Eds.; Humana Press: Totowa, NJ, 2000; pp 197–220.
6. (a) Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J.; Arnheim, N.; Perucho, M.
Cell 1988, 53, 549; (b) Bos, J. L. Cancer Res. 1989, 49, 4682; (c) Hruban, R. H.; van
Mansfeld, A. D.; Offerhaus, G. J.; van Weering, D. H.; Allison, D. C.; Goodman, S.
N.; Kensler, T. W.; Bose, K. K.; Cameron, J. L.; Bos, J. L. Am. J. Pathol. 1993, 143,
545; (d) Fernandez, C.; Chetaille, B.; Tasei, A. M.; Sastre, B.; Sahel, J.; Payan-
Defais, M. J. Gastroenterol. Clin. Biol. 2005, 29, 465; (e) Loehr, M.; Klöppel, G.;
Maisonneuve, P.; Lowenfels, A. B.; Luttges, J. Neoplasia 2005, 7, 17; (f) Takada,
S.; Koike, K. Oncogene 1989, 4, 189; (g) Auewarakul, C. U.; Lauhakirti, D.;
Tocharoentanaphol, C. Eur. J. Haematol. 2006, 77, 51; (h) van Dijk, M. C. R. F.;
Bernsen, M. R.; Ruiter, D. J. Am. J. Surg. Pathol. 2005, 29, 1145; (i) Vasko, V.;
Ferrand, M.; Di Cristofaro, J.; Carayon, P.; Henry, J. F.; de Micco, C. J. Clin.
Endocrinol. Metab. 2003, 88, 2745; (j) Boulalas, I.; Zaravinos, A.; Karyotis, I.;
Delakas, D.; Spandidos, D. A. J. Urol. 2009, 181, 2312.
21. (a) Bâcu, E.; Samson-Belei, D.; Nowogrocki, G.; Couture, A.; Grandclaudon, P.
Org. Biomol. Chem. 2003, 13, 2377; (b) Bâcu, E.; Belei, D.; Couture, A.;
Grandclaudon, P. Rev. Roum. Chem. 2007, 52, 253; (c) Bâcu, E.; Belei, D.;
Couture, A.; Grandclaudon, P. Rev. Roum. Chem. 2006, 51, 887.
22. Tominaga, Y.; Miyake, Y.; Fujito, H.; Kurata, K.; Awaya, H.; Matsuda, Y.;
Kobayashi, G. Chem. Pharm. Bull. 1977, 25, 1528.
23. Farnesyltransferase assay: Assays were realized in 96-well plates, prepared with
a Biomek NKMC and a Biomek 3000 from Beckman Coulter and read on a
Wallac Victor fluorimeter from Perkin–Elmer. Per well, 20
pyrophosphate (10 M) was added to 180 L of a solution containing 2
varied concentrations of potential inhibitors (dissolved in DMSO) and 178
a solution composed by 10 L of partially purified recombinant human FTase
(1.5 mg/mL) and 1.0 mL of Dansyl-GCVLS peptide (in the following buffer: 5.6
mM DTT, 5.6 mM MgCl2, 12 ZnCl2 and 0.2% (w/v) octyl-b-
lL
of farnesyl
L of
L of
l
l
l
l
l
lM
D-
glucopyranoside, 52 mM Tris/HCl, pH 7.5). Fluorescence development was
recorded for 15 min (0.7 sec per well, 20 repeats) at 30 °C with an excitation
filter to 340 nm and an emission filter of 486 nm. Each measurement was
realized twice, in duplicate or in triplicate. The kinetic experiments were
realized under the same conditions, either with FPP as varied substrate with a
7. Bell, I. M. J. Med. Chem. 1869, 2004, 47.
8. (a) Ohkanda, J.; Knowles, D. B.; Blaskovich, M. A.; Sebti, S. M.; Hamilton, A. D.
Curr. Top. Med. Chem. 2002, 2, 303; (b) Haluska, P.; Dy, G. K.; Adjei, A. A. Eur. J.
Cancer 2002, 38, 1685.
9. Caponigro, F.; Casale, M.; Bryce, J. Exp. Opin. Investig. Drugs 2003, 12, 943.
10. (a) Santucci, R.; Mackley, P. A.; Sebti, S.; Alsina, M. Cancer Control. 2003, 10,
384; (b) Rao, S.; Cunningham, D.; de Gramont, A.; Scheithauer, W.; Smakal, M.;
Humblet, Y.; Kourteva, G.; Iveson, T.; Andre, T.; Dostalova, J.; Illes, A.; Belly, R.;
Perez-Ruixo, J. J.; Park, Y. C.; Palmer, P. A. J. Clin. Oncol. 2004, 22, 3950.
constant concentration of Dns-GCVLS of 2.5
l
M, or with Dns-GCVLS as varied
substrate with constant concentration of FPP of 10
a
l
M. Non linear
regressions were performed by KaleidaGraph 4.03 software. Coudray, L.; de
Figueiredo, R. M.; Duez, S.; Cortial, S.; Dubois, J. J. Enz. Inhib. Med. Chem. 2009,
24, 972.

5892
C.-M. Abuhaie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5887–5892
24. Bell, I. M.; Gallicchio, S. N.; Abrams, M.; Beese, L. S.; Beshore, D. C.;
Bhimnathwala, H.; Bogusky, M. J.; Buser, C. A.; Culberson, J. C.; Davide, J.;
Ellis-Hutchings, M.; Fernandes, C.; Gibbs, J. B.; Graham, S. L.; Hamilton, K. A.;
Hartman, G. D.; Heimbrook, D. C.; Homnick, C. F.; Huber, H. E.; Huff, J. R.;
Kassahun, K.; Koblan, K. S.; Kohl, N. E.; Lobell, R. B.; Lynch, J. J., Jr.; Robinson, R.;
Rodrigues, A. D.; Taylor, J. S.; Walsh, E. S.; Williams, T. M.; Zartman, C. B. J. Med.
Chem. 2002, 45, 2388.
25. Berman, H. M.; Westbrook, J.; Feng, Z.; Gary, G.; Bhat, T. N.; Weissig, H.;
Shindyalov, I. N.; Bourne, P. E. Nucl. Acids Res. 2000, 28, 235.
26. SYBYL 6.9.1, Tripos Associates, Inc., 1699 South Hanley Road, St. Louis, MO
63144.
27. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267,
727.
28. Wang, R.; Lai, L.; Wang, S. J. Comput. Aided Mol. Des. 2002, 16, 11.