Phosphates of bridgehead alcohols as putative inositol monophosphatase inhibitors: Molecular design and synthetic approach

Article abstract of DOI:10.1016/j.mencom.2011.09.003

To enhance the lipophilicity of d-3,5,6-trideoxyinositol monophosphate, the IMPase inhibitor, its bridgehead analogues were suggested on the basis of molecular modeling. Adamantane-1,2- and 1,4-diols were converted into their 1-phosphates via the step of

Full text of DOI:10.1016/j.mencom.2011.09.003

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 242–244
Phosphates of bridgehead alcohols as putative inositol
monophosphatase inhibitors: molecular design and synthetic approach
Olga N. Zefirova,*a,b Ivan S. Raguzin,a Vladimir V. Gogol,a Evgeniya V. Nurievaa and Maxim S. Belenikina
a Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 0290; e-mail: olgaz@org.chem.msu.ru
b Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka,
Moscow Region, Russian Federation
DOI: 10.1016/j.mencom.2011.09.003
To enhance the lipophilicity of d-3,5,6-trideoxyinositol monophosphate, the IMPase inhibitor, its bridgehead analogues were sug-
gested on the basis of molecular modeling. Adamantane-1,2- and 1,4-diols were converted into their 1-phosphates via the step of
benzylic protection of the secondary hydroxy groups; the Baeyer–Villiger oxidation of 1-hydroxyadamantan-2-one occurred to initially
cleave C(1)–C(2) bond.
H
OH
OPO23–
HO
H
H
OPO23–
Inositol monophosphatase (IMPase) plays an important role in
the regulation of cell communication process in mammalian brain.
The enzyme catalyzes the hydrolysis of myo-inositol-1-phosphate
1 and can be inhibited by lithium ions. This is believed to be
essential in the lithium treatment of manic-depressive psychosis.
Alternative inhibitors of IMPase are attractive therapeutic targets,
but their application is limited by low bioavailability in vivo
caused by their high polarity and inability to cross lipophilic
blood-brain barrier. Thus, much effort was undertaken to over-
come the requirement for polarity for IMPase inhibitors.1,2 One
of the strategies suggests a design of the compounds interacting
with hydrophobic regions of the enzyme active site.
HO
OH
H
H
OPO23–
OH
H
HO
H
A
B
C
2–O3PO
H
OH
H
HO
HO
OH
OPO23–
H
OPO23–
HO
OH
H H
D
E
F
OH
HO
HO
HO
OPO23–
OH
OPO23–
2–O3PO
H
H
HO
1
H
OH
H
HO
2–O3PO
To enhance lipophilicity of the known inositol monophos-
phatase inhibitor, namely, d-3,5,6-trideoxyinositol monophos-
phate 2,3 we proposed to use our method4 of the ‘insertion’of the
parent structure into lipophilic bicyclo[3.3.1]nonane or adamantane
core. Herein, we carried out a molecular modeling study for the
suggested templates and tried to elaborate the synthetic routes to
the most promising structure.
OH
OH
H
OH
H
G
H
I
Figure 1 Structures docked to the IMPase active site.
According to the modeling data, only one of the two possible
ring flip conformers of 2 is present in the equilibrium mixture,
the one with phosphate group in equatorial position (2a) being
favorable for the enzyme binding. Thus, the functional carcasses
of structures A, B and H entirely match with the structure of the
parent inhibitor. Moreover, their additional (in comparison with 2)
rings are stretched to a vacant liphophilic pocket in the enzyme
active site, the positioning of H and A being sterically more
advantageous than that of B [Figure 2(a)].
OH, OH, OPO32–
OH, OH, OPO32–
OH
OPO23–
HO
2
Molecular docking† into the spatial model of the IMPase active
site was performed for a number of phosphoric acid esters of
bicyclo[3.3.1]nonane and adamantane alcohols A–E and H-I
(Figure 1) with an alternation of two hydroxyl and one phosphate
substituents similar to that in structure 2.
H
H
OH
H
HO
H
2–O3PO
H
OH
OH
H
OPO23–
2a
2b
†
The molecular docking into three-dimensional structure of the human
Docking studies indicate that the structures C and I do not fit
the enzyme binding site, and the binding mode of the structures
D and E is also poor due to the improper location of hydroxyl at
IMPase determined by X-ray crystallography (from Protein Data Bank)
was performed with the Silicon Graphics Group computing complex using
Sybyl software package for molecular modeling and QSAR studies.
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 242–244
OH
HO
BnO
HO
iv
5
10
O
O
O
P
v
i
Cl
6
BnO
OH
O
P
O
P
O
O
O
O
(a)
(b)
O
O
OH
OH
HNEt3
HNEt3
11
Figure 2 Models of (a) H and (b) E bound at the active site of IMPase. The
steric hindrance for the binding of E is clearly seen; the bridgehead core of
H is pointed directly to the empty pocket.
7
vi
ii
C5 (for D) or at C1 (for E) in bicyclo[3.3.1]nonane. Besides, an
additional six-membered ring of E is pointed to the area occupied
by C6-hydroxyl of d-3,5,6-trideoxyinositol monophosphate 2
[Figure 2(b)]. Interestingly, the modeling predicts a good binding
affinity for bicyclo[3.3.1]nonane derivatives F and G (Figure 1)
with functional carcasses different from 2a but with close orient-
ation of the three pharmacophoric groups.
HO
O
O
P
O
O
O
O
OH
Ba2+
P
O
O
OH
HNEt3
12
8
In general, the docked compounds can be arranged in the fol-
lowing sequence in diminishing the predicted activity: H ® A ®
® F/G ® B, while the inhibitory properties of C, D, E, I being
scarcely probable. Synthetic realization of this structural type
requires both methods for the preparation of the corresponding
bridgehead triols and their selective phosphorylation. As though
the synthesis of compounds B, F and G is complicated due to the
absence of the substituents in the bridged positions, we tried to
elaborate a synthetic route to structure H with the best predicted
activity.
iii
vii
Na+
Na+
O
O
O
O
OH
HO
O
P
O
P
O
Ba2+
O
9
13
viii
3
First, we studied the applicability of the known phosphorylating
agent, o-phenylene phosphorochloridate,5,6 in the reaction with
known adamantane diols aiming to obtain phosphates 3 and 4,
structurally close to compound H.
Scheme 1 Reagents and conditions: i, 6, NEt3, THF, room temperature, then
NEt3, H2O, room temperature, 51%; ii, Br2/H2O, Ba(OAc)2, room tempera-
ture, 52%; iii, Na2SO4, room temperature, 48 h, 100%; iv, NaH, BnCl, DMF,
room temperature, 15 h, 74%; v, 6, NEt3, THF, room temperature, then NEt3,
H2O, room temperature, 49%; vi, H2, Pd/C, MeOH, room temperature, 5 h,
84%; vii, Br2/H2O, Ba(OAc)2, room temperature, 42%; viii, Na2SO4, room
temperature, 48 h, 100%.
OPO23–(Na+)2
OH
OPO23–(Na+)2
the target sodium salt 3 (as stable trihydrate) in a quantitative
yield.¶ In 13C NMR spectrum of 3 C2 and C1 signals are observed
at 76.77 (3JCP 3.8 Hz) and 80.62 ppm (2JCP 7.11 Hz), respectively,
as distinct from the spectrum of isomeric phosphate 9 [70.6 ppm
(C2, 2JCP 6.9 Hz), 79.95 ppm (C1, 3JCP 3.7 Hz)]. The only reson-
ance at –0.34 ppm is present in 31P NMR spectrum of compound 3.
The absence of barium ions in all sodium salts reported herein
was confirmed by atomic emission spectroscopy.
Compound 4 was synthesized analogously (Scheme 2) from
adamantane-1,4-diol 14 (prepared by reduction of 1-hydroxyada-
mantan-4-one11 with lithium aluminum hydride). Compounds
14–18 and 4 were formed as mixtures of diastereomers at C4 in
a ratio of 1:1 (as follows from the integral intensities of H–C4
resonances at ~3.6 or ~3.8 ppm in 1H NMR spectra). Phosphate
group in the sodium salt 4 is manifested at –0.1 ppm in 31P NMR
spectrum.
OH
3
4
Adamantane-1,2-diol 5 was prepared in four steps from ada-
mantan-1-ol through the rearrangement of protoadamantan-
one.7–9 Phosphatation of diol 5 with equivalent amount of
o-phenylene phosphorochloridate 65 (Scheme 1) led to the form-
ation of the only secondary phosphate 7,‡ while benzylation of
the secondary hydroxyl in diol 5 (structure 10)§ allowed us to
obtain the desired compound 11 with a phosphate group at the
bridged atom (the resonance at –5.49 ppm is observed in 31P NMR
spectrum, and a signal of adamantane C1 atom at 80.8 ppm in
13C NMR spectrum has JCP 7.8 Hz). Hydrogenolysis of benzylic
ether 11 over palladium-charcoal afforded secondary alcohol 12,
while 2-hydroxyphenyl moiety of the latter was removed by the
action of bromine water with the formation of barium salt 13.
Ion exchange reaction of 13 with sodium sulfate in water gave
These experiments confirmed the applicability of o-phenylene
chloridophosphate for the phosphorylation of adamantane diols, so
we tried to elaborate a synthetic route to adamanatane-1,2,4-triol
(corresponding to structure H). One of the easiest way seemed
to be a rearrangement of 1-hydroxy-3-oxahomoadamantan-2-one
In 1H NMR spectrum of compound 7 a characteristic resonance of C2
proton at 4.35 ppm is shifted to a lower field in comparison with the one
in the initial diol 5. 3JHP of the C2 proton with phosphorus atom is ~7 Hz,
which conforms to the literature data for the secondary phosphates.10
‡
§
¶
Attempts to use trimethylsilyl or tetrahydropyranyl protection groups
Barium and sodium salts 8 and 9 were also obtained (for the synthetic
failed (in the latter case the protective group was cleaved by o-phenylene
phosphorochloridate with formation of compound 7).
details and characteristics of new compounds, see Online Supplementary
Materials).
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Mendeleev Commun., 2011, 21, 242–244
OBn
OH
Baeyer–Villiger reaction mixture contained also bicyclic keto
acid 20 (m/z 181 [M–H]+), the formation of which can be ration-
alized by the ring opening of the unstable isomeric lactone –
1-hydroxy-2-oxahomoadamantan-3-one (Scheme 4).†† Further
oxidation of 20 leads to lactone 21, a small amount of which has
also been detected in the reaction mixture (m/z 197 [M–H]+).
Obviously, acid 22 is a product of lactone 21 ring opening.‡‡
It should be mentioned, that oxidation only at the OH-substi-
tuted carbon of 1-hydroxyadamantan-2-one 19 was not expected
and represents an example of highly regioselective proceeding of
Baeyer–Villiger reaction. Among structurally similar a-substituted
ketones regioselectivity of this type was observed in the oxida-
tion of cis-4-tert-butyl-2-fluorocyclohexanone, the major product
resulting from migration of the CHF substituent (though still both
isomeric lactones were isolated in a ratio of 7.2:1 in CH2Cl2).15
Attempts to carry out Baeyer–Villiger reaction for 19 with
m-chloroperoxybenzoic acid or hydrogen peroxide in tert-butanol
in the presence of SeO2 as well as introduction of the bulky sub-
stituent to the substrate and subsequent oxidation of 1-benzyl-
oxyadamantan-2-one also led to the formation of complex mix-
tures, in which the desired lactone was not detected.
In summary, we have suggested a new class of putative IMPase
inhibitors on the basis of molecular modeling and proved the
applicability of o-phenylene phosphorochloridate for the bridge-
head polyols phosphorylation. Baeyer–Villiger oxidation of
1-hydroxyadamantan-2-one was found to proceed regioselec-
tively towards unstable 1-hydroxy-2-oxahomoadamantan-3-one
and thus cannot be used in the synthetic route to adamanatane-
1,2,4-triol. Studies of the alternative preparative strategies are
ongoing and will be reported in due course.
i
ii
HO
O
HO
14
15
OBn
OH
O
P
O
P
O
O
O
iii
O
O
OH HNEt3
OH HNEt3
16
17
OH
O
O
Ba2+
iv
v
P
4
O
O
18
Scheme 2 Reagents and conditions: i, NaH, BnCl, DMF, room temperature,
15 h, 72%; ii, 6, NEt3, THF, room temperature, then NEt3, H2O, room tem-
perature, 74%; iii, H2, Pd/C, MeOH, room temperature, 5 h, 93%; iv, Br2/H2O,
Ba(OAc)2, room temperature, 46%; vi, Na2SO4, room temperature, 48 h, 100%.
OH
OH
O
O
OH
OH
Scheme 3
(Scheme 3) as analogous to the method of synthesis of different
adamantane-2,4-diol isomers.12
To obtain the necessary lactone, the corresponding ketol, namely
1-hydroxyadamantan-2-one 19 (prepared from adamantane-
1,2-diol by Jones oxidation7) was subjected to Baeyer–Villiger
oxidation with hydrogen peroxide in trifluoroacetic anhydride.
However, this reaction led to a complex mixture of products, the
predominant one (>70%) proved to be cyclohexane hydroxy-
dicarboxylic acid 22. The identification of 22 was based on the
mass spectrometry data (m/z 214 [M–2H]+), 13C NMR data (two
signals of carboxylic groups at 173.77 and 182.35 ppm and a
resonance of carbon atom neighbour to hydroxyl at 68.32 ppm)
and NMR data of the dimethyl ester of 22 obtained by treatment
of the acid with ether solution of diazomethane (see Online Sup-
plementary Materials).
This work was supported by the Russian Foundation for
Basic Research (project no. 03-09-879). The authors are grateful
to Dr. A. G. Borzenko for providing the atomic emission spec-
troscopy experiments.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.09.003.
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OH
COOH
O
O
O
20
21
22
Scheme 4
†† Another synthetic way to ketoacid 20 has been reported by Renzoni
and Borden.13
‡‡ Interestingly, similar deformation of adamantane core to cyclohexane
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Received: 21st January 2011; Com. 11/3667
– 244 –