3-Aryl-4-aryloyl-1-(1H-imidazol-5-yl)methylpyrrole, a novel class of farnesyltransferase inhibitors

Article abstract of DOI:10.1016/S0960-894X(01)00593-5

Design, synthesis and structure-activity relationship of a class of 3-aryl-4-aryloyl-1-(1H-imidazol-5-yl)methylpyrroles as farnesyltransferase inhibitors are described. Compound 7 inhibits farnesyltransferase with an IC₅₀ value of 4.6 nM.

Full text of DOI:10.1016/S0960-894X(01)00593-5

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2963–2965
3-Aryl-4-aryloyl-1-(1H-imidazol-5-yl)methylpyrrole, a
Novel Class of Farnesyltransferase Inhibitors
Hyunil Lee, Jinho Lee, Youseung Shin, Wonhee Jung, Jong-Hyun Kim, Kiwon Park,
Seonggu Ro, Hyun-Ho Chung and Jong Sung Koh*
Life Science R & D, LGCI, Science Town, Taejon 305-380, South Korea
Received 12 June 2001; accepted 31 August 2001
Abstract—Design, synthesis and structure–activity relationship of a class of 3-aryl-4-aryloyl-1-(1H-imidazol-5-yl)methylpyrroles as
farnesyltransferase inhibitors are described. Compound 7 inhibits farnesyltransferase with an IC50 value of 4.6 nM. # 2001Elsevier
Science Ltd. All rights reserved.
Mutated versions of three human ras genes are fre-
quently found in many human cancers, most notably
cancers of the pancreas, colon, and lung, implying an
important role for aberrant Ras function in human
tumor growth.1À4 The p21Ras oncogenic products are
synthesized as cytosolic proteins, which undergo post-
translational modifications for attachment of the nor-
mal as well as mutated Ras proteins to the membrane.5,6
A key step in a series of posttranslational modifications
of the oncogenic product Ras is farnesylation of the
thiol group of cystein located at the C-terminal CAAX
sequence in Ras proteins, which is catalyzed by farne-
syltransferase (FTase).7,8 Farnesyltransferase inhibitors
(FTIs) would therefore have potential as anticancer
agents for tumors in which a ras gene is oncogenically
mutated.9À11 In fact, the efficacy of FTIs in murine
models has been demonstrated by their ability to inhibit
tumor growth in nude mice and to induce tumor
regression in transgenic mice.12À14
dipeptide (e.g., 1, IC50=0.5 nM), and the use of an imi-
dazole ring as an alternative to the cystein thiol group
(e.g., 2, IC50=1.4 nM) which is believed to be involved
in an important binding interaction with Zn++ of
FTase (Fig. 1).16,17 Although they are potent, inhibitors
with carboxylic acid moiety showed poor cell membrane
permeability and poor oral bioavailibility.17 Our efforts
focused on the design of inhibitors, without carboxylic
acid and thiol moiety, based on non-petidic template
with the putative zinc binding capacity. In our search
for a suitable template, we have investigated pyrrole
series as a hypothetical pharmacophore featuring an
aromatic binding interaction, the spacer for the central
hydrophobic dipeptide, an H-bond acceptor, and zinc
binding ligand. 3-Aryl-4-aryloyl-1-(1H-imidazol-5-yl)-
methylpyrroles were designed to satisfy those above
requirements by attaching the aryl ring, the central pyr-
role ring, the ketone oxygen carbonyl group and imida-
zole, respectively.
Numerous structurally diverse classes of FTIs that
mimic tetrapeptide of Ras C-terminal CAAX motif
have been reported.15À18 Avenues toward improving the
biological and pharmacokinetic properties of peptido-
mimetic inhibitors have included the use of nonpeptide
surrogates for the central AA portion, deletion of car-
boxyl containing terminus, and replacement of cystein
moiety. Notable examples have featured the substitu-
tion of 4-aminobenzoic acid for central hydrophobic
A general synthesis of the 3-aryl-4-aryloyl-1-(1H-imida-
zol-5-yl)methylpyrroles is illustrated in Scheme 1.
Synthesis of pyrroles are very well known in the chem-
istry literature.19 We prepared pyrroles by reacting tol-
uene-4-sulfonylmethyl isocyanide (TosMIC) with
appropriate chalcones in anhydrous THF in the pre-
sence of potassium t-butoxide. Chalcones were obtained
by the condensation of an aldehyde derivative with an
acetophenone derivative in ethanol with sodium
hydroxide as catalyst.19 5-chloromethyl imidazole
hydrochloride was prepared from 5-hydroxymethyl
imidazole by the literature procedure.20 Compound 3
was coupled with chloromethyl imidazole to give the
*Corresponding author. Tel.: +82-42-866-2114; e-mail: jskob@lgci.
co.kr
0960-894X/01/$ - see front matter # 2001Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00593-5

2964
H. Lee et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2963–2965
compound 4 in the presence of NaH. Deprotection of
trityl protecting group of the imidazole provided 5b.
Compounds 5a, c–i (Table 1) were synthesized analog-
ously by coupling the corresponding pyrroles with
chloromethyl imidazole. Compound 6 was prepared by
reduction of 5b in the presence of sodium borohydride.
Compound 7 was synthesized by coupling the corre-
sponding pyrrole with 5-chloromethyl-1H-1-methylimi-
dazole.
the hydrophobic group as well as the hydrogen bond-
accepting group. Substitutions in the region of ortho or
para position of the aryl group led to moderate increase
in activity. The potent inhibitor (5g) contained a
hydrophobic phenoxy to the para position. Reduction
of ketone in compound 5b to alcohol (6) led to 10-fold
active loss than the parent compound, suggesting the
ketone group plays roles both as a hydrogen bonding
acceptor and as a geometric restrictor. The methylation
at N-1of the imidazole ring in compound 7 increased
the potency, suggesting N-3 of imidazole be involved in
binding with Zn++ of Ftase.
The structure–activity relationships are presented in
Table 1. Initial lead compound 5a inhibited FTase with
modest activity with IC50 value of 5 mM. The dramatic
boost of inhibitory activity from 5a to 5b is clearly
noteworthy, indicating the hydrophobic aromatic sub-
stituent at C-3 of the pyrrole is critical to the inhibitory
potency of the imidazole-containing pyrrole. We utilized
the arylcarbonyl group at C-4 of the pyrrole to supply
In summary, a series of 3-aryl-4-aryloyl-1-(1H-imidazol-
5-yl)methylpyrroles 5 were designed and synthesized as
small molecular FTIs. These series of compounds inhi-
bit farnesyltransferase at concentration as low as IC50 of
4.6 nM. Structure–activity relationship studies were
focused primarily on pyrrole derivatives. Although fur-
ther studies are required to ascertain the utility of pyr-
role ring system as a template for the attachment of
pharmacophores, it represents a novel class of FTIs that
do not have the problematic thiol and carboxylate
functional groups. This new pharmacophore would be
valuable for the development of farnesyltransferase
inhibitor as a clinically useful anticancer agent.
Table 1. Farnesyltransferase inhibitory activities of compound 5a–i,6
and 7.a
Figure 1. Structure of compounds 1 and 2.
Compd
R1R2
Ftase IC
,
50
nMb
5a
5b
5c
5d
5e
5f
5g
5h
5i
Phenyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
2-Naphthyl
9-anthracenyl
—
Phenyl
Phenyl
5000
115
88
150
32
65
16
2300
470
1350
2-bromophenyl
3-bromophenyl
4-bromophenyl
4-methylphenyl
4-phenoxyphenyl
4-methylphenyl
4-methylphenyl
—
6
7
—
—
4.6
Scheme 1. General synthesis of 3-aryl-4-aryloyl-1-(1H-imidazol-5-
yl)methylpyrroles for compounds 5a–i. (a) Ethanol, NaOH; (b) tosyl-
methylisocyanide (TosMIC), t-BuOK/THF (c) NaH (2.5 equiv)/DMF,
0 ꢀC; (d) trifluoroacetic acid, triethylsilylhydride.
aThe farnesyltransferase inhibitory assays were performed as described
in ref 21.
bValues are means of three experiments.

H. Lee et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2963–2965
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described by Moores et al. (Moores, S.L.; Schaber, M. D.;
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for 30 min at 37 ꢀC with FTase enzyme (16.6 nM), [3H]-farne-
sylpyrophosphate(FPP) (0.3 mM, 20 Ci/mmol, Dupont NEN)
and serially diluted test compounds at given concentration in
the buffer containing 50 mM HEPES, pH 7.4, 250 mM MgCl2,
25 mM KCl, 0.5% N-octylglucoside, 50 mM ZnCl2, and 10 mM
DTT. The enzyme reactions were then quenched by adding the
solution containing 10% HCl in absolute ethanol. The [3H]
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FT IC50: the concentration of compound required to reduce
the FTase-catalyzed incorporation of [3H]FPP into H-Ras
protein by 50%.