Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing inositol 5′-phosphatase (SHIP)

Article abstract of DOI:10.1016/j.bmcl.2015.09.034

Recently, inhibition of the SH2-containing inositol 5′-phosphatase 1 (SHIP1) has become an attractive strategy for facilitating engraftment of MHC-I mismatched bone marrow grafts, increasing the number of adult stem cells in vivo, and inducing mobilization of hematopoietic stem cells. Utilizing high-throughput screening, two quinoline small molecules (NSC13480 and NSC305787) that inhibit SHIP1 enzymatic activity were discovered. New syntheses of these inhibitors have been developed which verified the relative stereochemistry of these structures. Utilizing this synthetic route, some analogs of these quinolines have been prepared and tested for their ability to inhibit SHIP. These structure activity studies determined that an amine tethered to the quinoline core is required for SHIP inhibition. SHIP inhibition may explain the antitumor effects of similar quinoline amino alcohols and provides an impetus for further synthetic studies in this class of compounds.

Full text of DOI:10.1016/j.bmcl.2015.09.034

Accepted Manuscript
Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-con-
taining inositol 5’-Phosphatase (SHIP)
Christopher M. Russo, Arijit A. Adhikari, Daniel R. Wallach, Sandra Fernandes,
Amanda N. Balch, William G. Kerr, John D. Chisholm
PII:
S0960-894X(15)30069-X
http://dx.doi.org/10.1016/j.bmcl.2015.09.034
BMCL 23115
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 August 2015
10 September 2015
14 September 2015
Please cite this article as: Russo, C.M., Adhikari, A.A., Wallach, D.R., Fernandes, S., Balch, A.N., Kerr, W.G.,
Chisholm, J.D., Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing inositol 5’-
Phosphatase (SHIP), Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.
2015.09.034
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Synthesis and Initial Evaluation of
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Quinoline-Based Inhibitors of the SH2-
Containing Inositol 5'-Phosphatase (SHIP)
Christopher M. Russo, Arijit A. Adhikari, Daniel R. Wallach, Sandra Fernandes, Amanda N. Balch, William G.
Kerr and John D. Chisholm*
+
N
+
HO
HO
N
H
H
H H
Cl
Cl-
Cl-
N
N
Cl

Bioorganic & Medicinal Chemistry Letters
Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing
inositol 5'-Phosphatase (SHIP)
Christopher M. Russoa, Arijit A. Adhikaria, Daniel R. Wallacha, Sandra Fernandesa, Amanda N. Balchb,
William G. Kerrb, John D. Chisholma,*
aDepartment of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, NY, 13244-4100 USA
bDepartment of Microbiology & Immunology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Recently, inhibition of the SH2-containing inositol 5'-phosphatase 1 (SHIP1) has become an
attractive strategy for facilitating engraftment of MHC-I mismatched bone marrow grafts,
increasing the number of adult stem cells in vivo, and inducing mobilization of hematopoietic
stem cells. Utilizing high-throughput screening, two quinoline small molecules (NSC13480 and
NSC305787) that inhibit SHIP1 enzymatic activity were discovered. New syntheses of these
inhibitors have been developed which verified the relative stereochemistry of these structures.
Utilizing this synthetic route, some analogs of these quinolines have been prepared and tested
for their ability to inhibit SHIP. These structure activity studies determined that an amine
tethered to the quinoline core is required for SHIP inhibition. SHIP inhibition may explain the
antitumor effects of similar quinoline amino alcohols and provides an impetus for further
synthetic studies in this class of compounds.
Keywords:
quinoline
SHIP
inositol
phosphatase
inhibitor
2015 Elsevier Ltd. All rights reserved.
cell membrane
Genetic analysis has indicated the SHIP1 gene is necessary for
acute bone marrow graft rejection1 and bone marrow retention of
hematopoietic stem cells (HSC) and their homeostasis.2 We have
therefore recently focused on the inhibition of the SH2 domain
containing inositol-5'-phosphatase-1 (SHIP1) as a potential
therapeutic approach to facilitate engraftment of MHC-I
mismatched bone marrow grafts,3 increase the number and
recovery of adult stem cells in vivo4 and mobilization of HSC.4 In
addition, SHIP inhibition has been shown to be effective in
killing cancer cells in a number of systems.5 SHIP plays an
important role in modulating cell signaling through its
phosphatase activity, which modifies the phosphorylation pattern
of Phosphatidylinositol Phosphates (PIPs). PIPs play an
important role in cell signaling, with molecules like
phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3, 2) and
phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2, 3) functioning
as second messengers that can activate PH domain containing
Serine/Threonine kinases like Akt and PDK1.6 In response to
extracellular stimuli, enzymes like Phosphatidylinositide 3-
Kinase (PI3K), Phosphatase and tensin homolog (PTEN) and
SHIP1 modify the phosphorylation patterns on PIPs while they
are embedded in the internal leaflet of the plasma membrane lipid
bilayer (Figure 1). The concentration of different PIPs
significantly influences many downstream effector cascades
through what is commonly referred to as the PI3K/Akt signaling
pathway, which regulates a number of aspects of cellular
physiology.7
O
P
O
P
O
P
O-
O
O-
O
O-
O
O
O
O
OP
OP
5
OH
5
HO
HO
HO
PI3K
SHIP
OH
OH
OH
OP
PI(3,4)P3, 3
OH
OP
OP
5
PTEN
3
3
3
OP
OP
2-
P = PO3
PI(4,5)P2, 1
PI(3,4,5)P3, 2
Figure 1. Enzymatic modification of phosphatidylinositol phosphate second
messengers in the PI3K/Akt pathway
The two major SHIP paralogs encoded in mammalian
genomes are SHIP1 and SHIP2. Expression of SHIP1 is
primarily confined to cells of the hematopoietic lineage, typically
blood and bone marrow cells, although it is also expressed by
embryonic (ES)8 and mesenchymal stem cells (MSC).2b,9 SHIP2
is ubiquitously expressed in all cell and tissue types in rodents
and humans, with especially high levels of SHIP2 being found in
the heart, skeletal muscle, and the placenta.10 While SHIP1 and
SHIP2 share a high rate of amino acid conservation,11 they differ
significantly in their cellular expression and receptor
recruitment.12 These differences partially explain the different
roles these two highly homologous proteins play in cellular
pathology. For example, SHIP2 acts as a significant negative
regulator of the insulin-signaling pathway.13 Alternatively, SHIP1
functions as an important negative controller in immunoreceptor

signaling,14
in
hematopoietic
progenitor
cell
biological assays, specifically as antibacterials,22 as inhibitors of
biofilm formation,22b and as inducers of vacuolization and cell
death in glioblastoma cells.23 As the SHIP gene is not present in
bacteria, SHIP inhibition is not likely to play a role in these
antibacterial activities or in inhibiting biofilm formation.
Nevertheless, SHIP inhibition has been shown to be cytotoxic for
a number of cancer types both in vitro and in vivo.5,6,17
proliferation/survival,11 and as an inducer of cellular apoptosis.15
Interestingly, SHIP1 has also been implicated both as a
hematopoietic tumor suppressor and activator.6 The SHIP1/2
proteins influence cellular events in two separate ways: through
their phosphatase activity and as part of a scaffolding system,
which recruits other proteins to the cell membrane utilizing their
SH2 domains.6 While genetic knockout studies have been utilized
to remove the enzyme entirely,16,6 and thereby deleting both
functions of the protein, the use of a small molecule inhibitor to
halt the enzymatic function provides the opportunity to evaluate
the effects that are primarily associated with the phosphatase
activity. In addition, an inhibitor can be introduced and then be
allowed to dissipate, so the effects of transient and reversible
inhibition on the signaling pathway may be evaluated, in a
manner where sequelae associated with long-term SHIP1
deficiency are avoided.
In order to fully evaluate the biological properties of
quinolines 4 and 5, we designed a scalable synthetic route to
provide gram-scale quantities of the molecules. Initially, the
relative stereochemistry of the amino alcohol portion of
quinolines 4 and 5 was indeterminate, as the structure from the
NCI library did not specify the stereochemistry, and the original
syntheses of the two molecules were not obviously
1
stereoselective. Preliminary H NMR analysis of samples from
the NCI showed a single diastereomer. Based on the anti
(erythro) aminoalcohol relationship seen in mefloquine (8), it
was assumed that quinolines 4 and 5 contained the same relative
stereochemistry, and structures with this stereochemistry became
the desired synthetic targets. As the literature syntheses of these
molecules24 did not form the aminoalcohol portion of the
molecule in a stereocontrolled manner, efforts were directed
towards a route that could selectively provide the parent
Given the role of SHIP in regulating many aspects of cellular
pathology, interest has become focused on influencing the
enzymatic activity of the 5'-phosphatase using small molecule
inhibitors and agonists.17 Modulation of PIP levels has become a
hotly pursued goal, as these molecules play a critical role in
signal transduction. Controlling the synthesis of PI(3,4,5)P3 by
inhibiting PI3K has been the most heavily pursued strategy.18
However, while several excellent inhibitors have been developed,
efforts have been complicated by the requirement of selectively
targeting PI3K isoforms to disrupt PI3K signaling in specific cell
types. An alternative approach to modify PI3K signaling involves
increasing or decreasing the activity of the phosphatases that
modulate distal effectors (PI(3,4,5)P3, PI(3,4)P2) of PI3K, such as
SHIP1. Intrigued by the possibility of influencing signals in the
PI3K/Akt pathway by modulating a phosphatase instead of a
kinase, a high-throughput screen utilizing the National Cancer
Institute (NCI) diversity set was conducted to find inhibitors of
SHIP1.5a This screen successfully identified several compounds,
including two quinoline-based amino alcohols, NSC13480
(4•HCl) and NSC305787 (5•HCl) (Figure 2), as SHIP1/2
inhibitors.5b
compounds and that could eventually be adapted to
a
stereoselective and enantioselective approach. The route defined
by the retrosynthetic analysis presented in Figure 3, featuring a
stereospecific epoxide opening-cyclization procedure, met these
requirements and was therefore investigated further. First used in
the synthesis of quinuclidines by Lygo,25 this route appeared to
be the most promising means of rapidly accessing the
aminoalcohol section of the SHIP1/2 inhibitors, especially since
this method has seen widespread application26 in syntheses of
quinine, mefloquine, and their analogues, all of which are
structurally similar to 4 and 5. The required epoxide 10 may be
obtained from the corresponding alkene 11 by way of an E-
selective olefination between 12 and 13. Utilization of a Horner-
Wadsworth-Emmons (HWE) olefination was anticipated based
on precedence established by Kobayashi and co-workers on
several similar substrates.26c High selectivity in this olefination
was critical, as the olefin stereochemistry defines the desired
anti-amino alcohol configuration in the final product.
+
N
+
HO
HO
N
H
H
H H
Cl
Cl-
Cl-
O
N
N
HO
NPhth
N
H
Cl
NSC13480 (4•HCl)
NSC305787 (5•HCl)
R1
R1
N
R2
N
R2
9
10
N
N
PhthN
R1
OH
HO
HO
H
H
N
H
(MeO)2(O)P
R1
MeO
MeO
+
NPhth
O
13
N
quinine (6)
N
N
CF3
mefloquine (8)
N
R2
N
R2
quinidine (7)
CF3
11
12
Figure 2. Quinoline-based SHIP Inhibitors and similar compounds
Figure 3. Retrosynthetic analysis of quinoline SHIP inhibitors 4 and 5
Both quinolines 4•HCl and 5•HCl are derived from a program
to develop antimalarial agents undertaken by the Walter Reed
Army Institute of Research.19 This program developed synthetic
analogues of quinine 6 (these products are also similar to
quinidine (7), see Figure 2) and culminated in the discovery of
mefloquine (8),20 marketed as Larium for prophylactic and
therapeutic use against malaria. More recent research has shown
that mefloquine possesses anticancer21 properties that are
observed at significantly higher concentrations than those
required for antimalarial activity. A number of similar quinoline
amino alcohols have also shown significant bioactivity in other
The synthesis of quinoline 4 commenced with the Doebner
condensation of 1-naphthylamine, benzaldehyde, and pyruvic
acid which produced carboxylic acid 15 in 26% yield (Scheme
1).24a While not high-yielding, the low cost of the starting
materials, the ease with which the product is isolated (simple
vacuum filtration provided the product in high purity), and the
ease of scale-up made this transformation attractive. Reduction of
carboxylic acid 15 to alcohol 16 using BH3•THF was found to be
superior to other methods such as sodium borohydride-iodine
reduction of the acid, which resulted in incomplete conversion, or
lithium aluminum hydride reduction of the corresponding ethyl

ester, which resulted in decomposition of the starting material.
Conversion of alcohol 16 to chloride 17 using thionyl chloride
followed by an Arbuzov reaction provided the desired
phosphonate 18.
While a scalable synthesis of quinoline 5 has been
published,24b it required access to a high-pressure reactor capable
to attaining 200 psi of hydrogen on large scale. Instead of
pursuing a route that required special equipment, we chose to
instead adapt our route for making quinoline 4 to the synthesis of
5 (Scheme 3). Dichlorination of isatin (22) with TCCA, which
functions as an effective chlorinating agent when sulfuric acid is
utilized as a promoter, provided 5,7-dichloroisatin (23) in good
yield as reported by Ribeiro and co-workers.29 On large scale this
process resulted in a highly exothermic reaction, so the procedure
was modified to begin the reaction as a heterogeneous mixture at
-78 ºC, which was then allowed to mix and warm slowly to room
temperature providing 5,7-dichloroisatin 23 in 75% yield.
Adamantyl carboxylic acid 24 was conveniently converted to
ketone 25 with methyl lithium and was then used in the
Pfitzinger quinoline synthesis to provide the desired quinoline
carboxylic acid 26. Refluxing isatin 23 with 1.1 equivalents of
ketone 25 in EtOH for 24 h consistently provided 20-25% of
quinoline 26 after recrystallization, with complete consumption
of the starting isatin 23, but with approximately 50% of starting
ketone 25 recovered. This was not surprising, as the Pfitzinger
reaction is high-yielding with aryl ketones, but increasing the
steric bulk of the starting ketone, as in this example, significantly
decreases the efficiency of the process.30 To compensate, the less
expensive isatin was used in 2-fold excess, which provided
carboxylic acid 26 in 43% yield after recrystallization. As with
quinoline 4, reduction of carboxylic acid 26 to alcohol 27 was
optimally performed with BH3•THF. The conversion to chloride
28 was unexpectedly difficult. Thionyl chloride at room
temperature, though successful in the synthesis of quinoline 17,
gave inconsistent results with alcohol 27. Lowering the
temperature of the reaction to 0 °C and shortening the reaction
time to 1 h gave a moderate, but consistent, yield of 50%, and so
these conditions were adopted. Arbuzov reaction with trimethyl
phosphate then provided phosphonate 29. The HWE olefination
using DBU/LiCl, epoxidation with m-CPBA, cyclization, and
acidification steps followed to provide the mono-HCl salt of
quinoline 5. A comparison of synthetic 5•HCl with a sample
obtained from the NCI showed that they were essentially
identical, verifying the structure of NSC305787 as 5•HCl.
HO
O
OH
pyruvic acid
PhCHO
BH3•THF
THF, 18 h
NH2
EtOH
reflux, 3 h
then
Ph
NaOH, H2O
N
Ph
N
15
26%
16
80%
14
O
P
MeO
MeO
Cl
SOCl2
P(OMe)3
toluene
reflux, 72 h
DCM
18 h
N
Ph
N
Ph
17
72%
18
87%
Scheme 1. Synthesis of phosphonate 18
With phosphonate 18 in hand, the aldehyde condensation
partner 13 was synthesized in two steps from 5-aminopentan-1-ol
(19) (Scheme 2). The TEMPO oxidation conditions of De Luca,
Giacomelli and Porcheddu27 which utilized trichloroisocyanuric
acid (TCCA) as the stoichiometric oxidant proved to be superior
to PCC for the oxidation, consistently providing the desired
aldehyde in high yields. No chlorination of the phthalimide was
observed under these conditions. Sodium hydride was initially
used for the HWE olefination; however, this base proved to be
unreliable, as the olefination yields varied unpredictably.
Masamune and Roush's modified conditions28 for HWE
olefinations provided more reproducible yields, with the
combination of DBU and lithium chloride providing olefin 20 in
1
68% yield with >20:1 E-selectivity (as determined by H NMR
analysis). Subsequent electrophilic epoxidation of the olefin with
m-CPBA was predictably reliable, as was removal of the
phthalimide protecting group followed by spontaneous
cyclization to produce the piperidinylmethanol moiety with anti-
stereochemistry. Formation of the mono-HCl salt then provided
the desired 4•HCl. Only the mono-HCl salt was observed in the
precipitate (the identity of which was confirmed by 1H NMR and
combustion analysis), which was attributed to 4•HCl
precipitating from the diethyl ether solvent as a white solid
before formation of the bis-HCl salt could occur. Comparison by
1H NMR of our synthetic sample of 4•HCl with the NCI sample
showed that they were identical. Therefore, the anti-
stereochemistry was correctly anticipated. With the structure of
quinoline 4•HCl established, we turned our attention to the other
quinoline-based SHIP inhibitor, 5•HCl.
With the structures secure, attention was turned to the
biological activity of these molecules and their synthetic
intermediates (Table 1). The original high-throughput screen was
performed utilizing a Fluorescence Polarization assay for
phosphatase activity,5a but more recently we have employed a
colorimetric Malachite Green assay to evaluate SHIP activity, as
this assay is less expensive and less care needs to be taken with
compounds that have fluorescent signatures like the quinolines.
Unfortunately, attempts to test the activity of quinoline 4•HCl in
the Malachite Green assay proved difficult, as the compound
formed a precipitate under the assay conditions, which made the
assay results unreliable. Utilizing the citrate salt avoided this
issue and allowed for evaluation of the compound, but SHIP1
inhibition was somewhat moderate. Quinoline 5 provided more
significant inhibition of SHIP1/2, showing an especially strong
inhibition of SHIP2. Additionally, mefloquine hydrochloride
8•HCl showed significant inhibition of both SHIP paralogs. This
SHIP1/2 inhibition may account for the antitumor activity of
mefloquine that has been previously reported.21 Both quinine
sulfate 6•(0.5 H2SO4) and quinidine sulfate 7•(0.5 H2SO4)
showed little to no activity against SHIP1 or SHIP2. Prior to
beginning an enantioselective synthesis of 4 and 5, some
synthetic intermediates (carboxylic acids 15 and 26 as well as
alcohols 16 and 27) were tested to determine if the aminoalcohol
core of the molecule was important to the pharmacophore. Little
1) phthalic anhydride,
PhthN
H2N
toluene, reflux, 24 h
DBU, LiCl, 8
19
2) TEMPO (1 mol %)
TCCA
13
O
THF, rt, 18 h
HO
86% (2 steps)
DCM, 20 min
PhthN
PhthN
O
N
m-CPBA
CHCl3
reflux
NH2NH2
EtOH
reflux
18 h
N
Ph
Ph
18 h
20, 68%
>20:1 E:Z
21
61%
+
N
HO
HO
N
H
H
H
HCl
Et2O
Cl-
Ph
N
Ph
N
4
4•HCl
60%
62%
Scheme 2. Synthesis of 4•HCl

activity was seen for these molecules, except for moderate
activity from carboxylic acid 26 against SHIP1. From these
results, it was hypothesized that perhaps the aminoalcohol
portion of the molecule was more significant, so (1R, 2S)-(-)-
ephedrine 32 and (1S, 2S)-(+)-pseudephedrine 33 were evaluated
to determine if the quinoline core was essential, but these also
showed no SHIP activity. These results led us to hypothesize that
both the amine and the quinoline core were necessary for
significant SHIP activity, and this was tested with the synthesis
of quinoline 34•HCl (synthesized from alcohol 16 utilizing
classical Gabriel conditions, see the supporting information for
details). Quinoline 34•HCl gave significantly better activity
against both SHIP paralogs than acid 15 or alcohol 16. This result
verifies the importance of the quinoline core and the pendant
amine, and also indicates that the piperidine ring and the alcohol
present in amino alcohols 4, 5 and 8 are not critical for SHIP
phosphatase inhibition.
O
O
Cl
TCCA
O
O
H2SO4
-78°C-rt
72 h
N
O
OH
N
OH
H
H
22
23
92%
Cl
Cl
Cl
BH3•THF
KOH
+
EtOH/H2O
reflux
THF, 18 h
then NaOH, H2O
N
N
O
O
MeLi
Cl
Cl
27
26
Et2O, -10°C - rt
60%
43%
HO
3 h
24
25
80%
O
PhthN
Cl
Cl
P
OMe
OMe
DBU, LiCl,
then 13
Cl
SOCl2
P(OMe)3
Cl
toluene
reflux, 72 h
CH2Cl2
THF, rt, 18 h
N
N
N
Cl
Cl
28
50%
29
74%
Cl 30
68%
>20:1 E:Z
PhthN
O
+
HO
HO
N
H
N
NH2NH2
MCPBA
CHCl3
reflux
HCl
H
H
Cl
Cl
Cl
Cl-
Et2O
EtOH
reflux
N
5
51%
N
31
75%
N
Cl
5•HCl
Cl
Cl
60%
Scheme 3. Synthesis of 5•HCl
as a SHIP inhibitor at high concentrations. The SHIP1/2 activity
of mefloquine may explain the reports of the antitumor activity of
the molecule, as the concentration seen for SHIP inhibition is
similar to the concentration observed for cancer cell killing.20
Quinine and quinidine were not active in the assay, and neither
were ephedrine or pseudoephedrine. A brief structure activity
study showed that both the quinoline core and a pendant amine at
the 4-position of the quinoline were required for significant
SHIP1/2 inhibition, but the alcohol and the piperidine ring were
not critical components for this activity. Future studies exploring
the structure-activity relationships in these systems are underway
and will be reported in due course.
Table 1. SHIP inhibitory activity of quinolines 4 and 5 and
related moleculesa
SHIP1
SHIP2
Entry
Compound
Inhibition Inhibition
1
2
3
4
5
6
7
8
9
10
11
12
13
4•HCl
4•citrate
5•HCl
N/Ab
38%
38%
54%
0%
N/Ab
17%
73%
54%
8%
mefloquine hydrochloride (8•HCl)
quinine sulfate (6•0.5 H2SO4)
quinidine sulfate (7•0.5 H2SO4)
carboxylic acid 15
carboxylic acid 26
alcohol 16
19%
7%c
44%c
2%c
0%c
0%
5%
0%c
0%c
18%c
14%c
0%
alcohol 27
Acknowledgments
(1R, 2S)-(-)-ephedrine 32
(1S, 2S)-(+)-pseudephedrine 33
34•HCl
2%
41%
13%
66%
This work was supported by grants from the NIH (RO1
HL72523, R01 HL085580) and the Paige Arnold Butterfly Run.
W.G.K. is an Empire Scholar of the State University of New
York and a Senior Scholar of the Crohn’s & Colitis Foundation
of America (CCFA). S.F. is a Research Fellow of the CCFA.
Support for the Syracuse University NMR facility was provided
by the NSF (CHE-1229345), which is gratefully acknowledged.
aResults from the Malachite Green assay performed at 1mM concentration.
bCompound precipitated during testing. cEvaluated at 500µM
+H3N
Cl-
OH
OH
NHMe
CH3
Ph
Ph
33
N
Ph
CH3
NHMe
32
34•HCl
References and notes
In summary, new synthetic routes to quinoline-based SHIP
inhibitors 4 and 5 have been developed which do not require
special equipment for their synthesis. These routes provide the
products in a stereoselective manner. The parent quinolines,
several intermediates and similar commercially available
compounds have been tested for activity against SHIP1 and
SHIP2. In addition to the activity demonstrated by the parent
compounds, mefloquine hydrochloride 8•HCl proved to be active
1.
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1
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