Identification and structure-activity relationship of 8-hydroxy-quinoline-7-carboxylic acid derivatives as inhibitors of Pim-1 kinase

Article abstract of DOI:10.1016/j.bmcl.2010.03.061

Pim-1 kinase is a cytoplasmic serine/threonine kinase that controls programmed cell death by phosphorylating substrates that regulate both apotosis and cellular metabolism. A series of 2-styrylquinolines and quinoline-2-carboxamides has been identified as potent inhibitors of the Pim-1 kinase. The 8-hydroxy-quinoline 7-carboxylic acid moiety appeared to be a crucial pharmacophore for activity. Molecular modeling indicated that interaction of this scaffold with Asp186 and Lys67 residues within the ATP-binding pocket might be responsible for the kinase inhibitory potency.

Full text of DOI:10.1016/j.bmcl.2010.03.061

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2801–2805
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification and structure–activity relationship of 8-hydroxy-quinoline-7-
carboxylic acid derivatives as inhibitors of Pim-1 kinase
Faten Sliman a, Mélina Blairvacq b, Emilie Durieu b, Laurent Meijer b, Jordi Rodrigo a, Didier Desmaële a,
*
a UMR 89076 BIOCIS, Faculté de Pharmacie, Université Paris Sud, 5 rue J.-B. Clément, 92296 Châtenay-Malabry, France
b USR3151, Protein Phosphorylation & Human Disease Group, Station Biologique, B.P. 74, 29682 Roscoff, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Pim-1 kinase is a cytoplasmic serine/threonine kinase that controls programmed cell death by phosphor-
ylating substrates that regulate both apotosis and cellular metabolism. A series of 2-styrylquinolines and
quinoline-2-carboxamides has been identified as potent inhibitors of the Pim-1 kinase. The 8-hydroxy-
quinoline 7-carboxylic acid moiety appeared to be a crucial pharmacophore for activity. Molecular mod-
eling indicated that interaction of this scaffold with Asp186 and Lys67 residues within the ATP-binding
pocket might be responsible for the kinase inhibitory potency.
Received 5 February 2010
Revised 11 March 2010
Accepted 12 March 2010
Available online 15 March 2010
Keywords:
Pim-1 kinase
Ó 2010 Elsevier Ltd. All rights reserved.
Inhibitors
Styrylquinolines
Quinoline-2-carboxamides
Molecular docking
Pim-1 is an oncogene-encoded cytoplasmic serine/threonine
kinase primarily expressed in hematopoietic and germ cell lines
which is involved in the control of cell growth, differentiation, pro-
liferation and apoptosis.1 Expression of Pim-1 is induced by a vari-
ety of growth factors, cytokines, mitogens and hormones
suggesting that Pim-1 may be involved in signal transduction ini-
tiated from these factors.2 Pim overexpression has been reported
in diffuse B cell lymphoma, chronic lymphocytic leukemia, prostate
cancer and FLT3-mediated acute myelogenous leukemia.3–6 Pim-2
and Pim-3, the two other members of the Pim kinase family, have
53% and 65% sequence homology respectively with Pim-1. The
kinase Pim-2 is ubiquitously expressed with highest levels in brain
and lymphoid cells. Elevated levels of Pim-2 were mostly found in
hematological malignancies and prostate cancer.7 Pim-3 is
expressed with highest levels in kidney, breast and brain. Increased
Pim-3 expression was observed in different solid tumors like hepa-
tocellular carcinoma, pancreatic and colon cancer.8
In light of its oncogenic potential, the Pim-1 kinase is emerging as
an important new target for drug discovery. The fact that Pim-1
knockout mice showed no obvious phenotype suggests that side ef-
fects for such a drug should be minimal.9 Given this promising target
profile, many academic institutions and pharmaceutical companies
have been involved in the development of Pim-1 inhibitors. Recent
crystallographic studies including co-crystal structures of com-
plexes with ATP analogue and inhibitors have provided characteris-
tic structural features for Pim-1 to help inhibitor design.10–19
Although the Pim-1 kinase displays a high degree similarity to other
serine/threonine kinases, it possesses a unique proline residue
(Pro123) in the hinge region where other hydrophobic amino acids
are more typically found. Thus, in the absence of the main chain
amide nitrogen available to participate in a hydrogen bond, novel
interactions will be required to design selective and potent ligands.
Hence, we can expect that new scaffolds which have not been previ-
ously reported as kinase inhibitors proved to be efficient inhibitors
for Pim-1. We here report the identification of a novel series of
Pim-1 inhibitors based on the 2-substituted 7-carboxy-8-hydroxy-
quinoline scaffold and outline the potential binding mode of these
molecules in the hinge pocket region using docking studies.
In 2005 Knapp and co-workers20 identified several scaffolds for
Pim-1 kinase inhibition including staurosporine, bisindoyl-malei-
mides, flavonoids, chromene[3,4]diones, imidazo[1,2-b]pyrida-
zines21,22 and pyrazolo[1,5-a]pyrimidines. Since this impressive
report, many other classes of inhibitors were discovered such as,
morpholino substituted chromones,11 3-arylimino-1,3-dihydro-in-
dol-2-ones and 3,4-dihydroxyquinolin-2-ones,13 substituted
2-cyanopyridones,15 ruthenium and osmium complexes of pyridoc-
arbazole ligands,16,23,24 4-aryl-pyrimidin-2-amines and 2,3-diphe-
nyl-indole-7-carboxylic acid,25 indolyl-pyrrolones,26 isoxazolo[3,4-
b]quinolin-3,4-diones,27 triazolo[4,3-b]pyridazines,28 5-(benzyli-
dene) thiazolidin-2,4-diones,29 3-(3-pyrazin-2-yl-phenyl)-acrylic
acids,17 pyrrolo[2,3-a]carbazoles,18 3H-benzo[4,5]thieno[3,2-d]pyr-
imidin-4-ones.19
Recent reports concerning the potency of flavonoids against
Pim-1 kinase20,30,31 prompted us to evaluate polyhydroxylated
styrylquinolines on this target. The styrylquinoline class, which
* Corresponding author. Tel.: +33 01 46 83 57 53; fax: +33 01 46 83 57 52.
E-mail address: didier.desmaele@u-psud.fr (D. Desmaële).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.061

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F. Sliman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2801–2805
was initially described as HIV-1 integrase inhibitors32–36 was re-
1) Ac2O, Δ
OHC
+
2) py, H2O, Δ
cently found to display antiproliferative activity on tumor cell
lines.37 On the other hand, quercetagetin is a known HIV-1 integr-
Y
N
N
Y
Y
X
ase inhibitor with IC50 of 0.8 l
M.38 These findings clearly show that
X
1
2
3
both classes of molecules not only share common structural fea-
tures but also some biological targets.
O
O
Hence, as an initial approach to the identification of Pim-1 inhib-
itors a small set of quinoline derivatives was screened. The synthesis
of most compounds has been previously reported.32–36,39,40 Briefly,
the styrylquinoline derivatives 3 were prepared from the corre-
sponding quinaldine1 by Perkin-typecondensation in refluxing ace-
tic anhydride, followed by hydrolysis in a pyridine water mixture.
Styrylquinolines 12, 27, 34, 36 were obtained according to this gen-
eral procedure from 2-methyl-8-hydroxy-5-quinoline carboxylic
acid41 and 2-methyl-8-hydroxy-7-quinoline carboxylic acid,32
respectively. The others derivatives were obtained from the pivotal
N-hydroxysuccinimidyl ester 5 available in five steps from the 8-hy-
droxy-2-methylquinoline-7-carboxylic acid 4. Condensation of 5
with the requisite amines followed by TFA-deprotection provided
quinoline-2-carboxamides 6 in 15–90% overall yield. Similarly con-
N
t-BuO2C
Y
N
HO2C
N
OPiv
O
OH
OH
O
5
4
1)
H2N
N
H
1)
H2N
2) TFA
2) TFA
H
N
H
Y
Y
N
N
HO2C
N
HO2C
N
H
OH
O
O
7
6
Scheme 1. General synthetic scheme for styryquinolines 3, quinoline-2-carbox-
amides 6 and hydrazides 7.
Table 1
Pim-1 inhibition assay results for compounds 4, 8–19
R2
R3
N
R1
R4
a
Compd
R1
R2
R3
R4
IC50 (lM)
4
8
9
CH3
CH3
CH3
CH3
H
H
Ph
H
CO2H
H
CO2H
H
OH
CO2H
OH
>10
>10
>10
>10
10
NHSO2Me
OH
11
12
H
H
OH
OH
>10
>10
OH
OH
CO2H
H
H
OH
OH
N
13
OH
>10
OH
OH
O
14
15
16
H
H
H
H
CO2H
OH
>10
1.7
5
OH
OH
CO2H
CO2H
OH
OH
OH
OH
O
OH
N
H
17
18
19
Cl
H
H
Cl
OH
>10
2.1
OH
O
O
OH
OH
N
H
CO2H
OH
N
H
H
CO2H
>10
OH
a
IC50 values are shown as the average of three experiments. Variations between determinations are less than 5%.

F. Sliman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2801–2805
2803
densation of 5 with arylhydrazines afforded the corresponding
hydrazides 7 (Scheme 1). Compounds 17 and 19 were prepared as
described above for 6, from 2-methyl-quinoline-8-carboxylic acid34
and 5,7-dichloro-2-methyl-quinolin-8-ol,42 respectively.
The compounds were submitted to a preliminary biological as-
say to evaluate the percent inhibition of Pim-1 activity at 10 lM.
IC50 values were determined only for compounds able to reduce
significantly Pim-1 activity (>50%).43 Results of the biological eval-
uation are listed in Table 1.
Simple quinolines bearing hydroxyl and/or carboxyl groups in
various positions were found to be inactive. On the other hand,
compounds which displayed an ancillary aromatic ring bound to
the C-2 position of the 8-hydroxy-quinoline-7-carboxylic acid
scaffold through various spacers exhibited micromolar Pim-1
inhibitory potency (compounds 15, 16, 18). The fact that a simple
vinyl spacer as well as a saturated two-carbon linker or an amide
groups provided almost equally potent compounds indicated that
the coplanar conformation of the two aromatic rings seemed to
be not a stringent structural requisite. Replacement of the 7-car-
boxyl-8-hydroxy substitution pattern by other groups while main-
taining the free catechol moiety (12, 13, 17) led to inactive
compounds.
Following these initial results, we screened additional 8-hydro-
xy-styrylquinoline-7-carboxylic acid derivatives bearing various
substituents on the ancillary ring (Table 2). Within this series most
compounds were found active whatever the substitution of the
ancillary aromatic ring. While a simple phenyl ring was sufficient
to insure micromolar activity, the 2,4-dihydroxyl, 3,5-dihydroxyl
and 3-hydroxyl-4-methoxy patterns (compounds 25, 26, 30) were
found to provide submicromolar Pim-1 inhibitors which seems to
indicate the importance of hydrogen bonding of the ancillary part
to substantially stabilize the inhibitor-enzyme complex but also
illustrating the fragile nature of the H-bonding network in this
area.
Figure 1. Computational docking of styrylquinoline 26 to the Pim-1 kinase showing
interaction with the amino acid residues of the ATP-binding pocket. Close contacts
are indicated by dotted lines and distances are provided in Angstroms.
docking studies using the GOLD 4.0 software.44 The starting point
to establish the most suitable settings for docking experiments
was the crystallographic structure of the co-crystal of Pim-1 with
substituted 2-cyanopyridones (PDB ID: 2OBJ).15 Docking studies
showed that the styrylquinoline 26 fit into the active site deep
inside the pocket, with both its C-7 carboxylate group and the oxy-
gen atom of the C-8 phenol group participating in hydrogen bonds
with the backbone NH group of Asp186. Additional interaction
involved in the anchoring of the quinoline ring is a hydrogen bond
between the C-8 phenol group and the charged amino group of
Lys67. The ancillary ring is projected toward the Gly-rich loop
of the active site and is in close proximity to the main chain of
Phe49. Such conformation allows formation of hydrogen bonds
between the C-30 hydroxyl group and Ser46 while the C-50 forms
other H-bonds with the backbone NH groups of Phe49 and Gly48
(Fig. 1).
The SAR around the substitution pattern on the phenyl ring is
difficult to rationalize. Clearly, a suitable hydroxyl substitution
pattern seems to be necessary to insure sufficient hydrogen bond-
ing within the ATP-binding site. However, the fairly good activity
of non-substituted styrylquinoline 20 can be explained by stronger
hydrophobic interactions between its aromatic ring and the phenyl
ring of Phe49. 2,4-Dihydroxy substitution (compound 25) led to
high inhibitory activity, while the close styrylquinoline 27 which
displays the 2,3-dihydroxy pattern was more than ten-fold less po-
tent. Docking studies with these derivatives (see Supplementary
data) indicated a strong hydrogen bond interaction between the
C-20 hydroxyl group and Asp186. The additional interaction with
Phe49 that strongly favored the binding of 25 is not possible with
the ortho-hydroxyl group in 27.
In search for more potent inhibitors we screened 7-carboxyl-8-
hydroquinoline derivatives possessing a functionalized linker such
as amide, hydrazide or urea, assuming that additional interactions
from these groups might improve the overall binding. The results
are depicted in Table 3. All the compounds tested were found to
be active including urea 45 whose ancillary ring was tethered with
a long four-atom linker. Among them, the quinoline-2-carboxam-
ide 40 which displayed the 2,4-dihydroxy pattern exhibited an
IC50 of 200 nM.
Docking studies with this compound indicated that the binding
pose of the quinoline core is roughly identical with that of the sty-
rylquinoline 26. However, because of the greater length of the lin-
ker the whole molecule must be substantially bent to
accommodate the crucial hydrogen bonds with Lys67, Asp186
and Phe49 and Gly48. In this conformation, which belongs to the
cluster of lowest energy conformations initially selected, the hy-
droxyl group in C-20 is perfectly positioned to make a strong hydro-
In an attempt to get deeper insight into the molecular bases of
the inhibitory potency of the styrylquinoline class we performed
Table 2
Pim-1 inhibition assay results for styrylquinolines 15, 20–38
R1
R2
R3
HO2C
N
OH
R4
a
Compd
R1
R2
R3
R4
IC50 (lM)
15
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
H
H
H
H
H
H
OH
H
OH
H
H
H
H
H
H
H
H
H
H
H
OH
H
H
H
H
OH
H
H
H
H
H
H
H
H
OH
H
H
H
H
OH
OH
OMe
Cl
Br
OMe
H
1.7
3.2
5.0
0.7
3.4
4.0
0.5
0.4
7.0
3.1
2.0
0.5
5.5
3.1
2.5
4.5
2.1
2.8
4.5
3.0
CH2OH
OH
NO2
NH2
OH
H
H
H
OH
OH
CO2H
OMe
OH
H
OH
OH
OMe
OH
OH
OH
OH
OH
OH
F
OH
OMe
OMe
OMe
Br
NO2
F
OCH2O
H
a
IC50 values are shown as the average of three experiments. Variations between
determinations are less than 5%.

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F. Sliman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2801–2805
good selectivity towards Pim-1 compared to CDK-1 and GSK-3.45
Table 3
Pim-1 inhibition assay results for compounds 18, 39–48
By contrast these compounds were almost equally potent to inhibit
DYRK 1A a serine/threonine kinase known to play a critical role in
neurodevelopment.46 The ability of DYRK 1A to accommodate Pim-
1 ligands such as pyrazolidine-3,5-diones derivatives have been
previously observed.47
R2
R3
R4
R1
HO2C
N
X
OH
In conclusion, we have identified a novel class of Pim-1 kinase
inhibitors in which several candidates endowed with a significant
activity emerged. The active compounds displayed the 8-hydroxy-
quinoline-7-carboxylic acid core. Docking experiments seem to
indicate that the heterocyclic core was critically positioned within
Pim-1 binding site and that the ancillary ring reinforced the bind-
ing through hydrogen bonds. Following these promising results,
further studies including synthesis of new analogues and evalua-
tion of the antiproliferative effect in cell-based assays are under
investigation.
a
Compd
X
R1
R2
H
OH
H
OH
OH
OH
H
H
H
H
H
R3
R4
IC50 (lM)
18
39
40
41
42
43
44
45
46
47
48
CONHCH2
CONHCH2
CONHCH2
CONHCH2
CONHCH2
CONH
H
OH
H
OH
H
OH
OH
OH
OH
OMe
H
OH
H
H
OH
OMe
OMe
OH
OH
H
2.1
2.8
0.2
0.6
3.3
1.0
1.0
0.5
2.0
5.1
3.0
OH
OH
H
H
H
H
H
H
H
HNCONH
HNCONHCH2
HNCONHCH2
CONHNH
H
H
CONHNH
NO2
NO2
Acknowledgments
a
IC50 values are shown as the average of three experiments. Variations between
This work was made possible by an initial screening of the BIO-
CIS compound library. Fellowship (FS) from Tishreen University,
Lattakia, (Syria) is gratefully acknowledged. This work was also
supported by grants from the ‘Cancéropole Grand-Ouest’, the
‘Association France-Alzheimer Finistère’, the ‘Association pour la
Recherche sur le Cancer’ (ARC-1092) and the ‘Ligue Nationale con-
tre le Cancer (Comité Grand-Ouest)’ (L.M.).
determinations are less than 5%.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.03.061.
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Pim-1
GSK-3a/b
0.50 0.04
>10
>10
>10
>10
0.40 0.03
>10
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>10
CDK1/cyclin B
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