Non-thiol farnesyltransferase inhibitors: Evaluation of different AA(X)-peptidomimetic substructures in combination with arylic cysteine replacements

Article abstract of DOI:10.1002/1521-4184(200204)335:4<135::AID-ARDP135>3.0.CO;2-7

In the course of our studies on non-thiol farnesyltransferase inhibitors based on the 2,5-diaminobenzophenone AAX-peptidomimetic substructure, we have developed the (4-nitrophenyl)butyryl (R¹), the (2-naphthyl)acryloyl (R²), the 4-nitrocinnamoyl (R³), and the 5-(4-nitrophenyl)furylacryloyl (R⁴) groups as useful cysteine replacements. In this study, we combined these four groups with other AA(X)-peptidomimetic substructures (5-10: R = H) reported in the literature. The 5-(4-nitrophenyl)furylacryloyl moiety (R⁴) turned out to be the most useful non-thiol cysteine replacement yielding in all cases the most active inhibitors. By combination of this 5-(4-nitrophenyl)furylacryloyl moiety (R⁴) with the structurally simple AAX-peptidomimetics 4-aminobenzophenone (5) and 4-aminodiphenylsulfone (6) potent, readily accessible non-thiol farnesyltransferase inhibitors were obtained (IC₅₀ = 12 nM and 10 nM).

Full text of DOI:10.1002/1521-4184(200204)335:4<135::AID-ARDP135>3.0.CO;2-7

Arch. Pharm. Pharm. Med. Chem. 2002, 4, 135–142
Non-Thiol Farnesyltransferase Inhibitors 135
Jacek Sakowskia,
Non-Thiol Farnesyltransferase Inhibitors: Evaluation
of Different AA(X)-Peptidomimetic Substructures in
Combination with Arylic Cysteine Replacements
Markus Böhma,
Isabel Sattlerb,
Martin Schlitzera
aInstitut für Pharmazeutische
Chemie, Philipps-Universität
Marburg, Marburg, Germany
bHans-Knöll-Institut für
Naturstoff-Forschung e.V.,
Jena, Germany
In the course of our studies on non-thiol farnesyltransferase inhibitors based on the
2,5-diaminobenzophenone AAX-peptidomimetic substructure, we have developed
the (4-nitrophenyl)butyryl (R1), the (2-naphthyl)acryloyl (R2), the 4-nitrocinnamoyl
(R3), and the 5-(4-nitrophenyl)furylacryloyl (R4) groups as useful cysteine replace-
ments.In this study, we combined these four groups with other AA(X)-peptidomimet-
ic substructures (5–10: R = H) reported in the literature.The 5-(4-nitrophenyl)furyl-
acryloyl moiety (R4) turned out to be the most useful non-thiol cysteine replacement
yielding in all cases the most active inhibitors. By combination of this 5-(4-nitrophe-
nyl)furylacryloyl moiety (R4) with the structurally simple AAX-peptidomimetics
4-aminobenzophenone (5) and 4-aminodiphenylsulfone (6) potent, readily accessi-
ble non-thiol farnesyltransferase inhibitors were obtained (IC50 = 12 nM and 10 nM).
Keywords: Farnesyltransferase inhibitors; Peptidomimetics
Received: April 11, 2001 [FP 562]
have shown that the cysteine residue in CAAX-peptido-
mimetic farnesyltransferase inhibitors can be replaced
Introduction
by aryl moieties, a finding that led to the postulation of
two hitherto unknown aryl binding sites in or near the far-
nesyltransferase’s active site [13, 14].Employing flexible
docking of several non-thiol farnesyltransferase inhibi-
tors known from literature and some model compounds
based on our benzophenone scaffold [16–18] as well as
performing GRID searches, we have identified two re-
gions in or near farnesyltransferase’s active site which
we suggest as being the postulated aryl binding sites
[10, 19].
One of the most important posttranslational modifica-
tions of proteins is protein prenylation [1], which is the
transfer of either a farnesyl or a geranylgeranyl residue
from the corresponding pyrophosphates to the thiol of a
cysteine side chain of proteins carrying the C-terminal
CAAX-sequence (C: cysteine, A: amino acid with
aliphatic side chain, X: variable amino acid). Due to the
involvement of farnesylated proteins in carcinogenesis,
inhibition of farnesyltransferase has received much in-
terest in recent years [2–5]. Farnesyltransferase inhibi-
tors have been demonstrated to inhibit a wide range of
tumor cell lines in vitro and to display synergistic effects
with other tumor therapeutics [6–8].Farnesyltransferase
inhibitors are therefore regarded as a major emerging
strategy in tumor therapy.
In the course of our studies on non-thiol farnesyltrans-
ferase inhibitors based on the 2,5-diaminobenzophe-
none AAX-peptidomimetic substructure [16–18], we
have investigated a number of different aryl-containing
moieties as cysteine replacements.These different aryl-
containing cysteine replacements stem either from
structural variations of model compounds which we
used to explore the aryl binding sites [11, 19] or from
docking experiments and subsequent synthesis and
evaluation of residues displaying a good fit into the aryl
binding site in these docking studies [10, 19].The (4-ni-
trophenyl)butyryl (R1), the (2-naphthyl)acryloyl (R2), the
4-nitrocinnamoyl (R3), and the 5-(4-nitrophenyl)furyl-
acryloyl residue (R4), turned out to be useful cysteine re-
placements, as for instance in compounds 1–4 (Fig-
ure 1) [10, 11, 19].
Most farnesyltransferase inhibitors described to date are
structural analogs of the CAAX recognition sequence of
farnesylated proteins, and thus carry a free thiol func-
tion.However, a free thiol is an undesirable feature in po-
tential drugs because of its sensitivity towards oxidation
and, more importantly, as a potential source of severe
adverse drug effects such as taste disturbance and, more
seriously, skin reactions [9]. Development is therefore di-
rected towards the so called “non-thiol” farnesyltrans-
ferase inhibitors [2–4]. We [10, 11] and others [12–15]
Correspondence: Martin
Schlitzer,
Department
für
Pharmazie Zentrum für Pharmaforschung, Ludwig-
–
In this study, we combined these four residues with vari-
ous AA(X)-peptidomimetic substructures (5–10: R = H)
(Table 1) reported in the literature [20–23] which are
Maximilians-Universität München, Butenandtstraße 5–13,
81377 München. Phone +49 (0) 89 2180 7804, e-mail:
martin.schlitzer@cup.uni-muenchen.de.
© WILEY-VCH Verlag GmbH, 69451 Weinheim, 2002
0365-6233/04/0135 $ 17.50+.50/0

136 Sakowski et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 135–142
Table 1. Structures and farnesyltransferase inhibitory
activitya of compounds 5–10.
Figure 1. Structures and activity of 2,5-benzophenone-
based non-thiol farnesyltransferase inhibitors 1–4.
structurally different from our benzophenone scaffold.
Our aim was to evaluate novel peptidomimetic substruc-
tures in combination with cysteine replacements origi-
nating from our studies in order to find possible novel
lead structures for further development of non-thiol far-
nesyltransferase inhibitors. Potential candidates for fur-
ther development should display nanomolar activity and
should give easy access to structural variations. AA(X)-
peptidomimetic substructures were selected from the lit-
erature on the basis of structural simplicity and potential
for structural variation.
Chemistry
Target compounds 5a–d to 10a–d (Table 1) were pre-
pared by acylation of the respective peptidomimetic moi-
eties (5–10: R = H) [20–23] using 4-nitrocinnamoyl chlo-
ride, 3-[5-(4-nitrophenyl)-2-furyl]acryloyl chloride, 3-(2-
naphthyl)acryloyl chloride, and 4-(4-nitrophenyl)butyryl
chloride, respectively.
Biological evaluation
The inhibitory activity of the compounds on farnesyl-
transferase was determined using a fluorescence en-
hancement assay.This assay, established by Pompliano
et al. [24] (Merck Inc.) as an easy to handle test system
for the evaluation of potential farnesyltransferase inhibi-
tors, yields equivalent results to those assays which em-
ploy ras and tritium-labeled FPP as substrates [24].The
assay employed yeast farnesyltransferase (FTase)
fused to glutathione S-transferase at the N-terminus of
the β-subunit [25]. Yeast farnesyltransferase is a close
homolog and functionally similar to the human enzyme;it
is widely used for the evaluation of farnesyltransferase
inhibitors [25]. All active site amino acid side chains
which are in contact with the inhibitors are identical in hu-
man, rat, and yeast farnesyltransferase [26]. Farnesyl-
aThe reported [23] value of a standard inhibitor FTI-276
(thiol-containing) is 0.5 nM.
pyrophosphate and the dansylated pentapeptide Ds-
GlyCysValLeuSer were used as substrates. Upon far-
nesylation of the cysteine thiol the dansyl residue is

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 135–142
Non-Thiol Farnesyltransferase Inhibitors 137
placed into a lipophilic environment; the resulting en-
hancement of fluorescence at 505 nm is used to monitor
the enzyme reaction.
Replacement of the carbonyl function of the benzophe-
none 5c by a sulfonyl group resulted in a slight reduction
of activity (6c:IC50 = 650 nM).Inhibitory activity recorded
for the 5-(4-nitrophenyl)furylacryloyl (R4) derivatives 5–
10d was significantly higher than in the other series of
compounds. Furthermore, the range of IC50 values was
significantly smaller with values between 10 nM and
870 nM. In this series of compounds, peak activity was
obtained with the 4-aminobenzophenone peptidomimet-
ic substructure (5d: IC50 = 12 nM). Replacement of the
carbonyl moiety by a sulfonyl group resulted in an equal-
ly potent inhibitor (6d: IC50 = 10 nM), whereas the biaryl
ether derivative 7d was 3-fold less active than benzo-
phenone (IC50 = 36 nM).As in the series of the 4-nitrocin-
namoyl (R3) derivatives 5–10c, in the series of the 5-(4-
nitrophenyl)furylacryloyl (R4) derivatives the N-(4-ami-
nobenzoyl)methionine methyl ester 9d displayed the
weakest activity (IC50 = 870 nM). Saponification of the
carboxylic ester moiety of 9d resulted in an almost 10-
fold improvement in activity (10d:IC50 = 90 nM) although
this compound is still nearly one order of magnitude less
potent than the structurally more simple inhibitors 5d
and 6d.
Molecular modeling
Flexible docking of inhibitors 5d, 6d, and 7d was per-
formed using the program FlexX [27].Based on the coor-
dinates of the published crystal structure [28] of a terna-
ry complex of farnesyltransferase, a farnesylpyrophos-
phate analog and N-acetyl-Cys-Val-Ile-selenoMetOH
(PDB-code 1QBQ), we have calculated the solvent-
accessible surface of the farnesyltransferase’s active
site using the program MOLCAD which is implemented
in the molecular modeling software package SYBYL
[29].Farnesylpyrophosphate was included as part of the
enzyme’s molecular surface.The position of the 5-(4-ni-
trophenyl)furyl moiety as has been calculated for inhibi-
tor 4 in a previous study [19] was used as a starting frag-
ment for the docking of inhibitors 5d, 6d, and 7d into the
farnesyltransferase’s active site. Subsequently, the
docking program places the remaining fragments of the
inhibitors in a piece-wise fashion into the active site
searching for favorable hydrophobic and H-bond interac-
tions while avoiding steric overlaps. The docking runs
provided sets of solutions which were inspected accord-
ing to their suggested binding energy.
Compared to the original 4-nitrocinnamoyl (R3) substitut-
ed 2,5-diaminobenzophenone 3, the most active novel
4-nitrocinnamoyl derivative 7c displayed the same far-
nesyltransferase inhibitory activity. In the case of the
5-(4-nitrophenyl)furylacryloyl (R4) substituted inhibitors,
the most active novel derivatives, the 4-aminobenzophe-
none 5d and the 4-aminodiphenylsulfone 6d, are about
3-fold more active than the 2,5-diaminobenzophenone
4.
Results and discussion
Combination of the (4-nitrophenyl)butyryl residue (R1)
with AA(X)-peptidomimetic substructures 5–10 (R = H)
did not result in particularly active compounds (5–10a)
(Table 1). Most of the compounds displayed micromolar
acitivity. Only the 4-aminodiphenylsulfone derivative 6a
showed a submicromolar IC50 value of 440 nM which
represented a slight improvement compared to the 2,5-
diaminobenzophenone derivative 1. In contrast to the
2,5-diaminobenzophenone derivative 2, the (2-naph-
thyl)acroyl residue (R2) yielded only weakly active com-
pounds (5–10b). Only the sulfonamide 8b displayed
submicromolar activity (IC50 = 760 nM), but this com-
pound was still about 7-fold less potent than the corre-
sponding 2,5-diaminobenzophenone 2 (IC50 = 115 nM).
Figure 2 shows the eight energetically most favorable
solutions of the docking run performed with the 4-ami-
nobenzophenone inhibitor 5d. In this figure, hydropho-
bic (brown color) and hydrophilic (green color) proper-
ties are displayed on the enzyme’s surface.The 5-(4-ni-
trophenyl)furyl moiety is placed in the aryl binding site
(indicated by a yellow box) which is located next to the
CAAX-peptide binding site (indicated by a light blue
box). The 4-aminobenzophenone peptidomimetic sub-
structure occupies the upper portion of the peptide bind-
ing site. Figure 3 shows inhibitor 5d in the same orienta-
tion as in Figure 2 but with the enzyme's surface omitted
and the active site amino acids visible. Amino acid side
chains which contribute to inhibitor binding are highlight-
ed. The 5-(4-nitrophenyl)furyl moiety is surrounded by
the amino acid side chains which make up the aryl bind-
ing site (Tyr 300β, Leu 295β, Lys 294β, Lys 353β and Lys
356β). For the 4-aminobenzophenone peptidomimetic
substructure a hydrogen bond is calculated between the
benzophenone carbonyl oxygen and the guanidino
group of Arg 202β. In addition to this polar interaction
there are hydrophobic contacts between the two phenyl
The 4-nitrocinnamoyl (R3) derivatives 5–10c displayed
variable inhibitory activity with IC50 values ranging from
46 nM to >10 µM. Peak inhibition of farnesyltransferase
was obtained with the biaryl ether derivative 7c (IC50
=
46 nM) while the N-(4-aminobenzoyl)methionine deriva-
tives 9c and 10c were only weakly active (IC50 >10 µM
and 3.9 µM, respectively). Submicromolar activity was
recorded for the 4-aminobenzophenone derivative 5c
(IC50 = 485 nM) and the sulfonamide 8c (IC50 = 960 nM).

138 Sakowski et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 135–142
Figure 2. Eight energetically most favorable solutions of
the docking run performed with the 4-aminobenzophe-
none inhibitor 5d (colors: carbon: white; oxygen: red;
nitrogen: blue). Hydrophobic (brown color) and
hydrophilic (green color) properties are displayed on the
enzyme’s surface. Aryl binding site: yellow box; CAAX-
peptide binding site: light blue box.
Figure 4. Second solution for the 4-aminodiphenylsul-
fone inhibitor 6d (colors as in Figure 2; sulfur: yellow).
The hydrogen bond is shown as an orange dotted line.
HFP: Hydroxyfarnesylphosphonate, a FPP-analog.
phenyl upwards.In this conformation a hydrogen bond is
calculated between one sulfonyl oxygen and the hydroxy
group of Ser 99β. The solution provided for the biaryl
ether derivative 7d (not shown) is nearly identical to that
calculated for the 4-aminobenzophenone inhibitor 5d
with the exception of the hydrogen bond to the side chain
of Arg 202β which is not found for 7d, presumably be-
cause of the larger distance between the guanidino
group and the acceptor oxygen.The lack of the hydrogen
bond may be the explanation for the lower activity of the
biaryl ether derivative 7d in comparison to the 4-ami-
nobenzophenone 5d and the 4-aminodiphenylsulfone
6d.
From this study two major results warrant mention. First,
the 5-(4-nitrophenyl)furylacryloyl moiety (R4) turned out
to be the most useful non-thiol cysteine replacement
yielding in every case the most active inhibitors when
combined with different AA(X)-peptidomimetic substruc-
tures.Secondly, by combination of this 5-(4-nitrophenyl)-
furylacryloyl moiety (R4) with the structurally simple
AAX-peptidomimetics 4-aminobenzophenone (5) and 4-
aminodiphenylsulfone (6), potent, readily accessible
non-thiol farnesyltransferase inhibitors were obtained.
These compounds may serve as lead structures for fur-
ther development.
Figure 3. Inhibitor 5d (colors as in Figure 2) in the same
orientation as in Figure 2.Enzyme’s surface omitted and
the amino acids visible. Amino acid side chains contrib-
uting to inhibitor binding highlighted.The hydrogen bond
is shown as an orange dotted line. HFP: Hydroxyfar-
nesylphosphonate, a FPP-analog.
residues and the lower portion of the farnesyl residue as
well as the side chains of Tyr 166α, Ala 151β, Trp 102β,
Trp 106β, and Tyr 361β.The docking run of the 4-amino-
diphenylsulfone inhibitor 6d provides two clusters of rea-
sonable solutions.One (not shown) is identical to the so-
lution obtained for the 4-aminobenzophenone 5d as de-
scribed in Figures 2 and 3. Figure 4 shows the second
solution for the 4-aminodiphenylsulfone inhibitor 6d
which is different from the first set as the phenylsulfonyl
moiety is rotated around the bond between the sulfonyl
sulfur and the central phenyl residue shifting the terminal
Acknowledgement
The pGEX-DPR1 and pBC-RAM2 plasmids were kindly
provided by Prof. F.Tamanoi (UCLA). M. Schlitzer thanks
Ms. K. Burk for technical assistance. All facilities needed
for the modeling were kindly provided by Prof. G. Klebe.
Financial support by the Deutsche Pharmazeutische

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 135–142
Non-Thiol Farnesyltransferase Inhibitors 139
2H), 7.76 (m, 3H), 7.88 (m, 4H), 8.28 (m, 2H), 10.65 (s, 1H). –
EI-MS: m/z (%) 372 (16) [M+], 146 (100), 197 (37), 176 (35).
Anal. (C22H16N2O4) C, H, N.
Gesellschaft is gratefully acknowledged.I.Sattler wishes
to thank Prof. Dr. S. Grabley for generous support and
Ms. S. Egner for technical assistance.
N-(4-Benzoylphenyl)-3-[5-(4-nitrophenyl)-2-furyl]acrylic acid
amide 5d
From 3-[5-(4-nitrophenyl)-2-furyl]acrylic acid chloride (0.221 g,
0.8 mmol) and 4-aminobenzophenone (0.158 g, 0.8 mmol) ac-
cording to the general procedure. Purification: recrystallization
from toluene.Yield: 0.22 g (63%). – Mp 250°C. – IR (KBr): ν =
Experimental
1H- and 13C-NMR spectra were recorded on a Jeol JMN-GX-
400 and a Jeol JMN-LA-500 spectrometer. Mass spectra were
obtained with aVacuum GeneratorsVG 7070 H using aVector 1
data acquisition system from Teknivent or an AutoSpec mass
spectrometer from Micromass. IR spectra were recorded on a
Nicolet 510P FT-IR-spectrometer. Microanalyses were ob-
tained from a CH analyzer according to Dr. Salzer from Labor-
matic and from a Hewlett Packard type 185 CHN analyzer. All
compounds gave microanalyses within ± 0.4% of the theoreti-
cal values. Column chromatography was carried out using sili-
ca gel 60 (0.062–0.200 mm) from Merck.Peptidomimetic moie-
ties 5–10 (R = H) are commercially available or were prepared
as described [17–20].
1
3444, 3361, 1682, 1653, 1628, 1598, 1521 cm–1. – H NMR
(DMSO-d6): δ = 6.81 (d, J = 16 Hz, 1H), 7.02 (m, 1H), 7.37 (m,
2H), 7.43 (d, J = 16 Hz, 1H), 7.48 (m, 1H), 7.59 (m, 1H), 7.65
(m, 2H), 7.70 (m, 2H), 7.82 (m, 2H), 7.96 (m, 2H), 8.27 (m,
2H), 10.55 (s, 1H). – EI-MS: m/z (%) 438 (2) [M+], 44 (100), 73
(88), 129 (46). Anal. (C26H18N2O5) C, H, N.
N-(4-Phenylsulfonylphenyl)-4-(4-nitrophenyl)butyric acid
amide 6a
From 4-(4-nitrophenyl)butyric acid chloride (0.273 g, 1.2 mmol)
and 4-aminodiphenylsulfone (0.280 g, 1.2 mmol) according to
the general procedure. Purification: recrystallization from tolu-
ene. Yield: 0.35 g (68%). – Mp 184°C. – IR (KBr): ν = 3446,
3333, 2923, 1695, 1593, 1538, 1513 cm–1. – 1H NMR (DMSO-
d6):δ = 1.93 (m, 2, H), 2.36 (m, 2H), 2.76 (m, 2H), 7.48 (m, 2H),
7.59 (m, 2H), 7.64 (m, 1H), 7.78 (m, 2H), 7.86 (m, 2H), 7.90
(m, 2H), 8.12 (m, 2H), 10.24 (s, 1H).– EI-MS:m/z (%) 424 (37)
[M+], 275 (100), 233 (72), 136 (18). Anal. (C22H20N2O5S) C, H,
N.
General procedure: Reaction of carboxylic acid chlorides with
various AA(X)-peptidomimetics
Appropriate acyl chlorides were dissolved in toluene or dioxane
(approx. 10 mL) and added to a solution of the appropriate aro-
matic amine in hot toluene (approx. 50 mL).The mixtures were
heated under reflux for 2 h. Then, the solvent was removed in
vacuo to give the crude products.
Acyl chlorides were prepared form the corresponding carboxyl-
ic acids.These were dissolved in toluene and 0.1 mL of SOCl2
per mmol acid was added.The mixture was heated under reflux
for 2 h and the volatiles were evaporated in vacuo.The residue
obtained was used for the acylation step as described above.
N-(4-Phenylsulfonylphenyl)-3-(2-naphthyl)acrylic acid amide
6b
From 3-(2-naphthyl)acrylic acid chloride (0.216 g, 1.0 mmol)
and 4-aminodiphenylsulfone (0.217 g, 1.0 mmol) according to
the general procedure. Purification: recrystallization from tolu-
ene. Yield: 0.30 g (71%). – Mp 208°C. – IR (KBr): ν = 3435,
3337, 3062, 1724, 1679, 1627, 1592, 1527 cm–1.- 1H NMR
(DMSO-d6): δ = 6.89 (d, J = 16 Hz, 1H), 7.49 (m, 2H), 7.54 (m,
2H), 7.59 (m, 1H), 7.69 (m, 1H), 7.72 (d, J = 16 Hz, 1H), 7.87
(m, 9H), 8.07 (m, 1H), 10.54 (s, 1H). – EI-MS: m/z (%) 413 (18)
[M+], 181 (100), 182 (14), 153 (14).Anal.(C25H19NO3S) C, H, N.
N-(4-Benzoylphenyl)-4-(4-nitrophenyl)butyric acid amide 5a
From 4-(4-nitrophenyl)butyric acid chloride (0.342 g, 1.5 mmol)
and 4-aminobenzophenone (0.395 g, 1.5 mmol) according to
the general procedure. Purification: recrystallization from tolu-
ene. Yield: 0.54 g (91%). – Mp 172°C. – IR (KBr): ν = 3431,
2853, 1692, 1636, 1596, 1507 cm–1. – 1H NMR (DMSO-d6): δ =
2.05 (m, 2H), 2.36 (t, J = 7 Hz, 2H), 2.76 (t, J = 7 Hz, 2H), 7.29
(m, 2H), 7.41 (m, 3H), 7.51 (m, 1H), 7.56 (m, 2H), 7.69 (m,
2H), 7.73 (m, 2H), 8.07 (m, 2H).– EI-MS:m/z (%) 388 (12) [M+],
120 (100), 119 (97), 239 (40). Anal. (C23H20N2O4) C, H, N.
N-(4-Phenylsulfonylphenyl)-4-nitrocinnamic acid amide 6c
From 4-nitrocinnamic acid chloride (0.253 g, 1.2 mmol) and
4-aminodiphenylsulfone (0.280 g, 1.2 mmol) according to the
general procedure. Purification: recrystallization from toluene.
Yield: 0.30 g (62%). – Mp 243°C. – IR (KBr): ν = 3374, 1687,
1623, 1592, 1515 cm–1. – 1H NMR (DMSO-d6): δ = 7.01 (d, J =
16 Hz, 1H), 7.61 (m, 2H), 7.65 (m, 1H), 7.72 (d, J = 16 Hz, 1H),
7.88 (m, 2H), 7.92 (m, 6H), 8.27 (m, 2H), 10.75 (s, 1H). – EI-
MS: m/z (%) 408 (44) [M+], 176 (100), 233 (30), 130 (12). Anal.
(C21H16N2O5S) C, H, N.
N-(4-Benzoylphenyl)-3-(2-naphthyl)acrylic acid amide 5b
From 3-(2-naphthyl)acrylic acid chloride (0.324 g, 1.5 mmol)
and 4-aminobenzophenone (0.296 g, 1.5 mmol) according to
the general procedure. Purification: recrystallization from tolu-
ene. Yield: 0.46 g (81%). – Mp 194°C. – IR (KBr): ν = 3456,
1
3339, 3071, 1687, 1633, 1594, 1558, 1525 cm–1. – H NMR
(DMSO-d6): δ = 6.99 (d, J = 16 Hz, 1H), 7.51 (m, 5H), 7.63 (m,
1H), 7.70 (m, 2H), 7.75 (m, 2H), 7.77 (d, J = 16 Hz, 1H), 7.88
(m, 2H), 7.95 (m, 3H), 8.13 (m, 1H), 10.55 (s, 1H).– EI-MS:m/z
(%) 377 (18) [M+], 181 (100), 59 (40), 152 (29). Anal.
(C26H19NO2) C, H, N.
N-(4-Phenylsulfonylphenyl)-3-[5-(4-nitrophenyl)-2-furyl]acrylic
acid amide 6d
From 3-[5-(4-nitrophenyl)-2-furyl]acrylic acid chloride (0.166 g,
0.6 mmol) and 4-aminodiphenylsulfone (0.140 g, 0.6 mmol) ac-
cording to the general procedure. Purification: recrystallization
from toluene.Yield: 0.18 g (64%). – Mp 238°C. – IR (KBr): ν =
3424, 1712, 1687, 1632, 1597, 1522 cm–1. – 1H NMR (DMSO-
d6):δ = 6.77 (d, J = 15 Hz, 1H), 7.04 (m, 1H), 7.40 (m, 1H), 7.44
(d, J = 15 Hz, 1H), 7.58 (m, 3H), 7.87 (m, 6H), 7.97 (m, 2H),
8.29 (m, 2H), 10.67 (s, 1H).– EI-MS:m/z (%) 474 (16) [M+], 242
(100), 243 (14), 196 (12). Anal. (C25H18N2O6S) C, H, N.
N-(4-Benzoylphenyl)-4-nitrocinnamic acid amide 5c
From 4-nitrocinnamic acid chloride (0.422 g, 2.0 mmol) and
4-aminobenzophenone (0.395 g, 2.0 mmol) according to the
general procedure. Purification: recrystallization from toluene.
Yield: 0.64 g (86%). – Mp 240°C. – IR (KBr): ν = 3362, 3080,
1685, 1636, 1619, 1596, 1516 cm–1. – 1H NMR (DMSO-d6): δ =
7.03 (d, J = 16 Hz, 1H), 7.55 (m, 2H), 7.65 (m, 1H), 7.71 (m,

140 Sakowski et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 135–142
N-[3-[1-(1,2,3,4-Tetrahydro)quinolinyl]sulfonylphenyl]-3-(2-
naphthyl)acrylic acid amide 8b
N-(4-Phenoxyphenyl)-4-(4-nitrophenyl)butyric acid amide 7a
From 4-(4-nitrophenyl)butyric acid chloride (0.173 g,
0.8 mmol) and 4-aminodiphenyl ether (0.142 g, 0.76 mmol)
according to the general procedure. Purification: recrystalliza-
tion from toluene.Yield:0.28 g (62%).– Mp 94°C.– IR (KBr):ν =
From 3-(2-naphthyl)acrylic acid chloride (0.173 g, 0.8 mmol)
and 3-[1-(1,2,3,4-tetrahydro)quinolinyl]sulfonylaniline (0.230 g,
0.8 mmol) according to the general procedure. Purification: re-
crystallization from toluene.Yield: 0.23 g (60%). – Mp 164°C. –
IR (KBr): ν = 3429, 3059, 2958, 2855, 1744, 1685, 1630, 1596,
1
3460, 3133, 2945, 2862, 1663, 1598, 1541, 1521 cm–1. – H
NMR (DMSO-d6): δ = 1.66 (m, 2H), 1.94 (m, 2H), 2.33 (t, J = 7
Hz, 2H), 2.74 (t, J = 7 Hz, 2H), 2.75 (t, J = 7 Hz, 2H), 3.74 (t, J =
7 Hz, 2H), 7.04 (m, 2H), 7.14 (m, 1H), 7.19 (m, 1H), 7.41 (m,
1H), 7.48 (m, 2H), 7.56 (m, 1H), 7.76 (m, 1H); 8.03 (m, 1H),
8.13 (m, 2H), 10.09 (s, 1H).– EI-MS:m/z (%) 479 (86) [M+], 132
(100), 133 (46), 480 (26). Anal. (C22H20N2O4) C, H, N.
1
1543 cm–1. – H NMR (DMSO-d6): δ = 1.67 (m, 2H), 2.44 (m,
2H), 3.82 (m, 2H), 6.75 (d, J = 16 Hz, 1H), 7.00 (m, 1H), 7.07
(m, 1H), 7.15 (m, 1H), 7.23 (m, 1H), 7.37 (m, 1H), 7.49 (m,
2H), 7.68 (m, 1H), 7.78 (m, 2H); 7.82 (m, 3H), 7.88 (d, J = 16
Hz, 1H), 7.94 (m, 1H), 8.29 (m, 1H), 8.32 (m, 1H).– EI-MS:m/z
(%) 468 (77) [M+], 181 (100), 132 (56), 469 (25). Anal.
(C28H24N2O3S) C, H, N.
N-(4-Phenoxyphenyl)-3-(2-naphthyl)acrylic acid amide 7b
N-[3-[1-(1,2,3,4-Tetrahydro)quinolinyl]sulfonylphenyl]-4-ni-
trocinnamic acid amide 8c
From 3-(2-naphthyl)acrylic acid chloride (0.173 g, 0.8 mmol)
and 4-aminodiphenyl ether (0.148 g, 0.8 mmol) according to
the general procedure. Purification: recrystallization from tolu-
ene. Yield: 0.23 g (79%). – Mp 182°C. – IR (KBr): ν = 3423,
3266, 1656, 1623, 1598, 1506 cm–1. – 1H NMR (DMSO-d6): δ =
6.89 (d, J = 16 Hz, 1H), 6.3 (m, 4H), 7.03 (m, 1H), 7.30 (m, 2H),
7.49 (m, 2H), 7.68 (m, 4H), 7.87 (m, 1H), 7.90 (m, 2H), 8.05
(m, 1H), 10.13 (s, 1H). – EI-MS: m/z (%) 365 (45) [M+], 181
(100), 190 (76), 152 (51). Anal. (C25H19NO2) C, H, N.
From 4-nitrocinnamic acid chloride (0.253 g, 1.2 mmol) and
3-[1-(1,2,3,4-tetrahydro)quinolinyl]sulfonylaniline (0.346 g,
1.2 mmol) according to the general procedure. Purification: re-
crystallization from toluene.Yield: 0.46 g (82%). – Mp 248°C. –
IR (KBr):ν = 3417, 1687, 1653, 1636, 1596, 1539, 1517 cm–1.–
1H NMR (DMSO-d6): δ = 1.68 (m, 2H), 2.50 (m, 2H), 3.76 (m,
2H), 6.93 (d, J = 16 Hz, 1H), 7.05 (m, 2H), 7.15 (m, 1H), 7.26
(m, 1H), 7.48 (m, 1H), 7.55 (m, 1H), 7.70 (d, J = 16 Hz, 1H),
7.88 (m, 3H); 8.16 (m, 1H), 8.26 (m, 2H), 10.57 (s, 1H). – EI-
MS: m/z (%) 463 (22) [M+], 132 (100), 117 (26), 130 (24). Anal.
(C24H21N3O5S) C, H, N.
N-(4-Phenoxyphenyl)-4-nitrocinnamic acid amide 7c
From 4-nitrocinnamic acid chloride (0.317 g, 1.5 mmol) and
4-aminodiphenyl ether (0.277 g, 1.5 mmol) according to the
general procedure. Purification: recrystallization from toluene.
Yield: 0.27 g (61%). – Mp 162°C. – IR (KBr): ν = 3424, 3227,
1659, 1625, 1522 cm–1. – 1H NMR (DMSO-d6): δ = 6.62 (d, J =
16 Hz, 1H), 6.94 (m, 4H), 7.03 (m, 1H), 7.26 (m, 2H), 7.47 (m,
1H), 7.52 (m, 2H), 7.59 (m, 2H), 7.72 (d, J = 16 Hz, 1H), 8.17
(m, 2H). – EI-MS: m/z (%) 360 (46) [M+], 185 (100), 146 (77),
176 (22). Anal. (C21H16N2O4) C, H, N.
N-[3-[1-(1,2,3,4-Tetrahydro)quinolinyl]sulfonylphenyl]-3-[5-(4-
nitrophenyl)-2-furyl]acrylic acid amide 8d
From 3-[5-(4-nitrophenyl)-2-furyl]acrylic acid chloride (0.277 g,
1.0 mmol) and 3-[1-(1,2,3,4-tetrahydro)quinolinyl]sulfonyl-
aniline (0.288 g, 1.0 mmol) according to the general procedure.
Purification: recrystallization from toluene. Yield: 0.345 g
(65%). – Mp 238°C. – IR (KBr): ν = 3433, 1697, 1653, 1598,
1535, 1517 cm–1. – 1H NMR (DMSO-d6): δ = 1.70 (m, 2H), 2.51
(m, 2H), 3.78 (m, 2H), 6.78 (d, J = 16 Hz, 1H), 7.06 (m, 3H),
7.16 (m, 1H), 7.25 (m, 1H), 7.43 (m, 2H), 7.48 (m, 1H), 7.58
(m, 1H), 7.89 (m, 1H), 7.88 (m, 3H); 8.01 (m, 1H), 8.19 (m,
1H), 8.32 (m, 2H), 10.56 (s, 1H). – EI-MS: m/z (%) 529 (21)
[M+], 132 (100), 242 (86), 73 (68). Anal. (C28H23N3O6S) C, H, N.
N-(4-Phenoxyphenyl)-3-[5-(4-nitrophenyl)-2-furyl]acrylic acid
amide 7d
From 3-[5-(4-nitrophenyl)-2-furyl]acrylic acid chloride (0.270 g,
1.0 mmol) and 4-aminodiphenyl ether (0.185 g, 1.0 mmol) ac-
cording to the general procedure. Purification: recrystallization
from toluene.Yield: 0.25 g (57%). – Mp 195°C. – IR (KBr): ν =
3453, 1704, 1659, 1624, 1598, 1506 cm–1. – 1H NMR (DMSO-
d6):δ = 6.62 (d, J = 15 Hz, 1H), 6.71 (m, 1H), 6.92 (m, 1H), 6.99
(m, 4H), 7.07 (m, 1H), 7.30 (m, 2H), 7.46 (m, 1H), 7.52 (m,
1H), 7.57 (m, 2H), 7.81 (m, 2H), 8.24 (m, 2H).– EI-MS:m/z (%)
426 (37) [M+], 242 (100), 185 (86), 212 (55).Anal.(C25H18N2O5)
C, H, N.
N-[4-[4-(4-Nitrophenyl)butyroylamino]benzoyl]methionine
methyl ester 9a
From 4-(4-nitrophenyl)butyric acid chloride (0.173 g, 0.8 mmol)
and N-[(4-amino)benzoyl]methionine methyl ester (0.214 g,
0.76 mmol) according to the general procedure.Purification:re-
crystallization from toluene.Yield: 0.33 g (90%). – Mp 119°C. –
IR (KBr): ν = 3309, 3295, 3284, 1746, 1687, 1634, 1595, 1517
1
cm–1. – H NMR (DMSO-d6): δ = 2.09 (m, 7H), 2.27 (m, 1H),
N-[3-[1-(1,2,3,4-Tetrahydro)quinolinyl]sulfonylphenyl]-4-(4-ni-
trophenyl)butyric acid amide 8a
2.40 (t, J = 7 Hz, 2H), 2.57 (m, 2H), 2.81 (t, J = 7 Hz, 2H), 3.77
(m, 3H), 4.90 (m, 1H), 6.93 (m, 1H), 7.34 (m, 2H), 7.49 (s, 1H),
7.58 (m, 2H), 7.75 (m, 2H), 8.13 (m, 2H). – EI-MS:m/z (%) 473
(1) [M+], 120 (100), 311 (64), 295 (41). Anal. (C23H27N3O6S) C,
H, N.
From 4-(4-nitrophenyl)butyric acid chloride (0.173 g, 0.8 mmol)
and 3-[1-(1,2,3,4-tetrahydro)quinolinyl]sulfonylaniline (0.219 g,
0.76 mmol) according to the general procedure.Purification:re-
crystallization from toluene.Yield: 0.28 g (62%). – Mp 94°C. –
IR (KBr): ν = 3460, 3133, 2945, 2862, 1663, 1598, 1541, 1521
N-[4-[3-(2-Naphthyl)acryloylamino]benzoyl]methionine methyl
ester 9b
1
cm–1. – H NMR (DMSO-d6): δ = 1.66 (m, 2H), 1.94 (m, 2H),
2.33 (t, J = 7 Hz, 2H), 2.74 (t, J = 7 Hz, 2H), 2.75 (t, J = 7 Hz,
2H), 3.74 (t, J = 7 Hz, 2H), 7.04 (m, 2H), 7.14 (m, 1H), 7.19 (m,
1H), 7.41 (m, 1H), 7.48 (m, 2H), 7.56 (m, 1H), 7.76 (m, 1H);
8.03 (m, 1H), 8.13 (m, 2H), 10.09 (s, 1H).– EI-MS:m/z (%) 479
(86) [M+], 132 (100), 133 (46), 480 (26). Anal. (C25H25N3O5S) C,
H, N.
From 3-(2-naphthyl)acrylic acid chloride (0.173 g, 0.8 mmol)
and N-(4-aminobenzoyl)methionine methyl ester (0.226 g,
0.8 mmol) according to the general procedure. Purification: re-
crystallization from toluene.Yield: 0.25 g (68%). – Mp 213°C. –
1
IR (KBr): ν = 3428, 2924, 1738, 1634, 1504 cm–1. – H NMR
(DMSO-d6): δ = 1.97 (m, 5H), 2.47 (m, 2H), 3.57 (m, 3H), 4.50

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 135–142
Non-Thiol Farnesyltransferase Inhibitors 141
δ = 1.97 (m, 5H), 2.49 (m, 2H), 4.43 (m, 1H), 6.93 (d, J = 16 Hz,
1H), 7.63 (d, J = 16 Hz, 1H), 7.69 (m, 2H), 7.80 (m, 4H), 8.19
(m, 2H), 8.34 (m, 1H), 10.39 (s, 1H). – EI-MS: m/z (%) 443 (1)
[M+], 176 (100), 120 (36), 312 (33). Anal. (C21H21N3O6S) C, H,
N.
(m, 1H), 6.89 (d, J = 16 Hz, 1H), 7.47 (m, 2H), 7.68 (m, 2H),
7.71 (m, 2H), 7.80 (m, 2H), 7.82 (m, 1H), 7.88 (m, 2H), 8.05
(m, 1H), 8.47 (m, 1H), 10.31 (s, 1H).– EI-MS:m/z (%) 462 (35)
[M+], 181 (100), 388 (93), 300 (88). Anal. (C26H26N2O4S) C, H,
N.
N-[4-(4-Nitrocinnamoylamino)benzoyl]methionine methyl
ester 9c
N-[4-[3-[5-(4-Nitrophenyl)-2-furyl]acryloylamino]benzoyl]me-
thionine 10d
From 4-nitrocinnamic acid chloride (0.211 g, 1.0 mmol) and
N-(4-aminobenzoyl)methionine methyl ester (0.282 g,
1.0 mmol) according to the general procedure. Purification: re-
crystallization from toluene.Yield: 0.29 g (62%). – Mp 222°C. –
IR (KBr): ν = 3407, 3376, 1713, 1687, 1634, 1598, 1539, 1522
From
N-[4-[3-[5-(4-nitrophenyl)-2-furyl]acryloylamino]ben-
zoyl]methionine methyl ester (9d) (0.260 g, 0.5 mmol) as de-
scribed above for 10a. Yield: 0.19 g (72%). – Mp 216°C. – IR
(KBr): ν = 3417, 1701, 1627, 1599, 1522 cm–1. – 1H NMR
(DMSO-d6): δ = 1.99 (m, 5H), 2.50 (m, 2H), 4.46 (m, 1H), 6.78
(d, J = 16 Hz, 1H), 7.00 (m, 1H), 7.36 (m, 1H), 7.40 (d, J = 16
Hz, 1H), 7.71 (m, 2H), 7.81 (m, 2H), 7.95 (m, 2H), 8.26 (m,
2H), 8.35 (m, 1H), 10.39 (s, 1H).– EI-MS:m/z (%) 509 (1) [M+],
242 (100), 120 (26), 243 (16). Anal. (C25H23N3O7S) C, H, N.
1
cm–1. – H NMR (DMSO-d6): δ = 1.98 (m, 5H), 2.47 (m, 2H),
3.57 (m, 3H), 4.49 (m, 1H), 6.94 (d, J = 16 Hz, 1H), 7.63 (d, J =
16 Hz, 1H), 7.70 (m, 2H), 7.80 (m, 4H), 8.20 (m, 2H), 8.48 (m,
1H), 10.42 (s, 1H). – EI-MS: m/z (%) 457 (18) [M+], 295 (100),
383 (75), 296 (28). Anal. (C22H23N3O6S) C, H, N.
N-[4-[3-[5-(4-Nitrophenyl)-2-furyl]acryloylamino]benzoyl]me-
thionine methyl ester 9d
Farnesyltransferase assay
From 3-[5-(4-nitrophenyl)-2-furyl]acrylic acid chloride (0.277 g,
1.0 mmol) and N-(4-aminobenzoyl)methionine methyl ester
(0.282 g, 1.0 mmol) according to the general procedure. Purifi-
cation: recrystallization from toluene.Yield: 0.40 g (76%). – Mp
204°C. – IR (KBr): ν = 3441, 3307, 1719, 1687, 1632, 1597,
The assay was carried out as described [21].The assay mixture
(100 µL volume) contained 50 mM Tris/HCl pH 7.4, 5 mM
MgCl2, 10 µM, ZnCl2, 5 mM DTT, 7 µM Ds-GCVLS, 20 µM FPP
and 5 nmol GST-FTase and 1% of various concentrations of the
test compounds dissolved in DMSO. The progress of the en-
zyme reaction was followed by the enhancement of the fluores-
cence emission at 505 nm (excitation: 340 nm). Fluorescence
emission was recorded with a Perkin Elmer LS50B spectrome-
ter. IC50 values (concentrations resulting in 50% inhibition)
were calculated from initial velocity of three independent meas-
urements of four to five different concentrations of inhibitor.
1
1527 cm–1. – H NMR (DMSO-d6): δ = 1.99 (m, 5H), 2.47 (m,
2H), 3.56 (m, 3H), 4.50 (m, 1H), 6.77 (d, J = 16 Hz, 1H), 6.98
(m, 1H), 7.34 (m, 1H), 7.39 (d, J = 16 Hz, 1H), 7.70 (m, 2H),
7.79 (m, 2H), 7.93 (m, 2H), 8.24 (m, 2H), 8.47 (m, 1H), 10.39
(s, 1H). – EI-MS: m/z (%) 523 (56) [M+], 212 (100), 242 (78),
120 (48). Anal. (C26H25N3O7S) C, H, N.
N-[4-[4-(4-Nitrophenyl)butyroylamino]benzoyl]methionine 10a
N-[4-[4-(4-nitrophenyl)butyroylamino]benzoyl]methionine me-
thyl ester (9a) (0.236 g, 0.5 mmol) was dissolved in a mixture of
THF/methanol and 1N LiOH (1.1 equivalents) was added and
stirred at room temperature for 12 h.Then, most of the solvent
was removed in vacuo and the residual solution was diluted
with water.The pH was adjusted to 2–3 by addition of 1N HCl.
The aqueous phase was extracted with EtOAc (3 × 50–100 mL)
and the combined organic extracts were thoroughly washed
with brine and dried over MgSO4. The product 10a was ob-
tained after the removal of the solvent.Yield:0.22 g (97%).– Mp
92°C.– IR (KBr):ν = 3433, 2922, 1737, 1690, 1637, 1597, 1520
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