Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype

Article abstract of DOI:10.1016/j.bmcl.2014.07.089

We discovered a new chemical class of antiproliferative agents, 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides. SAR-guided optimization of the two distinct terminal fragments yielded a compound with 120 nM potency in an antiproliferative assay. Biologi

Full text of DOI:10.1016/j.bmcl.2014.07.089

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides,
a new tubulin inhibitor chemotype
Mikhail Krasavin a, Andrey V. Sosnov b, Ruben Karapetian c, Igor Konstantinov c, Olga Soldatkina c,
Elena Godovykh c, Fedor Zubkov d, Ruoli Bai e, Ernest Hamel e, Andrei A. Gakh f,g,h,
⇑
a Department of Chemistry, St. Petersburg State University, Peterhof 198504, Russia
b ORCHIMED, Institute of Physiologically Active Compounds, Chernogolovka, Moscow Region 142432, Russia
c Chemical Diversity Research Institute, Khimki, Moscow Region 114401, Russia
d Peoples’ Friendship University of Russia, Moscow 117198, Russia
e Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research,
National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
f Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
g The University of Virginia, Charlottesville, VA 22908, USA
h The Discovery Chemistry Project, Bethesda, MD 20824, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We discovered a new chemical class of antiproliferative agents, 4-(1,2,4-oxadiazol-5-yl)piperidine-1-car-
boxamides. SAR-guided optimization of the two distinct terminal fragments yielded a compound with
120 nM potency in an antiproliferative assay. Biological activity profile studies (COMPARE analysis) dem-
onstrated that 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides act as tubulin inhibitors, and this con-
clusion was confirmed via biochemical assays with pure tubulin and demonstration of increased numbers
of mitotic cells following treatment of a leukemia cell line.
Received 25 April 2014
Revised 29 July 2014
Accepted 31 July 2014
Available online xxxx
Keywords:
Prostate cancer
Ó 2014 Elsevier Ltd. All rights reserved.
DU-145
Screening
Chemotherapeutic agents
Rational single-molecule polypharmacy
Tubulin inhibitor
Prostate cancer represents a major current public health threat
and is still an unmet medical need despite recent advances in med-
ical therapeutics. In the USA alone, 240,890 new cases of prostate
cancer and 33,720 deaths related to the disease were registered
in 2011,1 and the statistics remained similarly alarming in 2012.2
While the causal relationship between various risk factors and
the incidence of prostate cancer is poorly understood, a healthy
diet and exercise have been shown to help prevent the disease.3
Moreover, a difference in dietary patterns is considered to be the
main reason for the significantly lower prostate cancer incidence
in Eastern/Southeast Asia as compared with Western countries.4
Dietary supplementation with naturally occurring compounds is
now contemplated for prostate cancer prevention as a part of a dis-
ease-conscious lifestyle.5
surgery. The use of chemotherapy to treat prostate cancer remains
largely experimental.6 However, the development of targeted
small-molecule and antibody-based therapies offers hope for
imminent breakthroughs in the treatment of prostate cancer.7,8
The current study in the framework of the Discovery Chemistry
Project aims to identify novel anticancer compounds with rational
single-molecule polypharmacy potential9 toward the ‘classical’
DU-145 human prostate cancer cell line.10
We recently reported several novel classes of antiproliferative
agents that utilize the A–B–C tricyclic framework,11,12 including
novel tubulin inhibitors containing the 1,2,4-oxadiazole ring as a
O
N
Men diagnosed with prostate cancer are subject to standard
treatments, which include hormone and radiation therapy and
N
*
N
*
Figure 1. The structure of the 4-(1,2,4-oxadiazol-5-yl)piperidine dual heterocyclic
core.
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2014.07.089
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
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2
M. Krasavin et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 1
H
N
O
N
R
N
Chemical yields of p-fluoporphenyl 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxam-
ides (8) and their antiproliferative activities against DU-145 cells
N
O
Ar
NR1R2
1-3
1 Ar = 4-ClC6H4 R = (2-C4H3O)CH2 GI50 = 2.7 µM
2 Ar = 4-MeC6H4 R = 3-MeOC6H4 GI50 = 4.5 µM
3 Ar = 4-FC6H4 R = (2-C4H3O)CH2 GI50 = 3.3 µM
N
F
N
N O
O
b
Compound NR1R2
Synthetic
Yield
(%)
GI50 (lM)
routea
Figure 2. The structures and GI50 data (DU145 cell line) of the hit compounds (1–3).
*
*
O
N
8a
8b
8c
8d
8e
8f
B
A
B
A
A
A
B
B
62
88
51
86
93
92
71
64
17.0 1.1
Inactive
single central heterocyclic moiety.13 We further hypothesized that
additional biomedical benefits can be attained using a dual hetero-
cyclic core by adding a second heterocyclic fragment while retain-
ing the overall linear chain structure of the A–B–C heterocyclic
system. One dual heterocyclic core, 4-(1,2,4-oxadiazol-5-yl)piperi-
dine (Fig. 1), has been successfully employed for the design of
novel bioactive molecules14–16 and antiproliferative agents.17,18
High-throughput screening of the available collections yielded
three closely related 4-(1,2,4-oxadiazol-5-yl)piperidine carboxam-
ides (1–3) that inhibited the proliferation of DU-145 cells in a dose-
dependent manner, with GI50 values in low micromolar range
(Fig. 2). Other 4-(1,2,4-oxadiazol-5-yl)piperidine derivatives,
N-acyl, N-alkyl or N-sulfonyl (>100 compounds in total), did not
*
N
H
S
N
1.7 0.3
2.8 0.4
Inactive
H
*
Ph
N
H
*
MeOOC
Ph
N
H
*
N
H
13.6 0.6
0.65 0.08
1.1 0.2
H
S
N
8g
8h
*
H
N
O
*
show detectable activity at a 2 lM concentration. This preliminary
research indicated that the 1-carboxamide fragment might be an
essential part of this newly discovered pharmacophore.
8i
B
48
Inactive
N
Given the presence in the core of compounds 1–3 of two dis-
tinct elements, the 1,2,4-oxadiazol ring and the carboxamide resi-
due, we performed a SAR investigation around these two motifs
independently. Our aim was to identify the terminal substituents
that would improve antiproliferative activity. We reasoned that
subsequently combining the two independently optimized termi-
nal aromatic substituents within the same molecule might have
an additive effect and result in even more potent compounds.
Taking into account our previous success with monofluorinated
aromatic substituents,13,19 we initially prepared the 4-fluorophenyl
substituted compound 4 (Scheme 1) as a starting point of SAR opti-
mization. The first intermediate, amidoxime 5, was synthesized
*
*
N
8j
B
B
55
39
21.0 0.9
Inactive
H
N
8k
*
*
N
8l
B
44
Inactive
8m
8n
B
B
63
42
Inactive
Inactive
N
*
O
N
*
N
N
H
N
8o
B
38
0.94 0.05
NH2OH.HCl
NH2
N
*
F
CN
F
HN
DIPEA (1 equiv.)
EtOH, reflux
6 h
*
8p
8q
B
A
29
95
9.8 0.5
Inactive
5
HO
N
H
1) TBTU (1 equiv.)
HOBt(0.2 equiv.)
DIPEA (5 equiv.)
DMF, r. t., 10 min
H
N
*
O
N
NBoc
H
N
N
*
8r
8s
A
A
86
79
Inactive
Inactive
HOOC
NBoc
O
*
2) , r. t., 1 h
5
6
HN
3) DMF, 110 oC, 2 h
62%
F
TFA, DCM
r. t., 1 h
91%
*
O
N
8t
B
54
1.3 0.2
H
O
O
Cl
O
N
N
N
a
(Cl3CO)2CO
NH
Method A—via direct condensation of 4 with isocyanates; Method B—via car-
N
N
bamoyl chloride 7.
O
Et3N, DCM
r. t., 1 h
b
The data shown are the means of three experiments standard deviation.
Inactive—compounds showing <20% DU-145 growth inhibition at 50 lM.
4
7
R2
F
F
R1
R1NCO
N
DCM, r. t.
H
R1
N
R2
1 - 18 h
O
DCM, Et3N
r. t., 6-18 h
N
N
(R2 = H)
from 4-fluorobenzonitrile via the standard reaction with hydroxyl-
amine.20 The next intermediate, Boc-protected 4-[3-(p-fluoporphe-
nyl)-1,2,4-oxadiazol-5-yl]piperidine 6, was prepared by one-pot
TBTU mediated acylation/heterocyclization.21,22 Subsequent Boc
group removal provided the desired amine 4. This known com-
pound23 served as a starting material for the preparation of an array
N
O
8a-t
Method B
Method A
F
Scheme 1. Synthesis of p-fluoporphenyl 4-(1,2,4-oxadiazol-5-yl)piperidine-1-car-
boxamides (8a–t); TBTU—O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tet-
rafluoroborate, HOBt—1-hydroxybenzotriazole, DIPEA—N,N-diisopropylethylamine.
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M. Krasavin et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
NH2OH.HCl
H2N
R
CN
N
OH
DIPEA (1 equiv.)
EtOH, reflux
4-18 h
R
10a-m
45 - 91%
1) TBTU (1 equiv.)
HOBt (0.2 equiv.)
DIPEA (5 equiv.)
DMF, r. t., 10 min
HN
O
O
N
HN
O
N
Ph
HOOC
N
Ph
N
R
2) , r. t., 1 h
10
3) DMF, 110 oC, 2-4 h
11a-m
9
Scheme 2. Synthesis of N-benzyl 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides (11a–m).
of tri- and tetrasubstituted ureas 8a–t via a direct reaction with iso-
cyanates (Method A). An alternative method (Method B) involved the
preparation of the carbamoyl chloride 7 (Scheme 1).24
obviously favored (8c–d, 8g–h, 8o, 8t), while replacing them with
phenethyl-type groups (8f, 8p) appeared to lower antiproliferative
activity.
An assessment of the antiproliferative activity of the newly syn-
thesized carboxamides 8a–t (Table 1) led to several important SAR
generalizations. A mono-substituted carboxamide moiety was
found to be essential for antiproliferative activity: exhaustive sub-
stitution of the carboxamide nitrogen atom led to markedly lower
(8a, 8j) or a complete loss (8i, 8l–8n) of activity. The presence of an
aromatic or heteroaromatic ring also appeared to be essential,
since no activity was detected in the compounds containing ali-
phatic substituents (8b, 8e, 8k, 8q–s). Benzylic-type groups were
In parallel withthe carboxamide array, a series of 3-substituted1,
2,4-oxadiazoles was prepared by condensing N-(benzylcarbamoyl)
isonipecotic acid 9 with readily available amidoximes 10a–m
using the TBTU-mediated acylation/heterocyclization protocol
(Scheme 2).21 The starting compound, N-(benzylcarbamoyl)isonipe-
cotic acid 9, was conveniently prepared via a reaction of ethyl
piperidine-4-carboxylate with benzyl isocyanate followed by an
ester hydrolysis.
Evaluation of the antiproliferative potency of the resulting
1,2,4-oxazoles 11a–m (Table 2) revealed the importance of
additional aromatic groups in this region of the molecule and
established the beneficial effect of a flexible linker between the
1,2,4-oxadiazole moiety and an aromatic substituent, as exempli-
fied by compounds 11b and 11d.
From the initial orthogonal SAR survey of the 4-(1,2,4-oxa-
diazol-5-yl)piperidine-1-carboxamides 8a–t and 11a–m, we iden-
tified two sets of terminal substituents that appeared to have a
beneficial effect on the antiproliferative potency of compounds
having GI50 values in the submicromolar range (8g, 8o, 11b,
11d). We expected that combining these favorable substituents
in a ‘crossover’ set of compounds would have an additive effect
on the potency of the resulting compounds.
Table 2
Chemical yields of N-benzyl 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides (11)
and their antiproliferative activities against DU-145 cells
H
N
N
R
N
Ph
N O
O
a
Compound
R
Yield (%)
44
GI50 (lM)
*
11a
1.6 0.2
11b
11c
Bn
Ph
68
67
0.76 0.09
1.9 0.4
‘Crossover’ compounds 12a–d were subsequently synthesized
using methods similar to those presented in Schemes 1 and 2, and
the new compounds were then tested for antiproliferative activity
against DU-145 cells (Table 3). An additive effect of combining the
best terminal fragments was achieved only with compound 12a,
the most active compound in the series.
PhO
*
11d
58
0.52 0.05
*
N
11e
32
11.2 1.1
O
*
N
11f
45
51
8.6 0.4
11g
12.3 0.7
*
*
Table 3
11h
62
1.2 0.05
GI50 data (DU-145 cells) and structures of the SAR-merging ‘crossover’ compounds
12a–d
*
HN R2
O
11i
11j
73
46
Inactive
Inactive
N
N
Me
R1
N
O
Cl
11k
11l
38
67
9.3 0.4
2.9 0.2
a
*
Compound
R1
R2
GI50 (lM)
Cl
S
*
*
12a
Bn
0.12 0.03
0.95 0.12
1.7 0.3
F
*
*
N
N
N
12b
12c
12d
Bn
MeO
*
*
S
11m
64
4.4 0.4
PhOCH2
PhOCH2
MeO
N
2.8 0.2
a
The data shown are the means of three experiments standard deviation.
Inactive—compounds showing <20% DU-145 growth inhibition at 50 M.
l
a
The data shown are the means of three experiments standard deviation.
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4
M. Krasavin et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
H
N
known tubulin inhibitors, such as diaryl 5-amino-1,2,4-oxadiaz-
O
N
oles.13 This behavior is unusual but not exceptional27,28 among
structurally related compounds and warrants further investigation.
Finally, to verify further the antitubulin mechanism of action,
we examined whether selected compounds (8d, 11a, and 11c)
would cause mitotic arrest in K562 human leukemia cells. We ver-
ified that these three compounds inhibited the growth of these
N
N
O
S
12a
GI50 = 0.12 0.03 µM
S
H
N
O
N
cells (IC50 values were 1.2 0.4, 0.55 0.05, 1.5 0.7
tively), and their effects on the mitotic index were examined with
the compounds at 5.0 M. The mitotic indices for the three com-
lM, respec-
S
O
N
H
N
O
O
N
N
N
l
N
pounds were, respectively, 72 20%, 83 7%, and 75 2%. As a
positive control, we used the well described antitubulin, antimi-
totic agent combretastatin A-429,30 at 100 nM (82 5%), while
without compound the mitotic index was 2 1%.
14
13
Inactive
Inactive
S
H
N
While apparently conclusive, these mitotic and tubulin inhibi-
tion studies cannot completely rule out the possibility of other tar-
gets for 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides. An
example of a novel tubulin inhibitor chemotype with dual ligand
features was reported recently.31,32 In this particular case, the
ligand binds to tubulin at the colchicine site inducing a strong anti-
proliferative action that masks weaker growth inhibition effects
caused by heat shock protein 27 (Hsp27) binding.31 Small struc-
tural variations of the lead compound allow target-specific ligand
tuning.32
In conclusion, we have identified 4-(1,2,4-oxadiazol-5-yl)piper-
idine-1-carboxamides as a novel class of tubulin inhibitors that
have antiproliferative activity in the DU-145 prostate cancer cell
line. A two-vector SAR optimization improved the potency of the
compounds more than tenfold. The most active compound, 12a
(GI50 = 120 nM), can serve as a new lead for the development of
chemotherapeutic agents against prostate cancer.
O
O
O
N
O
N
N
N
N
S
H
N
N
15
16
Inactive
GI50 = 6.5 0.4 µM
Figure 3. Evaluation of alternative linkers (GI50 data—DU-145 cells).
We were also interested in seeing if the geometry of the
piperidine moiety could be altered to improve potency. It appeared,
however, that the 1,4-piperidine linker was the best, because
activity was drastically reduced (compound 15) or completely
eliminated (compounds 13, 14 and 16) for linkers with nonlinear
geometry (Fig. 3). Compounds 13–16 were synthesized similarly
to 12a using 2(3)-piperidine and 2(3)-pyrrolidine carboxylate
precursors in lieu of the piperidine-4-carboxylate precursor.
Good correlations were observed between some 4-(1,2,4-oxa-
diazol-5-yl)piperidine-1-carboxamides and antiproliferative diaryl
5-amino-1,2,4-oxadiazoles13,25 in the 60-cell line screening tests
performed at the National Cancer Institute and analyzed by online
COMPARE26 software tools (see Supporting information). These
diaryl 5-amino-1,2,4-oxadiazoles were recently identified as tubu-
lin inhibitors with polypharmacy potential.13
Acknowledgments
This Letter is a contribution from the Discovery Chemistry Pro-
ject funded in part by the U.S. Department of Energy in collabora-
tion with the National Cancer Institute. Oak Ridge National
Laboratory is managed and operated by UT-Battelle, LLC, under
contract DE-AC05-00OR22725 for the U.S. Department of Energy.
Subsequent direct biochemical experiments confirmed that all
tested 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides have
antitubulin activity (see Table 4), but display somewhat different
features. For example, hit compound 2 had reasonable tubulin
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.07.
089. These data include MOL files and InChiKeys of the most
important compounds described in this article.
inhibitor potential (IC50 = 3.0 0.1
a substantially weaker inhibition of colchicine binding (5.7 3% at
M, 8.2 3% at 5 M, and 19 0.5% at 50 M) compared to other
lM). At the same time, 2 elicited
1
l
l
l
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HN R2
O
N
N
N
R1
O
Compound
R1
R2
IC50
,
l
M
SD
*
*
1
4-ClC6H4
2.0 0.08
O
1a
4-MeC6H4
2.3 0.2
O
2
2a
8d
11a
11c
11k
4-MeC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
Ph
3-MeOC6H4
3-MeOC6H4
Bn
Bn
Bn
Bn
3.0 0.1
5.3 0.5
1.6 0.1
1.1 0.02
1.8 0.1
2.6 0.2
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Please cite this article in press as: Krasavin, M.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.07.089