3-Imidazolymethylaminophenylsulfonytetrahydroquinolines, a novel series of farnesyltransferase inhibitors

Article abstract of DOI:10.1016/S0960-894X(99)00686-1

Design, synthesis and structure-activity relationship of a series of 3-imidazolylmethylaminophenylsulfonyltetrahydroquinolines as farnesyltransferase inhibitors are presented. A working pharmacophore of inhibiting farnesyltransferase by this series of inhibitors is proposed. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(99)00686-1

Bioorganic & Medicinal Chemistry Letters 10 (2000) 273±275
3-Imidazolylmethylaminophenylsulfonyltetrahydroquinolines,
a Novel Series of Farnesyltransferase Inhibitors
Charles Z. Ding, a,* John T. Hunt, a Carol Ricca b and Veeraswamy Manne b
b
aDiscovery Chemistry, Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton,
NJ 08543-4000, USA
Received 29 October 1999; accepted 29 November 1999
AbstractÐDesign, synthesis and structure±activity relationship of a series of 3-imidazolylmethylaminophenylsulfonyltetrahydro-
quinolines as farnesyltransferase inhibitors are presented. A working pharmacophore of inhibiting farnesyltransferase by this series
of inhibitors is proposed. # 2000 Elsevier Science Ltd. All rights reserved.
Mutated ras oncogenes are frequently found in many
human cancers, most notably cancers of the pancreas
(90%), colon (50%) and lung (30%).1±6 The p21 Ras
oncogenic products are synthesized as cytosolic pro-
teins, which undergo post-translational modi®cations
before assuming their proliferative functions. The
®rst and obligatory step is farnesylation. The enzyme
farnesyltransferase (FT) catalyzes this reaction.2±9
Farnesyltransferase inhibitors (FTIs) could serve to
downregulate the ras activities; therefore, FTIs have
the potential to be anticancer chemotherapeutics.10±12
In fact, FTIs have been shown to inhibit tumor growth
in transgenic mice and mice bearing human tumor
xenografts (for representative publications, see refs 13
and 14).
potent in vitro activity, but they contain a labile thiol
group.
Earlier studies have shown that a thiol group could be
replaced by an imidazole ring with retention of high
farnesyltransferase inhibitory activity in a pseudopep-
tide series.24 For example, the thiol of compound 2 (FT
IC50: 0.6 nM) was replaced by an imidazole ring giving
compound 3 (FT IC50: 0.8 nM) without a detrimental
change in FT inhibitory activity. This retention of
activity was speculatively attributed to the capability of
the imidazole to serve as an alternative zinc ligand.25,26
The potent FT inhibitory activity of the piperazine ser-
ies led us to believe that this series of inhibitors bind to
the FT active site with the thiol group serving as a zinc
ligand. Our working knowledge in the FT area linked
together with the general chemical structure of the
piperazine series enabled us to formulate a working
pharmacophore model for inhibition of the enzyme.
This hypothetical pharmacophore model features an
aromatic binding interaction, an H-bond acceptor, a
lipophilic spacer, and a zinc-binding ligand. Satisfying
this pharmacophore, 3-imidazolylmethylaminophenyl-
sulfonyltetrahydroquinolines (Table 1) were designed
such that the fused tetrahydroquinoline aryl ring satis-
®ed the aromatic binding interaction, the sulfonamide
oxygens provided the H-bond acceptor, the central
phenyl ring provided the lipophilic spacer, and the imi-
dazole served as the putative zinc ligand.
Numerous structurally diverse classes of FTIs have been
reported in the literatures (for recent representative
publications, see refs 15±20). Pseudopeptidic FTIs based
on the Ras C-terminal CAAX motif contain a thiol and
a carboxylate residue, with both being necessary for
high inhibitory potency in vitro (for recent representa-
tive publications, see refs 21 and 22). In order to obtain
small molecule FTIs which would have the appropriate
pharmacokinetic properties to be potential chemothera-
peutics, it was sought to design a series of small mole-
cule FTIs that contain neither a thiol nor a carboxylate
group. The starting point was a reported piperazine
series of farnesyltransferase inhibitors (e.g. compound 1
of Fig. 1, FT IC50: 3 nM).23 These inhibitors are non-
peptidic, do not contain a carboxylate essential for
A general synthesis of the 3-imidazolylmethylamino-
phenylsulfonyltetrahydroquinolines is depicted in
Scheme 1. Reaction of 3-nitrobenzenesulfonyl chloride
4 with tetrahydroquinoline gave sulfonamide 5. The
*Corresponding author. Tel.: +1-609-2552-3494; fax: +1-609-252-
6804; e-mail: charles.ding@bms.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(99)00686-1

274
C. Z. Ding et al. / Bioorg. Med. Chem. Lett. 10 (2000) 273±275
Figure 1. Structures of compounds 1±3.
Table 1. Farnesyltransferase inhibitory activities of compound 7a±d.a
Compound 7d was prepared by reductive alkylation
of 6a using 3-cyanobenzaldehyde ®rst, followed by
4-formylimidazole in the presence of the reducing agent.
The structure±activity relationships are presented in
Table 1.27 Compound 7a inhibited FT with modest
activity. The bis-imidazole derivative 7b displayed a
more than two order of magnitude increase in inhibitory
potency over 7a. Modi®cation of the linker region by
addition of a n-butoxyl group (i.e. compound 7c) was
aimed at mimicking the methoxyethyl side chain of
compounds such as 1. Although an extensive SAR study
was not conducted, the addition of a butoxy side chain
slightly reduced potency. The dramatic boost of inhibi-
tory activity from 7a to 7b is clearly noteworthy and the
importance of the second imidazole was further studied.
Replacing one of the imidazole rings with a 3-cyano-
phenyl group gave compound 7d. This compound
exhibited similar inhibitory activity of 7b, indicating
that the presence of two imidazoles was not necessary.
It is possible that one imidazole binds to the active site
zinc, and the other binds to an unexpected pocket. This
binding pocket is tolerant since it can accommodate a
more lipophilic 3-cyanophenyl group to give similar
activity. Comparable binding pockets were also descri-
bed in other series of FTIs,28±30 which rearms our
discovery.
Compounds
R
X
FTIC50 (mM)b
7a
7b
7c
7d
H
H
H
n-BuO-
H
15
4-(5)-Imidazolylmethyl
4-(5)-Imidazolylmethyl
3-Cyanophenylmethyl
0.13
0.48
0.57
aThe farnesyltransferase inhibitory assays were performed as described
in ref 27.
bFTIC50 values are the means of three measurements.
In summary, we proposed a pharmacophore of inhibit-
ing farnesyltransferase with consideration of a known
piperazine series of FTIs. Based on this, we designed
and synthesized 3-imidazolylmethylaminophenylsulfo-
nyltetrahydroquinolines as small molecule FTIs. This
series of compounds inhibits farnesyltransferase with
good potency. Although further studies are required to
ascertain the utilities of this series of compounds, they
represent a novel series of FTIs that do not have the
problematic thiol and carboxylate functional groups.
The limited set of structure±activity relationship pre-
sented here further re®nes our working pharmacophore
model of inhibiting farnesyltransferase. We found that
there was a binding pocket that can accommodate aryls
(e.g. 3-cyanophenyl) or heteroaryls (e.g. imidazole) in
the vicinity of zinc binding site. Taking advantage of
this pocket can lead to substantial increases in inhibi-
tory activity.
Scheme 1. General synthesis of 3-imidazolylmethylaminophenyl-
sulfonyl-tetrahydroquinolines. (a) Tetrahydroquinaline, Py, CH2Cl2.
(b) n-BuOH, NaH. (c) SnCl2, EtOAc. (d) 3-Cyanobenzaldehyde,
Na(OAc)3BH and/or excess 4-formylimidazole, Na(OAc)3BH.
butoxy analogue 5c was prepared by displacing the
chlorine of the corresponding chlorobenzenesulfon-
amide 5b (prepared from 4b) in butanol in the presence
of NaH. Reduction of the nitro group in 5 with stan-
nous chloride produced aniline derivatives 6. Com-
pound 7a was prepared from 6a by reductive alkylation
using one equivalent of 4-formylimidazole in the pres-
ence of sodium triacetoxyborohydride. Compounds 7b
and 7c were prepared similarly except excesses of both
4-formylimidazole and the reducing agent were used.
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