Design, synthesis and biological evaluation of substituted dioxodibenzothiazepines and dibenzocycloheptanes as farnesyltransferase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.07.002

A new series of FTase inhibitors containing a tricyclic moiety-dioxodibenzothiazepine or dibenzocycloheptane-has been designed and synthesized. Among them, dioxodibenzothiazepine 18d displayed significant inhibitory FTase activity (IC₅₀ = 17.3

Full text of DOI:10.1016/j.bmcl.2007.07.002

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5465–5471
Design, synthesis and biological evaluation of substituted
dioxodibenzothiazepines and dibenzocycloheptanes
as farnesyltransferase inhibitors
Pauline Gilleron,a Nicolas Wlodarczyk,a Raymond Houssin,a Amaury Farce,b
a
a
a
a
´
Guillaume Laconde, Jean-Franc¸ois Goossens, Amelie Lemoine, Nicole Pommery,
a
a,
*
´
´
Jean-Pierre Henichart and Regis Millet
aInstitut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, IFR 114, Universite´ de Lille 2,
3 rue du Professeur Laguesse, BP 83, 59006 Lille, France
bLaboratoire de Chimie The´rapeutique, Faculte´ des Sciences Pharmaceutiques et Biologiques,
Universite´ de Lille 2, 3 rue du Professeur Laguesse, BP 83, 59006 Lille, France
Received 16 May 2007; revised 29 June 2007; accepted 1 July 2007
Available online 7 July 2007
Abstract—A new series of FTase inhibitors containing a tricyclic moiety—dioxodibenzothiazepine or dibenzocycloheptane—has
been designed and synthesized. Among them, dioxodibenzothiazepine 18d displayed significant inhibitory FTase activity
(IC50 = 17.3 nM) and antiproliferative properties.
Ó 2007 Elsevier Ltd. All rights reserved.
The finding that 30% of human cancers are related to the
presence of mutant ras genes, reaching as high as 90%
for pancreas cancer and 50% for colon cancer,1,2 has
prompted many works to target Ras proteins with a
view to developing new anticancer agents. Ras proteins
(H-Ras, K-Ras4A, K-Ras4B and N-Ras) are small G
proteins which have the crucial role of transducing
intracellular signals from growth factor receptor to sev-
eral signal transduction pathways, such as the MAP-ki-
nases cascade and the PI3-K/Akt pathway.3 Activation
of these signal transduction pathways by Ras is critical
for cell growth, proliferation and survival. Ras proteins
require localization at the plasma membrane to exert
their functions. However, as their primary structure
has no anchorage residue, Ras proteins must be post-
translationally modified by several sequential enzymatic
steps.4 The attachment of an isoprenoid residue to the
cysteine of the C-terminal CA1A2X box (C = cysteine,
A1 and A2 = aliphatic amino acid, X = C-terminal ami-
no acid) of Ras proteins is the first and essential step.
When X is serine, methionine, glutamine or alanine,
the protein is recognized by zinc-metalloenzyme farne-
syltransferase (FTase) which catalyzes the transfer of a
15 carbon isoprenoid chain from farnesyl pyrophos-
phate (FPP). Proteins with a C-terminal leucine or iso-
leucine are modified by the geranylgeranyltransferase-I
(GGTase-I) enzyme with a 20 carbon isoprenoid motif
from geranylgeranyl pyrophosphate (GGPP). Thus,
farnesyltransferase inhibitors (FTIs) have been devel-
oped to inhibit Ras processing and to design new anti-
cancer agents.5,6 Recent studies have however
suggested that the cytotoxic actions of FTIs are not
exclusively due to the inhibition of Ras proteins and
have indicated that other farnesylated protein targets,
other than Ras, have to be considered.7–9 These candi-
date targets include Ras-family GTPases such as
RhoB10 and Rheb,11 the centromere-binding proteins
CENP-E and CENP-F,12,13 the phosphatases PRL-1,
-2 and -3,14 or an unidentified protein that functions
as an activator of the PI3-K/Akt pathway.15
Knowledge of precise details about the structure and the
reaction mechanism of FTase has resulted in three gen-
eral approaches for the rational design of FTIs: a pepti-
domimetic design that competes for FTase with the
CA1A2X sequence of the protein; a design of FPP ana-
logs that competes for FTase with the substrate FPP; a
design of bisubstrate analogs that combines the features
Keywords: Farnesyltransferase; Cytotoxicity; Cancer; Diox-
odibenzothiazepine; Dibenzocycloheptane.
*
Corresponding author. Tel.: +33 3 2096 4374; fax: +33 3 2096
4906; e-mail: regis.millet@univ-lille2.fr
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.07.002

5466
P. Gilleron et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5465–5471
of both peptidomimetics and FPP analogs, mimicking a
transition state. A number of natural products have also
been identified as FTIs, and the screening of chemical
libraries backed up by structure-directed medicinal
chemistry optimization has led to the successful identifi-
cation of tricyclic FTIs.16,17
Considering these structures and their interactions with
the enzyme,18,19 we designed new derivatives 18a–d, 19,
23a and 25 including:
(i) a 4-cyanobenzylimidazole Zn-chelating group
(ii) a diazepane or a piperazine, making it possible to
lay out correctly in a ring the two central N atoms
of compounds 1 and 2, so as to take into account
the strong hydrogen bond between the secondary
amine proton and amide oxygen of compound 2.
These new heterocyclic linkers combine the
required features of 1 and 2 to obtain a correct
We recently described the design and the synthesis of
FTase peptidomimetic inhibitors. The most interesting
molecules 118 and 2,19 with a piperidinyl or a b-homo-
Phe linker, had IC50 values of 22 and 28.5 nM, respec-
tively, on an isolated FTase enzyme (Chart 1).
CN
CN
N
N
N
N
O
H
N
N
N
N
H
O
O
O
OCH3
NH2
1
FTase IC50 = 22 nM
2
FTase IC50 = 28.5 nM
O
CH3
N
N
N
SO2
CH3
N
O
CH3
PC-3 IC50 = 0.19 μM
3
CN
18a-d n = 2
a
b
c
d
X = SO2, Y = N, R = CH3
X = SO2, Y = N, R = C3H7
X = SO2, Y = N, R = C4H9
X = SO2, Y = N, R = C3H6
R
23a
n = 1
Y
N
( )n
N
X
N
-
N
O
N
19
25
n = 2
n = 1
X = Y = CH2
Chart 1.

P. Gilleron et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5465–5471
5467
fitting with the imidazole zinc-chelator and with
the ‘‘A2 binding site’’—delineated by Trp102b,
Trp106b and Tyr361b—of the FTase
(iii) a dioxodibenzothiazepine or a dibenzocyclohep-
tane residue corresponding to a constrained form
of the peptidyl residue of 1 and 2. Superposition
of the minimized conformation20 of compounds
1, 2 and 25 (Fig. 1) suggested that the geometry
of both aromatic terminal fragments could be
included in a condensed structure. Furthermore,
these fused tricyclic scaffolds are reminiscent of
new benzoindolinothiazepine derivatives recently
developed by us21 and which contain a piperazine
moiety, such as 3, and which have shown potent
antiproliferative activity against PC-3 tumor cell
lines but no FTase activity. In addition, other tri-
cyclic FTIs including a benzocycloheptapyridine
have been described,22 but they do not have the
4-cyanobenzylimidazole Zn-chelating group.
Figure 1. Superposition of the minimized conformation of compounds
1 (yellow), 2 (green) and 25 (cyan).
H
N
O
O
O
O
O
O
Path 1
Path 2
S
NH2
NH2
S
Cl
e
a
COOCH3
CO
N(C2H5)2
10
H3COOC
H3COOC
4
5
9
f
b
H
O
O
CH3
O
N
S
N
S
CO
N(C2H5)2
11
H3COOC
6
c
g
H
R
N
O
O
O
O
O
CH3
O
N
S
S
N
S
d
h
(when b-d)
HOOC
O
7
12
8a-d
i
R
N
O
O
R
N
O
O
S
S
a
b
R = CH3
j
R = C3H7
R = C4H9
R = C3H6
c
d
N
O
OH
13a-d
Cl
14a-d
Scheme 1. Reagents and conditions: (a) C6H5NH2, pyridine, DMF, 65 °C, 2 h, 45%; (b) i—NaH, DMF, rt, 3 h; ii—CH3I, DMF, rt, 16 h, 89%; (c)
NaOH, MeOH/H2O, reflux, 2 h, 95%; (d) i—SOCl2, CH2Cl2, rt, 16 h; ii—AlCl3, CHCl3, reflux, 1 h, 65%; (e) Et2NH, n-BuLi, Et2O, 0 °C, 4 h, 85%; (f)
C6H5SO2Cl, pyridine-THF, 60 °C, 1 h, 80%; (g) i—(i-Pr)2NH, n-BuLi, THF, ꢀ10 °C, 45 min; ii—rt, 20 h, 25%; (h) i—NaH, DMF, rt, 3 h; ii—R–I, rt,
20 h or R–Cl, KI, 80 °C, 24 h, 36–45%; (i) NaBH4, MeOH, rt, 3–4 h, 87–95%; (j) SOCl2, CH2Cl2, rt, 3–4 h, 90–100%.

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P. Gilleron et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5465–5471
We report here the synthesis, the pharmacological eval-
uation and the docking of these novel tricyclic FTase
inhibitors23 with potent isolated enzymatic and cellular
activities.
thiazepinone 8a. Chlorodibenzothiazepine 14a was ob-
tained by reducing dibenzothiazepinone 8a (sodium
borohydride) followed by the halogenation of the second-
ary alcohol 13a with thionyl chloride.
Synthesis of chlorodioxodibenzothiazepines 14a–d
(Scheme 1) was performed in two different ways (paths 1
and 2) which both preclude the formation, at the cycliza-
tion step, of a central saccharin-like isothiazolone ring
instead of the targeted thiazepinone cycle.21 Chloro-
dioxodibenzothiazepine 14a was prepared according to
path 1, where alkylation of the sulfonamido nitrogen
was completed before creating the mid heterocycle. Phe-
nylsulfonamide 5 was obtained by nucleophilic substitu-
tion of methyl 2-chlorosulfonylbenzoate 4 with aniline
(pyridine, DMF).21 Alkylation of sulfonamide 5 (sodium
hydride, methyl iodide) yielded N-methylsulfonamide 6.
After saponification of the ester group (sodium hydrox-
ide), carboxylic acid 7 was cyclized, via its non-isolated
acid chloride (Friedel–Crafts conditions) into dibenzo-
The second method (Scheme 1, path 2) was used to pre-
pare chlorodioxodibenzothiazepines 14b–d. In this case,
N-substituted dibenzothiazepinones 8b–d were easily ob-
tained from the unsubstituted parent tricycle 12. Car-
boxylic ester of methyl anthranilate 9 was converted
into diethylcarboxamide 10 (n-butyllithium, N,N-dieth-
ylamine)24 before creating the sulfonamide function
with benzenesulfonyl chloride. An intramolecular anio-
nic Friedel–Crafts equivalent annulation25 of 11 (lithium
diisopropylamide prepared in situ, ꢀ10 °C), favored by
the nucleophilicity of the transient carbanion and by
the sensitivity of the N,N-diethylcarboxamide to such
a nucleophilic attack, resulted in dibenzothiazepinone
12. Appropriate N-alkylation of the sulfonamido group
(sodium hydride, alkyl halide) gave dibenzothiazepinones
( )n
Boc
N
HN
15
n = 2
20 n = 1
a
CN
CN
CN
R
N
S
N
N
N
b
c
O
( )n
( )n
( )n
N
N
Boc
N
N
N
NH .3HCl
N
N
N
O
.3HCl
17 n = 2
22 n = 1
16 n = 2
21 n = 1
18a-d n = 2
23a
n = 1
(n = 2)
e
(n = 1)
d
CN
CN
+
N
f
N
N
( )n
( )n
N
N
N
(n = 1)
a
b
c
d
N
N
R = CH3
R = C3H7
R = C4H9
-
Cl
.3HCl
19 n = 2
25 n = 1
R = C3H6
N
O
24 n = 1
Scheme 2. Reagents and conditions: (a) n = 2: 1-(4-cyanobenzyl)-5-chloromethylimidazole, (i-Pr)2NEt, MeCN, 80 °C, 4 h, 72%; n = 1: 1-(4-
cyanobenzyl)-5-formylimidazole, NaBH3CN, MeOH, 50 °C, 40 h, 60%; (b) HCl/Et2O, MeOH, rt, 4 h, 90–95%; (c) n = 2: 14a–d, Et3N, MeCN, rt, 4 h,
65–68%; n = 1: 14a, Et3N, MeCN, rt, 2 h, 68%; (d) n = 1: dibenzosuberyl chloride, Et3N, MeCN, rt, 2 h, 40%; (e) n = 2: dibenzosuberyl chloride,
Et3N, MeCN, rt, 3 h, 63%; (f) MeOH, reflux, 6 h, 30%.

P. Gilleron et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5465–5471
5469
8b–d. Chloro tricycles 14b–d resulted from a subsequent
reduction of the ketone group (sodium borohydride)
into alcohol (compounds 13b–d) followed by halogena-
tion (thionyl chloride).
of piperazine 22 by dibenzosuberyl chloride (compound
24) followed by the regioselective N-dealkylation in con-
ditions used in classical N-detritylation (MeOH,
reflux).27
The means adopted for the preparation of target com-
pounds 18a–d and 23a (Scheme 2) involved a nucleo-
philic attack on chlorodioxodibenzothiazepines 14a–d
by the secondary amine of diazepane 17 or of piperazine
22. Diazepane 16 and piperazine 21 were, respectively,
obtained by substituting carbamate-monoprotected
diazepane 15 or piperazine 20 by 1-(4-cyanobenzyl)-5-
chloromethylimidazole,26 or by reductive amination
(NaBH3CN) using 1-(4-cyanobenzyl)-5-formylimidaz-
ole.18 If diazepane19 was classically prepared by
nucleophilic substitution of dibenzosuberyl chloride,
piperazine 25 resulted from the unexpected dialkylation
Compounds 18a–d, 19, 23a, and 25 were evaluated for
their in vitro inhibitory activity against FTase using
the continuous fluorescence spectrometry technique.23
Several SARs may be deduced from the results
(Table 1). A constrained structure such as the dibenzo-
cycloheptane skeleton (compounds 19 and 25) maintains
moderate FTase inhibition whatever the size of the
linker: diazepane for 19 (IC50 = 285 nM) or piperazine
for 25 (IC50 = 310 nM).
When cycloheptane was replaced by dioxothiazepine as
the central cycle and diazepane kept as the link (com-
Table 1. FTase activity of compounds 1, 2, 18a–d, 19, 23a and 25
CN
R
Y
N
N
( )n
N
X
N
a
IC50 (nM)
Compound
n
X
Y
R
1
—
—
2
—
—
—
—
N
N
N
N
—
—
22
2
28.5
44.8
46.5
43
18a
18b
18c
18d
SO2
SO2
SO2
SO2
CH3
C3H7
C4H9
2
2
2
17.3
-
C3H6 N
O
19
2
CH2
CH2
—
285
23a
25
1
1
SO2
CH2
N
CH2
CH3
—
45
310
a Values are means of three determinations (standard deviation lower than 10%).
Table 2. Antiproliferative effects of compounds 1, 2, 18a–d, 19, 23a and 25
a
Compound
IC50 (lM) or % inhibition
L1210
DU145
PC-3
MCF-7
1
4.95
41%
4.76
4.0
ndb
ndb
ndb
2
>100
59.8
38%c
100
>100
50.0
34.1
ndb
>100
48.0
ndb
18a
18b
18c
18d
19
3.0
66.0
33.0
41.0
76.0
45.0
4.57
34%d
3.90
4.85
47.4
51.3
100
27.3
ndb
23a
25
69.4
11.4
9.55
a Cell proliferation was measured from at least three independent determinations (standard deviation lower than 10%).
b Not determined.
c Compound tested at the concentration of 100 lM.
d Compound tested at the concentration of 10 lM.

5470
P. Gilleron et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5465–5471
pounds 18a–d, 23a), inhibition was significantly im-
proved (more than 6-fold) when comparing 18a–c to
19. This observation validates our hypothesis assuming
that the two lateral aromatic fragments of 1 and 2
may be advantageously combined through a rigid tricy-
cle. The IC50 values for FTase in the series 18a–d range
from medium (46.5 nM for 18b) to good (17.3 nM for
18d). Substitution of the nitrogen in sultam by an alkyl
chain did not modify the enzymatic activity, whereas
substitution of the propyl chain by morpholine in-
creased potency by about 2.5-fold, when considering
18d (IC50 = 17.3 nM) and 18b. This result suggests that
a hydrogen bond acceptor could improve activity.
Changing the linker size (diazepane for piperazine) did
and provide a reasonable explanation for its inhibitory
activity. Besides the coordination between the distal
imidazole nitrogen and the zinc ion, interaction was re-
vealed between one aromatic ring of the tricycle and the
hydrophobic pocket delineated by Trp102b, Trp106b
and Tyr361b (the ‘‘A2 binding site’’). In addition, com-
pound 18d interacts via hydrogen bonds with Arg202b
(between the two morpholinic oxygen doublets and side
chain hydrogens of Arg) as it was observed for tetrapep-
tide substrates CVLS (H-Ras), CVIM (K-Ras4B) or
CVIF (TC21).33 The presence of a morpholine at the
A2 residue strengthens interactions in the binding site
and may explain the better FTase inhibitory activity
throughout this series.
not modify the activity of 23a versus 18a (IC50
45 nM), as was already observed with 19 and 25.
#
To explain the improvement in potency of 18a–d and
23a over 19 and 25, docking simulations of compounds
18a and 19 were investigated. Studies established that
the tricyclic moiety of compound 19 only displayed
interaction in the hydrophobic pocket (data not shown)
whereas the bridgehead modified compound 18a inter-
acted via hydrogen bonds between the sulfonamide
oxygen and side chain hydrogens of Arg202b (Fig. 3).
Cellular proliferation was investigated on L1210 cells
using numeration, and on DU145, PC-3 and MCF-7
cells by the colorimetric MTT assay.23 These cellular
models are representative of different tumoral condi-
tions and were shown to be responsive to FTase inhibi-
tors. For example, recent studies28 have shown
synergistic effects for the combination of ZOL (Zoled-
ronic acid) with R115777 (Tipifarnib) in prostate adeno-
carcinoma models and, specifically, on androgen-
independent (PC-3 and DU145) prostate cancer cell
lines. These effects were paralleled by disruption of
Ras ! Erk and Akt survival pathways, a consequent de-
crease in phosphorylation of both mitochondrial bcl-2
and bad proteins, and a caspase activation. MCF-7 is
one of the most currently used models in human breast
cancer though Ras mutations are rare (less than 2%)29
but Ras signaling is frequently upregulated in these
tumors as a result of the activation of upstream growth
factor signaling pathways. In leukemia, ras mutations
are significant (6–40%) and cellular murine models
(L1210) have indicated how extensive the antitumor
activity is of many relevant inhibitors such as R115777
or SCH-66336 (Lonafarnib).30,31
In conclusion, we designed and synthesized a new series
of FTase inhibitors in which hydrophobic residues were
conformationally locked in a tricycle. These compounds
were tested for their ability to inhibit metalloenzyme
FTase activity and cellular proliferation; the presence
of an additional morpholine as hydrogen bond acceptor
resulted in enhanced binding to the enzyme. The broad
anticancer action of the compound 18d merits further
investigation as does the implication of other proteins
targets (like CENP-E and CENP-F). The determination
of other protein targets may also explain the potent anti-
cancer action of compounds 19 and 25 although they
The most potent inhibitor of FTase (18d) in the dib-
enzothiazepine series (18a–d and 23a) also displays the
best activity against DU145, PC-3 and MCF-7 (Table
2) and this is attributed to the presence of morpholine:
the increase in FTase inhibition and the cytotoxic effect
(in the micromolar range) may be induced by the crea-
tion of hydrogen bonds with Arg202b of the receptor
(see the docking analysis) and by greater hydrophilicity
in this region of the molecule. In addition, a direct com-
parison of mammalian antiproliferative effects showed
that the diazepane core was more favorable than the
piperazine spacer (18a vs 23a); this requirement was
not observed in the dibenzocycloheptane series (19 vs
25). The high sensitivity of the seven synthesized com-
pounds towards L1210 cells could be connected to the
significant efficacy of FTIs in myeloid leukemias32 and
to a weak resistance of L1210 cells.
Docking simulations, using GOLD software,23 were car-
ried out in order to clarify the binding mode of com-
pound 18d in the active site of FTase (Fig. 2). The
pharmacological results concord with modelization
Figure 2. Docking of compound 18d in the FTase binding site. The
farnesyl group (FPP) is colored magenta. Arg202b and Tyr166a are
shown in cyan, and the aromatic residue side chains that define a
hydrophobic pocket (Trp102b, Trp106b, Tyr361b) are shown in green.

P. Gilleron et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5465–5471
5471
9. Basso, A. D.; Kirschmeier, P.; Bishop, W. R. J. Lipid Res.
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Figure 3. Docking of compound 18a in the FTase binding site. The
farnesyl group (FPP) is colored magenta. Arg202b and Tyr166a are
shown in cyan, and the aromatic residue side chains that define a
hydrophobic pocket (Trp102b, Trp106b, Tyr361b) are shown in green.
18. Millet, R.; Domarkas, J.; Houssin, R.; Gilleron, P.;
´
Goossens, J.-F.; Chavatte, P.; Loge, C.; Pommery, N.;
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19. Gilleron, P.; Millet, R.; Houssin, R.; Wlodarczyk, N.;
Farce, A.; Lemoine, A.; Goossens, J.-F.; Chavatte, P.;
have no FTase enzymatic activity. Due to the role of
CENP-E and CENP-F in the mitotic spindle function,
inhibition of their farnesylation may contribute to the
synergistic interaction observed between cytotoxic
agents like taxanes and FTIs. This aspect is presently
being studied and will come under further discussion.
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20. A representative sample of the conformational space was
generated by a 200-cycle simulated annealing experiment.
Computation began at 1000 K and the system was
maintained at that temperature for 2000 fs. The temper-
ature was then reduced with exponential ramping until
300 K was reached. At this point, the lowest energy
conformation was selected and minimized.
Acknowledgments
21. Laconde, G.; Depreux, P.; Berthelot, P.; Pommery, N.;
´
Henichart, J.-P. Eur. J. Med. Chem. 2005, 40, 167.
This work was financially supported by the Association
pour la Recherche sur le Cancer (fellowship to P.G.).
22. Njoroge, F. G.; Vibulbhan, B.; Pinto, P.; Strickland, C.;
Bishop, W. R.; Nomeir, A.; Girijavallabhan, V. Bioorg.
Med. Chem. Lett. 2006, 16, 984.
23. For details concerning evaluation of FTase, cellular
activities and molecular modeling, see Refs. 18 and 26.
Supplementary data
`
24. Lebegue, N.; Flouquet, N.; Berthelot, P.; Pfeiffer, B.;
Renard, P. Synth. Commun. 2002, 32, 2877.
25. Iwema Bakker, W. I.; Familoni, O. B.; Padfield, J.;
Snieckus, V. Synlett 1997, 9, 1079.
26. Wlodarczyk, N.; Gilleron, P.; Millet, R.; Houssin, R.;
Goossens, J.-F.; Lemoine, A.; Pommery, N.; Wei, M. X.;
Supplementary data associated with this article (includ-
ing synthesis of compounds mentioned in Schemes 1 and
2) are provided. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.bmcl.2007.07.002.
´
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