Synthesis and biological evaluation of pentanedioic acid derivatives as farnesyltransferase inhibitors

Article abstract of DOI:10.1039/c4md00498a

Structure-based virtual screening of a commercial library identified pentanedioic acid derivatives (6 and 13b) as a kind of novel scaffold farnesyltransferase inhibitors (FTIs). Chemical modifications of the lead compounds, biological assays and analysis of the structure-activity relationships (SAR) were conducted to discover more potent FTIs. Some of them displayed excellent inhibition against FTase, and among them, the most active compound 13n with an IC₅₀ value of 0.0029 μM and SAR analysis might be helpful to the discovery of more potent FTIs. This journal is

Full text of DOI:10.1039/c4md00498a

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Synthesis and biological evaluation of
pentanedioic acid derivatives as
Cite this: DOI: 10.1039/
farnesyltransferase inhibitors†
c4md00498a
Liuqing Yang,‡ Wei Liu,‡ Hanbing Mei,‡ Yuan Zhang, Xiaojuan Yu, Yufang Xu,
*
*
*
Honglin Li, Jin Huang and Zhenjiang Zhao
Structure-based virtual screening of a commercial library identified pentanedioic acid derivatives (6 and
13b) as a kind of novel scaffold farnesyltransferase inhibitors (FTIs). Chemical modifications of the lead
compounds, biological assays and analysis of the structure–activity relationships (SAR) were conducted to
discover more potent FTIs. Some of them displayed excellent inhibition against FTase, and among them,
the most active compound 13n with an IC50 value of 0.0029 μM and SAR analysis might be helpful to the
discovery of more potent FTIs.
Received 3rd November 2014,
Accepted 2nd January 2015
DOI: 10.1039/c4md00498a
www.rsc.org/medchemcomm
Post-translational modifications, including prenylation, proteoly-
sis and carboxymethylation, are crucial biochemical features
of a majority of Ras superfamily proteins.1,2 Among them,
prenylation includes farnesylation and geranylgeranylation
which were catalyzed by farnesyltransferase and geranyl-
geranyltransferase.3,4 Farnesyltransferase is a key zinc meta-
lloenzyme, which facilitates the transfer of a 15-carbon farnesyl
to cysteine residue on proteins. The cysteine residue is located
at a conserved carboxyl-terminal CAAX motif where C is the
farnesylated cysteine, A is an aliphatic amino acid and X is a
serine, an alanine, a glutamine or a methionine.5,6 The farnesyl
group of the farnesylated cysteine leads to the increase in
hydrophobicity of Ras protein, thereby promoting its binding
to the plasma membrane for signal transduction.7 Since
mutation of the Ras protein could make this protein over-
activated which often results in some cancers, the inhibition of
farnesyltransferase has been shown as a potential pharmaco-
logical target for cancer chemotherapies.8
developed,12,13 the typical ones are quinolinone scaffold
tipifarnib 1 (R115777),14,15 ethylenediamine scaffold such as
compound 2,16,17 and tricyclic scaffold lonafarnib 3 (Fig. 1).18
Some of them have been evaluated in phase I and phase II
clinical trials. For example, a phase II study of FTI R115777
has been conducted in advanced melanoma, hematologic
malignancies19 and acute myelogenous leukemia (AML).14
But clinical data showed that the treatment of cancer such as
solid tumor or hematological malignancies using FTIs caused
various toxicities including myelosuppression, vomiting and
gastrointestinal toxicity.3,19 Although these reported FTIs
have some adverse effects and the molecular mechanism of
FTIs is not entirely clear, the present inspiring facts of com-
bining FTIs with other chemotherapies have put forward an
urgent need to develop new non-peptide and thiol-free based
FTIs with more potency for therapeutic applications.7,20,21
In our search for new FTIs by structure-based virtual
screening, we have shown previously the discovery of two
di-acid derivatives 4 and 5 as FTIs (Fig. 2), in which the
carboxyl groups could coordinate to Zn2+ in the hydrophilic
region of the binding site.3 Here we report a series of novel
non-peptide pentanedioic acid derivatives as FTIs from
structural optimization and biological evaluation of lead
compounds 6 and 13b. The predicted binding mode of lead
Although many peptidic and peptidomimetic FTIs have
been reported in recent several decades, these FTIs are
involved with several disadvantages, such as poor membrane
permeability and instability towards proteases. Some of thiol-
containing effective FTIs displayed some adverse effects
caused by the presence of the thiol moiety, which affected
their further applications as therapeutic agents.6,9–11 Cur-
rently,
a
majority of non-peptidic FTIs have been
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
University of Science and Technology, Shanghai 200237, China.
E-mail: zhjzhao@ecust.edu.cn, huangjin@ ecust.edu.cn, hlli@ ecust.edu.cn;
Tel: +86 10 64253962, +86 10 64255689, +86 10 64250213
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4md00498a
‡ The first three authors contributed equally.
Fig. 1 Structures of reported FTIs in the clinical stage.
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the proposed binding model described above by introducing
diverse substituents into phenyl ring B such as small hydro-
phobic or hydrophilic moieties, some substituent modifica-
tions in the para-position of phenyl ring A, and the replace-
ment of carboxyl with esters, amide or sulfamide (Fig. 3A).
The formation of amide from compound 13b was carried
out by 3-substituted glutaric anhydride derivatives and ani-
line derivatives in the presence of TEA.22 As reported, glutaric
anhydride derivatives 12a–d have been successfully synthe-
sized by the reaction of corresponding substituted benzalde-
hyde 10a–d with ethyl acetoacetate, followed by hydrolysis
with an aqueous solution of KOH (20 M) to form the
pentanedioic acid scaffolds 11a–d, and then heating in the
presence of acetyl chloride.23 The following synthesis steps of
the key aniline intermediates 9a–l were from nucleophilic
substituted reactions of substituted phenols and 1-fluoro-4-
nitrobenzene, followed by reduction of nitro (Scheme 1).
Compounds 13k and 13o were treated with BBr3 as a demeth-
ylation reagent to obtain compounds 13l and 13p. Synthesis
of 9l was different from those of 9a–k, which were directly
obtained from 1-fluoro-4-nitrobenzene and 4-aminophenol.
As docking suggested, the segment of chlorobenzene in
compound 13b was located in a hydrophobic pocket of FTase.
To test the size and the orientation of this pocket, the inser-
tion of methylene in diphenyl ether was carried out in order
to clarify the depth and width of the pocket. Four compounds
17a–d have been prepared in three steps from commercially
available materials starting from 4-acetamidophenol as
shown in Scheme 2.
Fig. 2 Structures of compounds 4, 5, 6 and 13b.
compound 13b implied that the carboxyl group could coordi-
nate to Zn2+ and formed a hydrogen bond with Tyr861, and
the link amide moiety and phenyl ring A are stabilized by
hydrophobic effects and Van der Waals force (VDW) interac-
tions with the farnesyl moiety of farnesyldiphosphate (FPP).
Moreover, chlorine-substituted phenyl ring
B (13b) has
aromatic interactions with an aromatic hydrophobic pocket,
which is composed of Trp602, Trp606, Tyr654, and Trp803.
Finally, phenyl ring A makes hydrophobic interaction with
an electronegative hydrophobic pocket composed of Tyr593,
Leu596, Trp606, Asp859 and Tyr861 (Fig. 3).
Results and discussion
Compound 13b with the farnesyltransferase inhibition IC50
of 0.01 μM was identified by structure-based virtual screening
and biological assays. In order to search novel FTIs with
improved activities and explicate structure–activity relation-
ships, a series of derivatives were designed on the basis of
Scheme
1 Synthesis route to compounds 13a–r. Reagents and
Fig.
3
A: Compound 13b is shown in yellow stick and ball
conditions: (a) 1-fluoro-4-nitrobenzene, K2CO3, DMSO, rt, overnight;
(b) conc. HCl, SnCl2Ĵ2H2O, 80 °C, 6 h; (c) 10% Pd/C, H2, ethanol, 6 h;
(d) ethyl acetoacetate (EAA), piperidine, rt, 3 days; (e) KOH, H2O, reflux,
4 h; (f) AcCl, reflux, 2 h; (g) dioxane, TEA, rt, 8 h; (h) BBr3, DCM, 0 °C →
rt, 30 min.
representation. FTase (PDB ID: 1LD8) is shown in pink. FPP is shown in
pink and Zn2+ is shown in grey. Residues interacting with carboxylic
acid, phenyl ring A, and phenyl ring B are shown in magenta, cyan and
purple, respectively. B: SAR studies on compound 13b.
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Scheme 2 Reagents and conditions: (a) aryl halide, K2CO3, DMSO, rt,
overnight; (b) KOH, CH3OH, H2O, reflux, 18 h; (c) glutaric anhydride
(12a), dioxane, TEA, rt, 8 h.
Scheme
5
Reagents and conditions: (a) 4-methoxybenzylamine,
ethanol, 2 h; (b) NaBH4, reflux, 2 h; (c) MsCl, TEA, DCM, 0 °C → rt, 5 h.
(d) 23, LiHMDS, ClPOIJOEt)2, THF, −20 °C to rt, 1 h; (e) DMM, NaOMe–
MeOH, MeCN, 2 days, reflux; (f) DMF, NaCl, H2O, reflux, 6 h; (g)
LiOH·H2O, CH3OH, H2O, 3 h; (h) HBTU, DIPEA, DMSO, rt, overnight; (i)
TFA, DCM, 10 h; (j) BBr3, DCM, 0 °C → rt, 30 min.
To explore the significance of carboxyl in compound 13b,
compounds 18a and 18b were obtained by esterification of
compound 13b as shown in Scheme 3 and by amidation of
compounds 13b and 20 as shown in Scheme 4. To the best of
our knowledge, sulfamide is a special functional group which
could coordinate to Zn2+, which might be effective for the
biological activity of FTIs.24 In order to construct FTIs with a
segment of sulfamide, four compounds 30a–d were synthe-
sized through some complicated reactions as shown in
Scheme 5.25 First, intermediate 23 was prepared by reductive
amination and protection of methylsulfonyl. Compound 23
was treated with LiHMDS and diethyl chlorophosphate
followed by the addition of benzaldehyde derivatives to form
alkenylsulfonamide 25, and then Michael addition reaction
was carried out with dimethyl malonate to form compound
26, followed by Krapcho decarboxylation to obtain ester 27.26
Acid 28 was obtained through hydrolysis of ester 27 and then
coupled with aniline derivatives to obtain the target com-
pounds described above.
The human FTase expression plasmid pRSF-Duet1-FTase
(a kind gift from Professor Gerrit J. K. Praefcke) was verified
by DNA sequencing and used to generate FTase. The expres-
sion and purification of recombinant human FTase was
performed using published protocols.27 Fluorescence assays
were performed as previously described (Fig. 4).3 Compounds
31, 32 and 33 were purchased (SPECS database) because of
the similarity of their structures with compound 13b to some
degree. Inhibition ratios of these compounds are all less than
50%, which reveals that phenyl ring A is an essential part for
maintaining the activity. This significant variety might be
caused by the abatement of the flexibility of carboxyl in the
presence of benzene and hence increases the interaction
between carboxyl and Zn2+. We next discuss the SAR of
synthetic compounds from modification of three parts as
suggested above: diverse substituents into phenyl ring B such
as small hydrophobic or hydrophilic moieties; modifications
of carboxyl into esters, amide or sulfamide; and para-position
modifications of phenyl ring A.
First, FTase inhibition data in Table 1 showed that com-
pounds 18a, 18b and 20 obtained through esterification and
amidation of compound 13b resulted in the complete loss of
the activity, which further prove our hypothesis that the car-
boxyl group on compound 13b was the key zinc binding
group. Then, we focused on compounds 30a–d (Table 4) from
the modification of the carboxyl group with another zinc
binding group sulfamide. To our disappointment, compound
30a (0.71 μM) showed less potency than compound 13b
Scheme 3 Methyl or ethyl esterification of compound 13b. Reagents
and conditions: SOCl2, CH3OH, 0 °C → rt, 1 h.
Scheme
4 Reagents and conditions: (a) ethyl acetoacetate (EAA),
piperidine, rt, 3 days; (b) KOH (20 M), H2O, reflux, 4 h; (c) AcCl, reflux,
2 h; (d) NH3, THF, rt, overnight; (e) HBTU, DIPEA, DMF, rt, overnight.
Fig. 4 Structures and inhibition ratios of compounds 31, 32 and 33.
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Table 1 Inhibitory activities of target compounds against human FTase
(hFTase)
phenyl ring B (compounds 13a, 13b, and 13c), which corre-
lated well with increased hydrophobicity and size (Br > Cl > F).
A
similar phenomenon could be observed from com-
pounds 13i and 13j. By substitution with two chlorine atoms
at 2,4-positions, compound 13h was the best one in this
series of compounds with an IC50 value of 0.0072 μM. Some
larger substitutions, such as methyl (13e), trifluoromethyl
(13d), cyan (13g), isopropyl (13f), methoxyl (13k), and nitro
(13q), in the para-position were sterically less tolerated, lead-
ing to a huge loss of activity. Meanwhile, compounds 13l and
13r with introduction of hydrophilic groups OH and NH2 into
the para-position resulted in a complete loss of activity which
further verifies that para-position substitution of small non-
polar groups was more preferential.
To further explore the SAR of the hydrophobic volume of
phenyl ring B, we next focus our efforts on the modification of
diphenyl ether. The strategy was performed by the insertion of
methylene between oxygen atom and phenyl ring to form
benzyl ether (Table 3). Compounds 17a (0.017 μM) and 17b
(0.023 μM) derived from lead compound 13b had resulted in a
little decrease in activity against FTase, which might have
resulted from the increased structural flexibility caused by
an inserted CH2 in diphenyl ether. Besides the variation of
flexibility, steric effects should be considered. For example,
compound 17c, with the replacement of naphthylmethylene,
showed a greatly reduced activity against FTase, which was
possible due to collision with that small hydrophobic pocket.
Finally, we focus on the effects of substituents on phenyl
ring A. As illustrated in the predicted binding mode of com-
pound 13b, this phenyl ring was pointed toward a small
hydrophobic cavity formed by residues Tyr593, Leu596,
Trp606, Asp859 and Tyr861. The introduction of hydrophilic
groups OH (13o) and OCH3 (13p) resulted in a sharp reduc-
tion in activity in comparison with compound 13b, which
demonstrated that a polar and large functional group was rel-
atively less acceptable. Similar results could be seen in com-
pounds 30c and 30d. On the contrary, compound 13n from
the introduction of methyl displayed stronger activity against
FTase with an IC50 value of 0.0029 μM than compound 13b.
We speculated that the results possibly suggested that methyl
Compound
R4
IC50 (μM)
Inhibition ratio
−19%
18a
18b
20
–COOCH3
–COOCH2CH3
–CONH2
—
—
—
−24%
6%
(0.010 μM). To some extent, compound 30b displayed better
FTase inhibition (IC50 0.038 μM), which showed that the
sulfamide group in this series really coordinated to the zinc
of FTase, but the affinity with zinc was weaker than that of
the carboxyl group.
Comparing compound 6 with compound 13b (Fig. 2), the
removal of 4-Cl from the phenyl ring B resulted in a 35-fold
decrease in potency against FTase. This significant variety
might be caused by preferable steric complementation with
the hydrophobic pocket composed of Trp602, Trp606, Tyr654
and Trp803. We next developed compounds 13a–r by intro-
ducing different substituents into phenyl ring B (Table 2).
First, compounds 13a, 13b, and 13c that resulted from intro-
ducing F, Cl, and Br atoms into the 4-position of the phenyl
ring B all showed good bioactivities against FTase with an
IC50 value at about 10 nM. 4-Cl and 4-Br (13b, 13c) were a lit-
tle better than 4-F (13a). Second, introduction of Cl and Br
into the 3-position of the phenyl ring B showed a similar phe-
nomenon. A gradual potency improvement was also observed
for those with a halogen atom at the para-position of the
Table 2 Inhibitory activities of target compounds against human FTase
(hFTase)
Compound
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
13o
13p
13q
13r
R1
H
H
H
H
H
H
H
H
H
H
H
H
Cl
CH3
OCH3
OH
H
R2
p-F
p-Cl
p-Br
p-CF3
p-CH3
p-CHIJCH3)2
p-CN
3,4-Cl2
m-Cl
IC50 (μM)
0.015
0.010
0.0096
0.071
0.027
0.58
Inhibition ratio
94.44
99.24
99.00
96.93
98.95
89.34
51.95
96.19
96.12
96.66
69.13
0.04
86.98
97.16
79.11
21.45
93.65
13.35
Table 3 Inhibitory activities of target compounds against human FTase
(hFTase)
7.1
0.0072
0.032
0.013
2.27
—
0.45
0.0029
1.94
—
0.91
—
Compound
17a
R3
IC50 (μM)
0.017
Inhibition ratio
98.75
m-Br
p-OCH3
p-OH
p-Cl
p-Cl
p-Cl
p-Cl
p-NO2
p-NH2
17b
0.023
98.62
17c
17d
0.15
0.24
88.14
88.79
H
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Table 4 Inhibitory activities of target compounds against human FTase
(hFTase)
Municipal Education Commission (grant 13SG32) and the Fok
Ying Tung Education Foundation (141035).
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Acknowledgements
This work was supported by the Fundamental Research Funds
for the Central Universities, the National Natural Science
Foundation of China (grants 81102375, 21372078, 81302697,
81222046 and 81230076) (X.L., Z.Z., L.Z., and H.L.), the Shanghai
Committee of Science and Technology (grants 14431902400
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