Potent and selective farnesyl transferase inhibitors

Article abstract of DOI:10.1021/jm030502y

We recently described a novel series of CA₁A₂X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A₁A ₂ residue. Extensive exploration of structure-activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC₅₀ = 4.60 nM on isolated enzyme, EC₅₀ = 20.0 nM for growth inhibition on a tumor cell line). The molecular docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.

Full text of DOI:10.1021/jm030502y

6812
J. Med. Chem. 2004, 47, 6812-6820
Potent and Selective Farnesyl Transferase Inhibitors
Re´gis Millet, Juozas Domarkas, Raymond Houssin, Pauline Gilleron, Jean-Franc¸ois Goossens,
Philippe Chavatte, Ce´dric Loge´, Nicole Pommery, Jean Pommery, and Jean-Pierre He´nichart*
Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Universite´ de Lille 2, BP 83, rue du Professeur Laguesse,
59006 Lille, France
Received October 3, 2003
We recently described a novel series of CA1A2X peptidomimetics as farnesyl transferase
inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking
A1A2 residue. Extensive exploration of structure-activity relationships revealed that replace-
ment of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro
activities (18e, IC50 ) 4.60 nM on isolated enzyme, EC50 ) 20.0 nM for growth inhibition on a
tumor cell line). The molecular docking of 18e and 19e in the active site of the enzyme provided
details of key interactions with the protein and showed that the methionine or phenylalanine
residue fits into the aryl binding site.
Chart 1
Introduction
The key role of Ras proteins in cell growth and cell
proliferation inducing the MAP kinase signal transduc-
tion pathway and consequently the prevalence of Ras
oncogene activation in a variety of human tumors (30%
on average, reaching up to 50% in colon cancer and up
to 90% in pancreas cancer) is well documented.1 Biologi-
cal activation of Ras proteins is directly related to their
membrane association, which is mainly dependent on
the prenylation of cysteine in the C-terminal tetrapep-
tide CA1A2X (C, Cys; A1, A2, any amino acid; X, Ser, Met,
Phe, Leu, or Ile) by Zn-metalloenzyme farnesyltrans-
ferase (FTase).2 As expected, inhibition of this enzyme
prevents membrane localization of the Ras oncogene and
constitutes, therefore, a valid target for the conception
of new cytostatic anticancer drugs.3
However, if farnesyltransferase inhibitors (FTIs) are
effective on the farnesylation and function of the H-Ras
isoform, then they also prevent the farnesylation of
K-Ras and N-Ras, which may undergo the alternative
geranylgeranyltransferase reaction provoking an onco-
genic effect. Unfortunately, H-Ras mutations are not
prevalent in some common cancers, and other targets
have to be considered. Experimental evidence supports
the possibility that RhoB proteins are important tar-
gets.4 Other candidate targets for proteins that mediate
the antitumor effects of FTIs include other Ras-family
GTPases such as Rheb5 and centromer-associated pro-
teins CENP-E and CENP-F, because functional as-
sociation of CENP-E with microtubules seems to require
farnesylation6 or an unidentified protein that functions
as activator of PI3K/AKT2 when farnesylated.7
or Trp.8 Stepwise modifications of the natural tetrapep-
tide resulted in a variety of FTIs when (a) Met was
retained or suppressed,9 (b) the A1A2 tensor was re-
placed by (i) a mono-10 or a biaryl11 moiety, (ii) pipera-
zine,12 (iii) benzodiazepine,13 or (iv) a diaryl ether or a
diaryl sulfone spacer,14 and (c) cysteine was replaced
by a heterocycle such as pyridine,15 imidazole,16 or
cyclohexylamine.17
Random screening of chemical libraries also led to the
identification of several nonpeptides, nonthiol com-
pounds, which were optimized into R-115777, SCH-
66336, and BMS-214662 presently engaged in clinical
trials (Chart 1).18
We reported recently the synthesis and the pharma-
cological evaluation of new FTIs derived from the CVFM
tetrapeptide and characterized by a piperidinyl spacer.19
The most interesting molecule 1 (Chart 2) possessed a
IC50 value (isolated enzyme FTase) as low as 22.8 nM
but did not inhibit the proliferation of tumor cells in
culture. Replacement of cysteine by thiazoline, thiazo-
lidine, or imidazole was found to decrease inhibitory
activity without disclosing any effect on cellular growth.
Early screening of tetrapeptide libraries established
that selective prenylation of the cysteine either by FTase
or by closely related geranylgeranyltransferase-I (GGTI)
is directed by the nature of X. Farnesylation is induced
by Ser or Met whereas Leu or Ile provokes geranylgera-
nylation, and both prenylations are possible with Phe
* To whom correspondence should be addressed. Phone: +33-3-
2096-4374.
Fax:
+33-3-2096-4906.
E-mail:
henicha@
pharma.univ-lille2.fr.
10.1021/jm030502y CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2004

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27 6813
Chart 2
H-Phe-OCH3, or H-Ile-OCH3), and reduction in situ
by sodium cyanoborohydride gave the corresponding
N-substituted amino esters 9-11. After benzoylation
and deprotection of piperidine with methanolic HCl,
compounds 15-17 were subjected to reductive amina-
tion with imidazolecarbaldehydes 7a-e to give final
compounds 18a-e, 19e, and 20e. Saponification of 19e
and 20e with 2 N NaOH in methanol gave carboxylic
acids 21e and 22e, respectively. The N-benzyl derivative
24 was prepared from 15 by reduction of the amide
function with BH3 (benzylaminopiperidine 23) followed
as above by reductive amination with 5-imidazolecar-
baldehyde 7e.
Biological Data
The compounds were tested for their ability to inhibit
the FTase catalyzed transfer of the FPP moiety to
dansyl-CVIM and GGT-I (which catalyses the transfer
of the GGPP moiety to dansyl-GCVLL).21 Biological data
is summarized in Table 1.
This paper reports the synthesis and study of the new
FTIs 18a-e, 19e, 20e, 21e, 22e, and 24 related to 1,
with potent isolated enzymatic and cellular activities,
where cysteine is replaced by substituted 1-(4-benzyl)-
4-imidazolylmethyl groups.
To obtain more insight into how this pharmacophore
interacts with the active site of the enzyme, substituents
on the benzyl ring ranged from withdrawing cyano and
trifluoromethyl groups to electron-donating methyl or
methoxy groups, with electronically inactive hydrogen
atom as reference. Conformational restraint imposed by
the carbonyl group of N-benzoylmethioninate was re-
leased with N-benzyl. Finally, to determine a specificity
profile (FTase versus GGTase I) of the molecules,
C-terminal methioninate was replaced by Phe and Ile
esters.
Results and Discussion
Among FTIs based on the CA1A2X C-terminus se-
quence of farnesylated proteins, the most active com-
pound 119 (IC50 ) 22.8 nM) includes Cys and Met,
respectively, on its N- and C-termini and N-(4-piperidin-
yl)benzamide as a nonpeptidic template instead of the
two central amino acid residues A1A2. The reported
structure-activity relationship study19 focused prima-
rily on cysteine derivatives in which substituents were
varied by different heterocycles such as thiazolidine,
thiazole, or imidazole. The results revealed19 decreased
FTase inhibition (IC50 > 2.14 µM), showing the impor-
tance of Cys in recognizing the enzyme. Despite the
modest activity of these analogues, we continued to
investigate the 4-aminopiperidinyl core with a view to
improving enzymatic and cellular potencies. We there-
fore decided to replace Cys by substituted 1-benzyl-4-
imidazoylmethyl fragments because imidazole is known
to be a putative binding element to the active site zinc
atom9b,20 and the 4-cyanobenzyl group a hydrophobic
substituent to boost FTase activity.
Compound 18e displayed a more potent inhibition
(4.5-fold) than that of 1 with an IC50 ) 4.60 nM on an
isolated enzyme assay. This finding concords with a
previous report9b where imidazole may be successfully
combined with a suitable hydrophobic substituent to
obtain an effective cysteine substitute for FTIs. More-
over, no GGTase activity was detected in 18e. GGT-I is
responsible for most protein prenylation, and it has been
shown that concomitant inhibition of FTase and GGT-I
leads to substantial in vivo toxicity.1c Therefore, the
highly significant FTase/GGTase selectivity led us to
assess the role of Met-OCH3 in recognizing the FTase
enzyme versus GGTase. A previous study8 revealed that
selective prenylation of the cysteine residue either by
FTase or by closely related GGT-I is triggered by the
nature of the amino acid X in the CA1A2X sequence.
Farnesylation is therefore induced by Ser or Met
whereas Leu or Ile is responsible for geranylgeranyla-
tion, and both prenylations are possible with Phe or Trp.
Changing Met for Phe (19e) or Ile (20e) varies the
inhibition of FTase. Compared with that of the parent
structure 18e, the IC50 value of 19e is 4-fold lower (IC50
Chemistry
The 5-formylimidazoles 7a-e (Scheme 1) were pre-
pared in five steps according to the standard proce-
dure9b,20 adopted for the synthesis of regiochemically
substituted imidazoleacetic esters.
Thus, 4-hydroxymethylimidazole 2 was protected by
a trityl group on the most accessible nitrogen to give
exclusively the trityl-protected 1,4-disubstituted isomer
following the methodology used to prepare regioselec-
tively alkylated histidines (i.e., classical imidazole
protection/deprotection strategy). Compound 3 was next
acetylated with acetic anhydride in pyridine to give ester
4. Alkylation of 4 was carried out with different com-
mercially available 4-substituted benzyl bromides in
EtOAc, with formation of the corresponding imidazo-
lium salts as intermediates. Removal of the trityl
protective group was effective (i) by solvolysis in reflux-
ing methanol9b (18 h) for the preparation of 5a,c,d or
(ii) by the more rapid (1 h) classical method using
trifluoroacetic acid giving 5b,e; the yields for 5a-e
depend exclusively on the formation of imidazolium salt
but not on the deprotection step. Further saponification
of the ester function of 5a-e with 2 N NaOH giving
primary alcohols 6a-e was followed by their oxidation
(MnO2, 30-40 °C, dioxane) providing 1-benzyl-5-formyl-
imidazoles 7a-e.
The key intermediates 15-17 were obtained (Scheme
2) from 4-piperidone according to our previously pub-
lished protocol.19
Once N-protected by Boc, 4-piperidone 8 was con-
densed with an amino acid methyl ester (H-Met-OCH3,

6814 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27
Millet et al.
Scheme 1a
a Reagents and conditions: (a) (C6H5)3CCl, NEt3, DMF, rt, 72 h, 71%; (b) Ac2O, pyridine, rt, 18 h, 84%; (c) (i) (p)R1-C6H4-CH2Br,
EtOAc, 55 °C, 24 h; (ii) MeOH, reflux, 18 h, 30-77% for 5a,c,d or TFA, rt, 1 h, 38-57% for 5b,e; (d) 2 N NaOH, MeOH, rt, 0.5-2 h,
36-99%; (e) MnO2, dioxane, 30-40 °C, 3 h, 70-97%.
Scheme 2a
a Reagents and conditions: (a) Boc2O, DIEA, dioxane/H2O (4:1), rt, 24 h, 75%; (b) H-(Met, Phe or Ile)-OCH3, NEt3, NaBH3CN, MeOH,
3-Å molecular sieves, 50 °C, 48 h, 40-68%; (c) Benzoyl chloride, NEt3, CH2Cl2, 0 °C, 1 h, then rt, 24 h, 30-55%; (d) HCl/MeOH, rt, 18 h,
95%; (e) (i) 7a-e, NEt3, MeOH, 3-Å molecular sieves, N2, 50 °C, 4 h; (ii) NaBH3CN, MeOH, 50 °C, 18 h, 42-52%; (f) (i) 2 N NaOH, MeOH,
rt, 6 h; (ii) 2 N HCl, 80-90%; (g) (i) BH3.THF, THF, 0 °C, 1 h, then rt, 18 h; (ii) 6 N HCl, H2O, reflux, 10 min, 30%; (h) (i) 7e, NEt3, MeOH,
3-Å molecular sieves, N2, 50 °C, 4 h; (ii) NaBH3CN, MeOH, 50 °C, 18 h, 47%.
) 22.0 nM) whereas the Ile analogue 20e is a compa-
rable FTase inhibitor (IC50 ) 32.7 nM), both of them
being devoid of GGTase activity. The N-(4-piperidinyl)-
benzamide scaffold therefore constitutes an interesting
platform for FTase affinity and selectivity.
restraints imposed by the carbonyl group of N-benzoyl-
methioninate (18e) were finally released with N-benzyl
(24) and gave a 2-fold increase in FTase activity (IC50
) 2.35 nM). Corresponding carboxylic acids of 18e and
19e revealed a good ability to inhibit the FTase enzyme
(21e, IC50 ) 10.0 nM; 22e, IC50 ) 54.1 nM).
Cellular proliferation (Table 2) was first investigated
on L-1210 cells for the most potent 4-aminopiperidine
derivatives (1, 18e, 24). The results showed a good
response for 18e (EC50 ) 20.0 nM) and encouraged us
to evaluate the affinity of these inhibitors in another
cell type.
The DLD-1 (mutant K-Ras) human cell line was
chosen because it is known that the K-Ras and N-Ras
isoforms are most frequently mutated in human cancers.
The results showed antiproliferative effects at low
micromolar concentrations. The most active compound
was 18e. These results are in the same range as those
To assess the importance of the electronic nature of
the benzylic substituent in this series of inhibitors, the
electronic character of para-substituted benzylimidazole
was varied. Inspection of Table 1 shows that FTase
inhibitory potency is relatively sensitive to the electronic
nature of this substituent rather than to its size.25 Thus,
an electron-donating group like methyl (18b, IC50 ) 600
nM), methoxy (18d, IC50 ) 575 nM), or a neutral
hydrogen atom (18a, IC50 ) 397 nM) led to a decrease
in FTase inhibition. In contrast, the last was most
effective with compounds containing strongly withdraw-
ing groups such as 4-trifluoromethyl (18c, IC50 ) 43.9
nM) or 4-cyano (18e, IC50 ) 4.60 nM). Conformational

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27 6815
Table 1. FTase and GGTase Activities of Reference Compounds (Chart 3) and of 1, 18a-e, 19e, 20e, 21e, 22e, and 24 (Chart 2)
IC50 (nM)
R1
R2
R3
R4
FTase
GGTase
a
b
FTI1
FTI2
34.0 ( 1.0
72.0 ( 15
56.2 ( 12.0
22.8 ( 2.1
397 ( 84
> 5000
> 100
12.4 ( 7.3
> 100
ndd
c
GGTI1
1
18a
18b
18c
18d
18e
19e
20e
21e
22e
24
H
(CH2)2SCH3
(CH2)2SCH3
(CH2)2SCH3
(CH2)2SCH3
(CH2)2SCH3
CH2C6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
CH2C6H5
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOH
CH3
CF3
OCH3
CN
600 ( 87
ndd
43.9 ( 4.2
575 ( 101
4.60 ( 2.36
22.0 ( 6.6
32.7 ( 3.8
10.0 ( 3.1
54.1 ( 12.0
2.35 ( 0.48
ndd
ndd
> 2000
> 2000
> 2000
> 2000
> 2000
> 2000
CN
CN
CH(CH3)CH2CH3
(CH2)2SCH3
CH2C6H5
CN
CN
COOH
CN
(CH2)2SCH3
COOCH3
a N-[2(S)-[2(R)-Amino-3-mercaptopropylamino]-3-methylbutyl]-Phe-Met-OH22 (B.581). b H-Cys-4-Abz-Met-OH.23 c H-Cys-4-(2-phenyl)-
Abz-Leu-OH24 (GGTI-287). FTI1 and FTI2 were used as positive controls for FTase activity and GGTI1 for GGTase activity. d Not determined.
Table 2. Effect of 4-Aminopiperidine FTIs 1, 18e, and 24 on
Cell Growth
EC50
L-1210 (nM)
DLD-1 (µM)
1
18e
24
> 10 000
20.0 ( 5.6
> 5000
18.1 ( 2.3
9.20 ( 2.47
12.9 ( 3.8
Figure 2. Overlap of compounds 18e (cyan) and 19e (red)
docked in the FTase binding site.
The pharmacological results are in agreement with
the predictions made by the modeling program GOLD
and provide a reasonable explanation for the inhibitory
activity of these compounds. In addition to the coordina-
tion observed between the distal nitrogen of imidazole
and the zinc ion used as a starting fragment for the
modeling study, the docking program revealed an ad-
ditional interaction between Met-OCH3 for 18e (or Phe-
OCH3 for 19e) and a hydrophobic pocket defined by
Trp102â, Trp106â, and Tyr361â in the â-submit. Thus,
the N-(4-piperidinyl)benzamide scaffold constitutes an
interesting pattern to position Met-OCH3 of 18e or Phe-
OCH3 of 19e in the aryl binding site of the FTase pocket
and the imidazole to coordinate Zn2+. This hydrophobic
pocket has often been referred to as an important
element for enzyme-inhibitor recognition.26,27 In the
case of CA1A2X peptide substrates, the hydrophobic
pocket hosts a second aliphatic residue such as Ile in
CVIM27c and could explain the FTase versus GGTase
Figure 1. Docking of compound 18e in the FTase binding
site. The farnesyl group (FPP) is colored magenta. Arg202â
and Tyr166R are shown in cyan, and the aromatic residue side
chains that define a hydrophobic pocket (Trp102â, Trp106â,
Tyr361â) are shown in green.
observed by Bell16 showing high resistance of DLD-1
cells. In addition, 18e blocks the growth of H-Ras
transformed NIH3T3 fibroblasts (EC50 ) 1.33 µM).
The docking experiment (Figure 1) shows how well
18e fits with the active site of FTase. Figure 2 shows
the superposition of compounds 18e and 19e after the
docking of each molecule with the enzyme.

6816 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27
Millet et al.
on a quadripolar Finnigan Mat SSQ 710 instrument. Elemen-
tal analyses were performed by the “Service Central d’Analyses”
at the CNRS, Vernaison (France). Commercially available
reagents and solvents were used throughout without further
purification.
selectivity of 18e and 19e. With regards to our modeling
studies, compounds 18e and 19e constitute two CA1A2X
competitive inhibitors. However, their interactions are
quite different from those of classical CA1A2X inhibitors.
The C-terminal side chain for X was positioned in the
large hydrophobic pocket where the A2 residue fits. This
could explain why modification of the C-terminal resi-
due X in our series failed to show dependence on FTase/
GGTase selectivity. The CA1A2X competitive nature was
also measured (18e, Kapp ) 6.66 ( 0.49; 19e, Kapp) 28.22
( 3.97) and confirmed the modeling studies.
Furthermore, we observed that the cyanobenzyl group
induces stacking with the FPP isoprenoid and fits
Tyr166R and Arg202â with possible direct interactions.
It is difficult to evaluate the importance of the electronic
nature of the benzylic substituent with regard to the
modeling study, but enzymatic studies show the impor-
tant role of the electronic nature of para substitu-
ent, which could also enhance stacking with the iso-
prenoid FPP moiety.26,27c No interaction of the terminal
-COOCH3 residue in 18e and 19e as well as hydrogen
bonds with the active site was observed, which confirms
the good results of enzymatic inhibition by the corre-
sponding carboxylic acids 21e and 22e.
(1-Trityl-1H-4-imidazolyl)methanol (3). Trityl chloride
(11.9 g, 40.7 mmol, 1.1 equiv) and NEt3 (15.4 mL, 111.0 mmol,
3.0 equiv) were added to a suspension of 1H-4-imidazolyl-
methanol hydrochloride 2 (4.98 g, 37.0 mmol, 1.0 equiv) in
dimethylformamide (100 mL). After being stirred at room
temperature for 72 h, the solution was poured into 1.5 L of
water. The precipitate was washed first with water and then
with ether and recrystallized from dioxane to give 3 as a white
solid (8.94 g, 71% yield). Rf ) 0.48 (CH2Cl2/MeOH 9:1). Mp:
237-238 °C. IR: 3412 (OH), 1430 (CdC) cm-1 1H NMR
.
(DMSO-d6): 4.62 (s, 2H), 6.58 (s, 1H), 7.05-7.17 (m, 7H), 7.28-
7.40 (m, 9H), 7.54 (bs, 1H). Anal. (C23H20N2O) C, H, N.
(1-Trityl-1H-4-imidazolyl)methyl Acetate (4). Acetic
anhydride (4.2 mL, 43.5 mmol, 1.5 equiv) was added to a
suspension of alcohol 3 (9.87 g, 29 mmol, 1.0 equiv) in pyridine
(100 mL). The solution was stirred at room temperature for
18 h and then concentrated under reduced pressure. The solid
obtained was recrystallized from cyclohexane to give 4 as a
white powder (9.32 g, 84% yield). Rf ) 0.81 (CH2Cl2/MeOH
9:1). Mp: 137-139 °C. IR: 1727 (CO) cm-1. 1H NMR (DMSO-
d6): 1.63 (s, 3H), 4.52 (s, 2H), 6.69 (s, 1H), 7.10-7.17 (m, 6H),
7.35-7.48 (m, 9H), 7.54 (s, 1H). Anal. (C25H22N2O2) C, H, N.
General Procedure for the Preparation of 1-Benzyl-
1H-5-acetoxymethylimidazole Derivatives (5a-e). Com-
pound 4 (7.65 g, 20.0 mmol, 1.0 equiv) in EtOAc (50 mL) was
added to a solution of commercial (except for 4-methoxy) benzyl
bromide derivatives (22.0 mmol, 1.1 equiv) in EtOAc (100 mL).
After being stirred at 55 °C for 24 h and being cooled to room
temperature, the resulting imidazolium salt was isolated by
filtration and washed with EtOAc. The trityl protecting group
was removed according to two procedures.
Conclusion
This study has revealed that the N-(4-piperidinyl)-
benzamide residue constitutes an effective platform for
the discovery of noncysteinyl inhibitors of FTase. Com-
pound 18e shows a nanomolar affinity on an isolated
FTase enzyme, significant FTase/GGTase selectivity,
and cellular activity on L-1210 cell lines. Molecular
modeling indicates possible interactions between the
amino acids in the active site, and the two inhibitors
18e and 19e demonstrate their interaction with a
hydrophobic pocket consisting of amino acids Trp102â,
Trp106â, and Tyr361â.
Procedure A. Imidazolium salt was added to MeOH (150
mL) and then stirred at reflux for 18 h. The solution was
evaporated under reduced pressure, and the residue was
triturated with a 5% citric acid solution. The solution was
filtered and adjusted to pH 6 with a 5% Na2CO3 solution. The
obtained precipitate was filtered, washed with ether, and used
as such in the following reaction.
The broad anticancer action of the N-(4-piperidinyl)-
benzamide series merits further investigation as a
potential lead structure in the search for new treat-
ments against cancer. Molecular docking studies help
to understand the interaction between these inhibitors
and FTase. Other modulations are scheduled; the first
step will consist of introducing diverse R1 and R4
substituents to increase bioavailability, antiproliferative
activity, and enzymatic interaction. In addition, other
proteins28,29 such as Rheb or p70S6K have been shown
to be functional when farnesylated and small nonpep-
tidic molecule inhibitors designed according to the
CA1A2X box can block the Akt/mTOR/p70S6K signaling
pathway.
Procedure B. Imidazolium salt was added to TFA (30 mL),
and the mixture was stirred for 1 h at room temperature. The
solution was concentrated under reduced pressure, and TFA
was evaporated with successive addition-evaporation cycles
of CH2Cl2. The obtained solid was washed with ether and used
as such in the following reaction.
(1-Benzyl-1H-5-imidazolyl)methyl Acetate (5a). Pro-
cedure A. White solid (4.79 g, 77% yield). Rf ) 0.59 (CH2Cl2/
MeOH 9:1). Mp: 99-100 °C. IR: 3122-2600 (CH), 1737 (CO)
1
cm-1. H NMR (DMSO-d6): 1.80 (s, 3H), 5.10 (s, 2H), 5.55 (s,
2H), 7.19-7.45 (m, 5H), 7.89 (s, 1H), 9.41 (s, 1H).
[1-(4-Methylbenzyl)-1H-5-imidazolyl]methyl Acetate
Trifluoroacetate (5b). Procedure B. White solid (2.72 g,
38% yield). Rf ) 0.50 (CH2Cl2/MeOH 9:1). Mp: 147-149 °C.
1
IR: 3126-2601 (CH), 1736 (CO) cm-1. H NMR (DMSO-d6):
1.85 (s, 3H), 2.30 (s, 3H), 5.08 (s, 2H), 5.47 (s, 2H), 7.18-7.29
(m, 4H), 7.85 (s, 1H), 9.33 (s, 1H).
Experimental Section
[1-(4-Trifluoromethylbenzyl)-1H-5-imidazolyl]meth-
yl Acetate (5c). Procedure A. White solid (5.23 g, 69% yield).
Rf ) 0.53 (CH2Cl2/MeOH 9:1). Mp: 76-78 °C. IR: 3054-2925
(CH), 1738 (CO) cm-1. 1H NMR (DMSO-d6): 1.84 (s, 3H), 4.97
(s, 2H), 5.25 (s, 2H), 7.15 (s, 1H), 7.25-7.36 (m, 4H), 7.55 (s,
1H).
Chemistry. Melting points were determined with a Bu¨chi
535 capillary melting point apparatus and remain uncorrected.
Analytical thin-layer chromatography was performed on pre-
coated Kieselgel 60F254 plates (Merck); the spots were located
by UV (254 and 366 nm); Rf values are given for guidance.
Silica gel 60 230-400 mesh purchased from Merck was used
for column chromatography. The structures of all compounds
were supported by IR (KBr pellets, FT-Bruker Vector 22
[1-(4-Methoxybenzyl)-1H-5-imidazolyl]methyl Acetate
(5d). Procedure A. White solid (2.05 g, 30% yield). Rf ) 0.51
(CH2Cl2/MeOH 9:1). Mp: 80-81 °C. IR: 3004-2837 (CH),
1739 (CO) cm-1 1H NMR (DMSO-d6): 1.93 (s, 3H), 3.78 (s,
.
1
instrument) and by H NMR at 300 MHz on a Bruker DRX-
3H), 4.97 (s, 2H), 5.08 (s, 2H), 6.85 (d, 2H, J ) 7.5), 7.01 (d,
300 spectrometer. Chemical shifts were reported in ppm using
tetramethylsilane as a standard, J values are in hertz, and
the splitting patterns were designated as follows: s, singlet;
d, doublet; t, triplet; m, multiplet. Mass spectra were recorded
2H, J ) 7.5), 7.13 (s, 1H), 7.54 (s, 1H).
[1-(4-Cyanobenzyl)-1H-5-imidazolyl]methyl Acetate Tri-
fluoroacetate (5e). Procedure B. White solid (4.21 g, 57%

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27 6817
yield). Rf ) 0.42 (CH2Cl2/MeOH 9:1). Mp: 198-200 °C. IR:
4-[(5-Formyl-1H-1-imidazolyl)methyl]benzonitrile (7e).
White solid (887 mg, 70% yield). Rf ) 0.35 (CH2Cl2/MeOH 9:1).
3093-2601 (CH), 2238 (CN), 1742 (CO) cm-1 1H NMR
.
1
(DMSO-d6): 1.84 (s, 3H), 5.09 (s, 2H), 5.69 (s, 2H), 7.48-7.92
(m, 4H), 7.88 (s, 1H), 9.41 (s, 1H).
Mp: 135-136 °C. IR: 2227 (CN), 1670 (CO) cm-1. H NMR
(CDCl3): 5.58 (s, 2H), 7.26 (d, 2H, J ) 8.5), 7.65 (d, 2H, J )
8.5), 7.78 (s, 1H), 7.88 (s, 1H), 9.73 (s, 1H). Anal. (C12H9N3O)
C, H, N.
General Procedure for the Preparation of 1-Benzyl-
1H-5-hydroxymethylimidazole Derivatives (6a-e). Com-
pounds 5a-e (10.0 mmol, 1.0 equiv) were dissolved in MeOH
(40 mL), 2 N NaOH (40 mmol, 4.0 equiv) was added, and the
resulting mixture was stirred at room temperature for 0.5-2
h. The solution was neutralized with 2 N HCl (41 mmol, 4.1
equiv), and the solvent was removed under reduced pressure.
The solid was filtered, washed with water and ether, and
finally purified by column chromatography on silica gel using
CH2Cl2/MeOH as eluent.
N-Boc-4-piperidone (8). DIEA (28.3 mL, 163 mmol, 2.5
equiv) was added to a solution of 4-piperidone hydrochloride
(8.80 g, 65.0 mmol, 1.0 equiv) in 200 mL of a dioxane/H2O (4:
1) mixture. Di-tert-butyl dicarbonate (21.1 g, 97.5 mmol, 1.5
equiv) was added dropwise (over 1 h), and the resulting
mixture was stirred at room temperature for 24 h. The solvent
was evaporated under reduced pressure, and the residue was
poured into a 5% citric acid solution and extracted with
dichloromethane. The organic phase was dried (MgSO4) and
concentrated to give a solid which was recrystallized from
cyclohexane: white solid (9.71 g, 75% yield). Rf ) 0.46
(cyclohexane/EtOAc 1:1). Mp: 73-75 °C. IR: 1715 (CO), 1680
1-Benzyl-1H-5-hydroxymethylimidazole (6a). White solid
(1.05 g, 56% yield). Rf ) 0.32 (CH2Cl2/MeOH 9:1). Mp: 135-
136 °C. IR: 3203 (OH), 3118-2876 (CH) cm-1 1H NMR
.
(DMSO-d6): 4.32 (s, 2H), 5.17 (s, 1H), 5.24 (s, 2H), 6.84 (s,
1H), 7.18 (m, 2H), 7.29-7.36 (m, 3H), 7.70 (s, 1H). Anal.
(C11H12N2O) C, H, N.
(CO) cm-1 1H NMR (CDCl3): 1.55 (s, 9H), 2.45 (t, 4H, J )
.
6.2), 3.75 (t, 4H, J ) 6.2). Anal. (C10H17NO3) C, H, N.
1-(4-Methylbenzyl)-1H-5-hydroxymethylimidazole (6b).
General Procedure for the Preparation of Piperidines
9-11. N-Boc-piperidone 8 (6.97 g, 35.0 mmol, 1.0 equiv) and
NEt3 (7.30 mL, 52.5 mmol, 1.5 equiv) in 100 mL of dry
methanol were added to a mixture of methyl ester of Met, Phe,
or Ile (52.5 mmol, 1.5 equiv) and 3-Å molecular sieves in 50
mL of dry methanol. The reaction was stirred at 50 °C for 4 h
(nitrogen), and then NaBH3CN (3.30 g, 52.5 mmol, 1.5 equiv)
was added in one batch. The mixture was stirred for 48 h. The
sieves were filtered off, and the solvent was removed under
reduced pressure. The residue was dissolved in EtOAc,
NEt3‚HCl was filtered off, and the filtrate was washed with a
5% Na2CO3 solution, and then H2O and brine. The organic
phase was dried (MgSO4) and concentrated under reduced
pressure. The residue obtained was triturated in petroleum
ether and recrystallized from pentane to give 9-11 as solids.
Methyl N-[4-(1-Boc-piperidinyl)]methioninate (9). White
solid (7.91 g, 68% yield). Rf ) 0.60 (hexane/EtOAc 2:8). Mp:
White solid (2.00 g, 99% yield). Rf ) 0.28 (CH2Cl2/MeOH 9:1).
1
Mp: 136-138 °C. IR: 3217 (OH), 2945-2880 (CH) cm-1. H
NMR (DMSO-d6): 2.27 (s, 3H), 3.37 (s, 1H), 4.30 (s, 2H), 5.17
(s, 2H), 6.80 (s, 1H), 7.05-7.16 (m, 4H), 7.68 (s, 1H). Anal.
(C12H14N2O) C, H, N.
1-(4-Trifluoromethylbenzyl)-1H-5-hydroxymethylimi-
dazole (6c). White solid (930 mg, 36% yield). Rf ) 0.26
(CH2Cl2/MeOH 9:1). Mp: 134-136 °C. IR: 3229 (OH), 3118-
2880 (CH) cm-1 1H NMR (DMSO-d6): 4.32 (s, 2H), 5.16 (s,
.
1H), 5.24 (s, 2H), 6.83 (s, 1H), 7.15-7.18 (m, 2H), 7.28-7.37
(m, 2H), 7.69 (s, 1H). Anal. (C12H11F3N2O) C, H, N.
1-(4-Methoxybenzyl)-1H-5-hydroxymethylimidazole
(6d). White solid (1.83 g, 84% yield). Rf ) 0.23 (CH2Cl2/MeOH
9:1). Mp: 129-130 °C. IR: 3196 (OH), 3118-2837 (CH) cm-1
.
1H NMR (DMSO-d6): 3.73 (s, 3H), 4.33 (s, 2H), 5.14 (s, 2H),
5.18 (s, 1H), 6.80 (s, 1H), 6.91 (d, 2H, J ) 8.5), 7.15 (d, 2H, J
) 8.5), 7.65 (s, 1H). Anal. (C12H14N2O2) C, H, N.
1
74-76 °C. IR: 1733 (CO), 1695 (CO) cm-1. H NMR (CDCl3):
1.20-1.40 (m, 4H), 1.50 (s, 9H), 1.65-1.80 (m, 4H), 1.90 (m,
1H), 2.10 (s, 3H), 2.50-2.70 (m, 3H), 2.85 (m, 1H), 3.45-3.55
(m, 1H), 3.70 (s, 3H), 4.00 (m, 1H). Anal. (C16H30N2O4S) C, H,
N.
Methyl N-[4-(1-Boc-piperidinyl)]phenylalaninate (10).
White solid (7.99 g, 63% yield). Rf ) 0.49 (cyclohexane/EtOAc
3:7). Mp: 53-54 °C. IR: 1733 (CO), 1694 (CO) cm-1. 1H NMR
(CDCl3): 1.30-1.70 (m, 4H), 1.44 (s, 9H), 2.45-4.11 (m, 11H),
4.20-4.25 (m, 1H), 7.13-7.33 (m, 5H). Anal. (C20H30N2O4) C,
H, N.
1-(4-Cyanobenzyl)-1H-5-hydroxymethylimidazole (6e).
White solid (2.04 g, 96% yield). Rf ) 0.19 (CH2Cl2/MeOH 9:1).
Mp: 168-169 °C. IR: 3121 (OH), 2883-2753 (CH), 2232 (CN)
cm-1. 1H NMR (DMSO-d6): 4.31 (s, 2H), 5.37 (m, 3H), 6.87 (s,
1H), 7.73 (m, 2H), 7.74 (s, 1H), 7.83 (d, 2H, J ) 8.5). Anal.
(C12H11N3O) C, H, N.
General Procedure for the Preparation of 1-Benzyl-
5-formylimidazoles (7a-e). Imidazoles 6a-e (6.0 mmol, 1.0
equiv) were dissolved in dioxane (50 mL) before adding MnO2
(30.0 mmol, 5.0 equiv). The suspension was stirred at 30-40
°C for 3 h, then MnO2 was filtered and washed with dioxane.
The solution was evaporated under reduced pressure, and the
residue was purified by column chromatography on silica gel
using CH2Cl2/MeOH (97:3 f 99:1) as eluent.
Methyl N-[4-(1-Boc-piperidinyl)]isoleucinate (11). White
solid (4.60 g, 40% yield). Rf ) 0.63 (cyclohexane/EtOAc 3:7).
Mp: 26-28 °C. IR: 1735 (CO), 1696 (CO) cm-1 1H NMR
.
(CDCl3): 0.83-0.92 (m, 6H), 1.18-2.54 (m, 9H), 1.44 (s, 9H),
3.38-4.12 (m, 5H), 3.75 (s, 3H). Anal. (C17H32N2O4) C, H, N.
General Procedure for the Preparation of Benzoylpi-
peridines 12-14. Compounds 9-11 (14.5 mmol, 1.0 equiv)
were added to a solution of NEt3 (21.8 mmol, 1.5 equiv) in 100
mL of dry CH2Cl2. The mixture was cooled to 0 °C, then
benzoyl chloride (17.4 mmol, 1.2 equiv) was added dropwise
over 1 h, and the solution was stirred at room temperature
for 24 h (reflux for 11). The solvent was evaporated under
reduced pressure, and the residue was partitioned between a
5% Na2CO3 solution and ether. The organic phase was washed
successively with 1 N HCl and brine, dried (MgSO4), and
evaporated under reduced pressure. The resulting oil was flash
chromatographied on a 5 cm × 40 cm column using cyclohex-
ane/EtOAc (2:1; 7:3; 3:1, respectively) as eluent to give 12-
14.
1-Benzyl-1H-5-imidazolecarbaldehyde (7a). White solid
(782 mg, 70% yield). Rf ) 0.35 (CH2Cl2/MeOH 9:1). Mp: 135-
1
136 °C. IR: 1670 (CO) cm-1. H NMR (CDCl3): 5.52 (s, 2H),
7.21 (d, 2H, J ) 8.5), 7.33 (m, 3H), 7.70 (s, 1H), 7.83 (s, 1H),
9.76 (s, 1H). Anal. (C11H10N2O) C, H, N.
1-(4-Methylbenzyl)-1H-5-imidazolecarbaldehyde (7b).
White solid (781 mg, 65% yield). Rf ) 0.49 (CH2Cl2/MeOH 9:1).
Mp: 92-94 °C. IR: 3087-2918 (CH), 1672 (CO) cm-1. 1H NMR
(CDCl3): 5.30 (s, 3H), 5.47 (s, 2H), 7.10-7.17 (m, 4H), 7.68 (s,
1H), 7.82 (s, 1H), 9.76 (s, 1H). Anal. (C12H12N2O) C, H, N.
1-(4-Trifluoromethylbenzyl)-1H-5-imidazolecarbalde-
hyde (7c). White solid (991 mg, 97% yield). Rf ) 0.58 (CH2Cl2/
MeOH 9:1). Mp: 34-35 °C. IR: 3111-2831 (CH), 1673 (CO)
1
cm-1. H NMR (CDCl3): 5.58 (s, 2H), 7.28 (m, 2H), 7.59 (m,
2H), 7.76 (s, 1H), 7.86 (s, 1H), 9.74 (s, 1H). Anal. (C12H9F3N2O)
C, H, N.
Methyl N-Benzoyl,N-(1-Boc-4-piperidin-4-yl)methioni-
nate (12). White solid (3.48 g, 55% yield). Rf ) 0.32 (cyclo-
hexane/EtOAc 1:1). Mp: 55 °C. IR: 1741 (CO), 1691 (CO), 1637
1-(4-Methoxybenzyl)-1H-5-imidazolecarbaldehyde (7d).
White solid (986 mg, 76% yield). Rf ) 0.59 (CH2Cl2/MeOH 9:1).
Mp: 40-41 °C. IR: 3088-2837 (CH), 1673 (CO) cm-1. 1H NMR
(CDCl3): 3.78 (s, 3H), 5.43 (s, 2H), 6.86 (d, 2H, J ) 6.7), 7.18
(d, 2H, J ) 6.7), 7.66 (s, 1H), 7.80 (s, 1H), 9.75 (s, 1H). Anal.
(C12H12N2O2) C, H, N.
1
(CO) cm-1. H NMR (DMSO-d6): 1.40 (s, 9H), 1.70-1.90 (m,
4H), 2.10 (s, 3H), 2.40-2.60 (m, 8H), 3.60 (s, 3H), 3.90 (bs,
1H), 4.10 (bs, 1H), 7.30-7.50 (m, 5H). Anal. (C23H34N2O5S) C,
H, N.

6818 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27
Millet et al.
Methyl N-Benzoyl,N-(1-Boc-4-piperidin-4-yl)phenyla-
laninate (13). Oil (3.04 g, 45% yield). Rf ) 0.37 (cyclohexane/
(s, 2H), 5.58 (m, 1H), 6.89 (s, 1H), 7.32-7.66 (m, 10H). MS
(EI): 588. Anal. (C30H35F3N4O3S) C, H, N.
EtOAc 1:1). IR: 1742 (CO), 1694 (CO), 1640 (CO) cm-1 1H
.
Methyl N-Benzoyl,N-{1-[1-(4-methoxybenzyl)imidazol-
5-ylmethyl]piperidin-4-yl}methioninate (18d). White solid
(1.40 g, 51% yield). Rf ) 0.54 (CH2Cl2/MeOH 9:1). Mp: 56-58
NMR (CDCl3): 1.40 (s, 9H), 1.72-2.04 (m, 4H), 2.95-3.15 (m,
2H), 3.42-3.71 (m, 4H), 3.83 (s, 3H), 4.00-4.31 (m, 2H), 7.20-
7.47 (m, 10H). Anal. (C27H34N2O5) C, H, N.
1
°C. H NMR (CDCl3): 1.80-2.18 (m, 5H), 2.14 (s, 3H), 2.32-
Methyl N-Benzoyl,N-(1-Boc-4-piperidin-4-yl)isoleuci-
2.91 (m, 7H), 3.76 (s, 3H), 3.80 (s, 3H), 3.89-4.14 (m, 3H), 5.15
(s, 2H), 5.57 (m, 1H) 6.80-6.91 (m, 3H), 7.03-7.52 (m, 8H).
MS (EI): 550. Anal. (C30H38N4O4S) C, H, N.
nate (14). Oil (1.88 g, 30% yield). Rf ) 0.50 (cyclohexane/
EtOAc 1:1). IR: 1742 (CO), 1694 (CO), 1643 (CO) cm-1 1H
.
NMR (CDCl3): 0.85-0.95 (m, 6H), 1.20-1.40 (m, 2H), 1.44 (s,
9H), 1.65-2.02 (m, 4H), 2.35-3.40 (m, 5H), 3.60-4.11 (m, 2H),
3.75 (s, 3H), 7.20-7.40 (m, 5H). Anal. (C24H36N2O5) C, H, N.
General Procedure for the Preparation of Piperidines
15-17. Compounds 12-14 (2.2 mmol, 1.0 equiv) were dis-
solved in MeOH (10 mL), and saturated methanolic hydro-
chloric acid (30 mL) was added. The solution was left standing
for 18 h. The solvent was evaporated under reduced pressure,
and the excess of HCl was eliminated by successive addition-
evaporation cycles of MeOH. The residue obtained was tritu-
rated with dry ether to give white hygroscopic compounds 15-
17, which were directly used in the following reaction.
Methyl N-Benzoyl,N-(piperidin-4-yl)methioninate Hy-
drochloride (15). White hygroscopic solid (807 mg, 95%
yield). Rf ) 0.06 (CH2Cl2/MeOH 9:1, saturated NH3). Mp: 109-
110 °C. IR: 1738 (CO), 1637 (CO) cm-1. 1H NMR (DMSO-d6):
1.62-1.80 (m, 4H), 2.11 (s, 3H), 2.50-2.70 (m, 4H), 3.10-3.30
(m, 4H), 3.62 (s, 3H), 3.80 (m, 1H), 4.01 (m, 1H), 7.30-7.50
(m, 5H), 8.82 (s, 2H).
Methyl N-Benzoyl,N-{1-[1-(4-cyanobenzyl)imidazol-5-
ylmethyl]piperidin-4-yl}methioninate (18e). White solid
(1.36 g, 50% yield). Rf ) 0.47 (CH2Cl2/MeOH 9:1). Mp: 182-
184 °C. 1H NMR (DMSO-d6): 1.78-2.17 (m, 5H), 2.14 (s, 3H),
2.30-2.54 (m, 4H), 2.80-3.10 (m, 2H), 3.66 (s, 3H), 3.73-4.05
(m, 3H), 5.58 (m, 1H), 5.79 (s, 2H), 6.86 (s, 1H), 6.92 (s, 1H),
7.11-7.82 (m, 10H). MS (EI): 545. Anal. (C30H35N5O3S) C, H,
N.
Methyl N-Benzoyl,N-{1-[1-(4-cyanobenzyl)imidazol-5-
ylmethyl]piperidin-4-yl}phenylalaninate (19e). White solid
(1.40 g, 50% yield). Rf ) 0.61 (CH2Cl2/MeOH 9:1). Mp: 103-
1
105 °C. H NMR (CDCl3): 1.78-1.92 (m, 4H), 2.41-2.47 (m,
2H), 2.79-3.16 (m, 4H), 3.70 (s, 3H), 3.83 (s, 2H), 4.20 (m, 1H),
4.98 (m, 1H), 5.24 (s, 2H), 6.92 (s, 1H), 7.09-7.80 (m, 15H).
MS (EI): 561. Anal. (C34H35N5O3) C, H, N.
Methyl N-Benzoyl,N-{1-[1-(4-cyanobenzyl)imidazol-5-
ylmethyl]piperidin-4-yl}isoleucinate (20e). White solid
(1.34 g, 51% yield). Rf ) 0.59 (CH2Cl2/MeOH 9:1). Mp: 81-83
1
°C. H NMR (CDCl3): 0.82-0.93 (m, 6H), 1.18-1.38 (m, 2H),
Methyl N-Benzoyl,N-(piperidin-4-yl)phenylalaninate
Hydrochloride (16). White hygroscopic solid (842 mg, 95%
yield). Rf ) 0.12 (CH2Cl2/MeOH 9:1, saturated NH3). IR: 1739
1.79-2.01 (m, 5H), 2.44-2.83 (m, 4H), 3.45 (s, 3H), 3.77 (s,
2H), 3.88-4.12 (m, 3H), 5.19 (m, 1H), 6.92 (s, 1H), 7.20-7.80
(m, 10H). MS (EI): 527. Anal. (C31H37N5O3) C, H, N.
1
(CO), 1633 (CO) cm-1. H NMR (CDCl3): 1.88-2.26 (m, 4H),
Methyl N-Benzyl,N-{1-[1-(4-cyanobenzyl)imidazol-5-
ylmethyl]piperidin-4-yl}methioninate (24). White solid
(1.25 g, 47% yield). Rf ) 0.50 (CH2Cl2/MeOH 9:1). Mp: 189
2.54-3.02 (m, 6H), 3.83 (s, 3H), 4.01 (m, 1H), 5.20 (m, 1H),
7.17-7.56 (m, 10H), 9.23 (bs, 2H).
1
Methyl N-Benzoyl,N-(piperidin-4-yl)isoleucinate Hy-
drochloride (17). White hygroscopic solid (771 mg, 95%
yield). Rf ) 0.23 (CH2Cl2/MeOH 9:1, saturated NH3). IR: 1741
-191 °C. H NMR (CDCl3): 1.74-2.18 (m, 6H), 2.09 (s, 3H),
2.31-2.78 (m, 7H), 3.53 (m, 2H), 3.65 (s, 3H), 3.75-4.10 (m,
3H), 5.23 (s, 2H), 6.84 (s, 1H), 7.16-7.61 (m, 10H). MS (EI):
531. Anal. (C30H37N5O2S) C, H, N.
1
(CO), 1637 (CO) cm-1. H NMR (CDCl3): 0.82-0.93 (m, 6H),
1.20-2.12 (m, 5H), 2.33-3.20 (m, 6H), 3.53 (s, 3H), 4.08 (m,
General Procedure for the Preparation of Carboxylic
Acids 21e and 22e. Esters 18e or 19e (0.1 mmol, 1.0 equiv)
were dissolved in methanol (10 mL), and 2 N NaOH (10 mL)
was added. The reaction was monitored by analytical TLC and
stirred for about 6 h. The solution was neutralized (2 N HCl,
pH 4) and evaporated under reduced pressure, and the residue
was purified by column chromatography on silica gel using
CH2Cl2/MeOH (97:3 f 99:1) as eluent.
1H) 5.14 (m, 1H), 7.02-7.26 (m, 5H), 8.80 (bs, 2H).
General Procedure for the Preparation of Imidazoles
18a-e, 19e, 20e, and 24. Amines 15-17 or 23 (7.5 mmol, 1.5
equiv), NEt3 (7.5 mmol, 1.5 equiv), and the corresponding
1-benzyl-5-imidazolecarbaldehydes 7a-e were dissolved in 50
mL of dry MeOH. Molecular sieves (3-Å) were added, and the
solution was stirred at 50 °C for 4 h in a nitrogen atmosphere.
Then NaBH3CN (0.32 g, 5.0 mmol, 1.0 equiv) was added, and
the mixture was stirred for 18 h. The sieves were filtered off,
and the solvent was removed under reduced pressure. The
residue was dissolved in EtOAc, NEt3‚HCl was filtered off, and
the filtrate was washed with a 5% Na2CO3 solution, then H2O
and brine. The organic phase was dried (MgSO4) and concen-
trated under reduced pressure. The residue obtained was flash
chromatographied on a 5 cm × 40 cm column using CH2Cl2/
MeOH 96:4 as eluent to give 18a-e, 19e, 20e, or 24.
Methyl N-Benzoyl,N-[1-(1-benzylimidazol-5-ylmethyl)-
piperidin-4-yl]methioninate (18a). White solid (1.14 g, 44%
yield). Rf ) 0.47 (CH2Cl2/MeOH 9:1). Mp: 64-66 °C. 1H NMR
(CDCl3): 1.80-2.17 (m, 5H), 2.15 (s, 3H), 2.32-2.90 (m, 7H),
3.68 (s, 3H), 3.88-4.13 (m, 3H), 5.24 (s, 2H), 5.60 (m, 1H) 6.87
(s, 1H), 7.07-7.67 (m, 11H). MS (EI): 520. Anal. (C29H36N4O3S)
C, H, N.
N-Benzoyl,N-{1-[1-(4-cyanobenzyl)imidazol-5-ylmeth-
yl]piperidin-4-yl}methionine (21e). White solid (42 mg,
1
80% yield). Rf ) 0.15 (CH2Cl2/MeOH 8:2). Mp: > 250 °C. H
NMR (DMSO-d6): 1.82-2.19 (m, 5H), 2.20 (s, 3H), 2.30-2.55
(m, 4H), 2.80-4.32 (m, 7H), 5.87 (s, 2H), 7.31-8.10 (m, 10H),
9.36 (s, 1H), 11.86 (bs, 1H). MS (EI): 531. Anal. (C29H33N5O3S)
C, H, N.
N-Benzoyl,N-{1-[1-(4-cyanobenzyl)imidazol-5-ylmeth-
yl]piperidin-4-yl}phenylalanine (22e). White solid (49 mg,
1
90% yield). Rf ) 0.15 (CH2Cl2/MeOH 8:2). Mp: > 250 °C. H
NMR (DMSO-d6): 1.80-1.95 (m, 4H), 2.41-2.47 (m, 2H),
2.78-3.15 (m, 4H), 3.83 (s, 2H), 4.00-4.30 (m, 2H), 5.85 (s,
2H), 7.08-7.90 (m, 15H), 9.10 (s, 1H), 11.80 (bs, 1H). MS
(EI): 547. Anal. (C33H33N5O3) C, H, N.
Methyl N-Benzyl,N-(piperidin-4-yl)methioninate Hy-
drochloride (23). Compound 15 (1.0 g, 2.6 mmol, 1.0 equiv)
was dissolved in 20 mL of dry THF. The solution was cooled
to 0 °C, then BH3 in THF (10.3 mL, 10.3 mmol, 4.0 equiv) was
added dropwise over 1 h. The reaction was stirred at room
temperature for 18 h and stopped by adding 5 mL of 6 N HCl.
THF was evaporated under reduced pressure, and the aqueous
residue was refluxed for 10 min. The solution was alkalinized
(K2CO3) to pH > 10 and extracted with ether. The organic
phase was dried (MgSO4) and flash chromatographied on a 5
cm × 40 cm column using CH2Cl2/MeOH 9:1 as eluent.
Piperidine 23 was finally obtained as a hydrochloride salt by
adding a solution of HCl saturated ether and recrystallized
from EtOAc. White hygroscopic solid (0.29 g, 30% yield). Rf )
Methyl N-Benzoyl,N-{1-[1-(4-methylbenzyl)imidazol-
5-ylmethyl]piperidin-4-yl}methioninate (18b). White solid
(1.39 g, 52% yield). Rf ) 0.47 (CH2Cl2/MeOH 9:1). Mp: 60-62
1
°C. H NMR (CDCl3): 1.81-2.18 (m, 5H), 2.14 (s, 3H), 2.30-
2.94 (m, 7H), 2.32 (s, 3H), 3.77 (s, 3H), 3.88-4.13 (m, 3H), 5.18
(s, 2H), 5.58 (m, 1H) 6.84 (s, 1H), 6.97-7.50 (m, 10H). MS
(EI): 534. Anal. (C30H38N4O3S) C, H, N.
Methyl N-Benzoyl,N-{1-[1-(4-trifluoromethylbenzyl)-
imidazol-5-ylmethyl]piperidin-4-yl}methioninate (18c).
White solid (1.23 g, 42% yield). Rf ) 0.52 (CH2Cl2/MeOH 9:1).
Mp: 84-86 °C. 1H NMR (CDCl3): 1.79-2.17 (m, 5H), 2.14 (s,
3H), 2.29-2.93 (m, 7H), 3.56 (s, 3H), 3.88-4.13 (m, 3H), 5.31

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27 6819
method available in the Maximin2 procedure was used for
energy minimization until the gradient value was smaller than
0.001 kcal/mol‚Å. The structure of the human FTase was
obtained from its complexed X-ray crystal structure with FPP
and inhibitor 66 (Chart 3) of the RCSB Protein Data Bank
(1LD7).26a Flexible docking of 18e and 19e into the enzyme
active site was performed using GOLD32 software. The distance
observed in the crystal structure between the distal nitrogen
of compound 66 imidazole and the zinc cation was applied as
a constraint. For each compound, the most stable docking
model was selected according to the best scored conformation
predicted by the GoldScore32 and X-Score33 scoring functions.
The complexes were energy-minimized using the Powell
method available in the Maximin2 procedure with the Tripos
force field and a dielectric constant of 4.0 until the gradient
value reached 0.01 kcal/mol‚Å.
Chart 3
Acknowledgment. The authors are grateful to the
“Association pour la Recherche contre le Cancer” for
their financial support.
0.18 (CH2Cl2/MeOH 9:1, saturated NH3). Mp: 125 °C. IR: 1741
(CO) cm-1. 1H NMR (CDCl3): 1.61-1.82 (m, 4H), 2.09 (s, 3H),
2.10-3.04 (m, 9H), 3.42 (m, 2H), 3.70 (s, 3H), 4.15 (m, 1H),
4.82 (m, 1H), 7.11-7.45 (m, 5H). MS (EI): 336.
References
Preparation of FTase from the Cytosolic Fraction of
Rat Brain.21a Sprague-Dawley male rats (9-10 weeks old)
were sacrified, and brains were placed in an ice-cold 0.1 M
HEPES buffer, pH 7.4, 25 mM MgCl2, and 10 mM DTT
(dithiothreitol). The brains were cleaned and homogenized in
a 0.1 M HEPES buffer, pH 7.4, 1 mM MgCl2, and 1 mM DTT.
The homogenates were centrifuged at 10 000g for 20 min at 4
°C. The supernatants were centrifuged at 100 000g for 1 h at
4 °C. The cytosolic fraction (the 100 000g supernatants) was
stored at -80 °C. Protein concentration was determined by
the bicinchonic acid protein assay method (Pierce) using bovine
serum albumin as protein standard.
Protein Prenyl Transferase Assay. FTase activity was
determined by a continuous fluorescence assay as previously
described.21b The data were collected on a Spex Fluoro Max
spectrofluorimeter. The optimal parameters are an excitation
wavelength at 340 nm and an emission at 505 nm (slit 10,10)
for dansyl-CVIM and dansyl-GCVLL. The standard reaction
mixture containing 50 mM TrisHCl, pH 7.5, 5 mM MgCl2, 10
µM ZnCl2, 5 mM DTT, 0.01% n-dodecyl-â-D-maltoside, 5.4 mg/
mL of cytosolic protein, 1.3 µM dansyl-CVIM, and 25 µM FPP
for the FTase assay and 4 µM dansyl-GCVLL and 10 µM GGPP
for the GGT-I assay was incubated at 25 °C, and fluorescence
intensity was recorded for 10 min. Study of cross prenylation
of dansyl-CVIM by GGTase with FPP or GGPP was performed.
No variation of fluorescence was observed in any cases.
Graphical representations of fluorescence variation ∆F/∆t )
f[ligand] gave sigmoid plots. Analysis of cell curves made it
possible to calculate the IC50 values of each compound by using
a theoretical equation (Graphpad Prism 3.03, Graphpad
software, San Diego, CA).
Competitive inhibition patterns of 18e and 19e were
performed as previously described21b by varying CVIM con-
centration in the presence of competitor concentration. The
mathematical method of Lineweaver and Burk21b showed
unvaried Vm and varied Km.
Cell Culture and Growth Assays. DLD-1 (human colon
adenocarcinoma transformed by K-Ras oncogene), L-1210
(mouse lymphocytic leukaemia), and H-Ras transformed
NIH3T3 fibroblasts were cultured in RPMI medium. All of the
media were supplemented with 10% fetal calf serum. Cells
were allowed to grow for 24 h in 96-microwell plates and then
treated with a range of inhibitor concentrations for 72 h (final
1‰ DMSO concentration). Cell growth was measured by
means of the colorimetric MTT assay.
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