Synthesis of THIQ derivatives as potential boron neutron capture therapy agents: N-functionalized o-carboranylmethyl benzopiperidines

Article abstract of DOI:10.1055/s-2006-926222

A method for synthesizing o-carborane substituted tetrahydroisoquinolines containing a polar functional group such as sulfonic or phosphoric acid on the nitrogen atom of the piperidine ring, starting from N-(2-arylethyl)sulfamic acid or 2-arylethylamidoph

Full text of DOI:10.1055/s-2006-926222

LETTER
275
Synthesis of THIQ Derivatives as Potential Boron Neutron Capture Therapy
Agents: N-Functionalized o-Carboranylmethyl Benzopiperidines
N
-Functionalized
h
o
-Carborany
a
lmethyl
B
e
i
nzopip
-
eridinesHo Lee,*a Jung Mee Oh,a Jong-Dae Lee,b Hiroyukiki Nakamura,c Jaejung Ko,*b Sang Ook Kang*b
a
Department of Bionanochemistry and Institute of Basic Natural Science, Wonkwang University, Iksan, Jeonbuk 570-74, South Korea
b
Department of Chemistry, Korea University, 208 Seochang, Chungnam 339-700, South Korea
Fax +82(41)8675396; E-mail: sangok@korea.ac.kr
c
Department of Chemistry, Faculty of Science, Gakushuin University, Toshima, Tokyo 171-8588, Japan
Received 28 July 2005
MeO
R
Abstract: A method for synthesizing o-carborane substituted tet-
rahydroisoquinolines containing a polar functional group such as
sulfonic or phosphoric acid on the nitrogen atom of the piperidine
ring, starting from N-(2-arylethyl)sulfamic acid or 2-arylethylami-
dophosphate, is described. In vitro studies showed that the desired
compounds 7a and 10b accumulate to high levels in B-16 melano-
ma cells despite low cytotoxicity.
NSO2NH2
= CH
unmarked vertices = B
R = H, OMe
1
2
R2N
N
NR2
Key words: BNCT, o-carborane, tetrahydroisoquinoline, 2-aryl-
ethylamine, iminium ion
N
N
N
Y
Y = SO3H, P(O)(OH)2
R = Me
–CH2CH2OH
o-Carborane is a stable, lipophilic molecule that resem-
bles benzene in terms of reactivity and bulkiness.1 Its re-
markable thermal and chemical stability makes it a unique
candidate molecule for use in several specialized appli-
cations in the fields of materials science, coordination
compounds, and radiopharmaceuticals. The medicinal
chemistry of o-carborane, which contains ten boron
atoms, gives it a clear advantage for use in boron neutron
capture therapy (BNCT).2 BNCT was first proposed as a
potential cancer therapy in 1936, but its successful appli-
cation in the treatment of cancer patients still presents a
challenge in medical research.3 A major challenge in
designing boron-containing drugs for BNCT of cancer is
the selective delivery of 10B to the tumor as well as water
solubility.4
4
3
Figure 1 BNCT agents developed in our laboratory including
1,2,3,4-tetrahydro isoquinolines (THIQ, 2), s-triazines (3), and pipe-
ridines (4).
and 13 containing sulfonic or phosphoric acid moieties on
the nitrogen atom of the piperidine ring, and tested the
accumulation of selected molecules in vitro (Scheme 1).
The starting sulfamic acid 6 and phosphates 8 and 12 were
prepared by treating chlorosulfonic acid or diethyl chloro-
phosphate with the corresponding 2-arylethylamines 5
and 11 at room temperature for 3 hours in dichloro-
methane, according to established synthetic protocols.6
The starting acetal 15 was obtained in 95% yield by direct
reaction of lithio-o-carborane with chloroacetaldehyde
diethyl acetal by the Rudolph method as shown in
Scheme 2.7
Previously, we synthesized 1,2,3,4-tetrahydro isoquino-
lines (THIQ, 2), s-triazines (3) and piperidines (4) con-
taining the o-carborane unit as potential BNCT agents
(Figure 1).5 Among these compounds, THIQ (2) deriva-
tives exhibited promising results in that they showed sig-
nificantly greater boron uptake compared to boron
phenylalanine (BPA). However, the water solubility of
compounds 2 needs to be improved if they are to be used
as BNCT agents. Our promising preliminary results led us
to investigate the possibility of developing water-soluble
THIQ derivatives.
Intramolecular cyclization of starting materials 6, 8, or 12
with acetal 15 proceeding through an iminium ion inter-
mediate in formic acid (96% in H2O) gave the desired
products 7, 9 and 13 in 42–70% yield. In these processes,
an electron-withdrawing substituent was introduced on
the nitrogen of 5 and 11 to increase the electrophilicity of
the iminium intermediate.8 Deethylation of 9 and 13 by
treatment with hydrogen bromide in acetic acid afforded
the free acids 10 and 14 in 42–45% yield.9
It has been suggested that the addition of sulfonic or phos-
phoric acid functionalities to molecules will increase their
water-solubility in biological systems. Therefore, in the
present study we synthesized the THIQ derivatives 7, 9,
Selected spectroscopic properties of the piperidine rings
and carborane units of 7, 9, 10, 13 and 14 are given in
Table 1. Compounds 7, 9, 10, 13, and 14 showed absorp-
tion bands in the infrared spectrum at 2583–2606 cm–1
characteristic of vibrations of the B–H group.10 Diagnos-
tic signals of compounds 7, 9, 10, 13 and 14 were ob-
served at d = 4.09–4.78 ppm in the 1H NMR spectra and
SYNLETT 2006, No. 2, pp 0275–0278
0
1.
0
2.
2
0
0
6
Advanced online publication: 24.01.2006
DOI: 10.1055/s-2006-926222; Art ID: U25405ST
© Georg Thieme Verlag Stuttgart · New York

276
C.-H. Lee et al.
LETTER
MeO
R
MeO
R
OEt
OEt
OEt
OEt
i
n-BuLi
Cl
1
NH2
NHSO3H
6a R = H
5a R = H
b R = OMe
15
b R = OMe
iii
ii
Scheme 2 Synthesis of o-carboranyl acetal 15.
MeO
R
MeO
R
NSO3H
NHP(O)(OEt)2
8a R = H
b R = OMe
7a R = H
b R = OMe
iv
MeO
R
MeO
v
NP(O)(OEt)2
NP(O)(OH)2
R
10a R = H
b R = OMe
9a R = H
b R = OMe
S
S
vi
NH2
NHP(O)(OEt)2
11
12
vii
S
S
viii
NP(O)(OH)2
NP(O)(OEt)2
Figure 2 Molecular structure of 9b with thermal ellipsoids drawn at
the 30% level.
14
13
Scheme 1 Reagents and conditions: (i) ClSO3H, CHCl3, 0–5 °C;
(ii) 15, CH2Cl2, r.t.; (iii) ClP(O)(OEt)2, CHCl3, 0–5 °C; (iv) 15,
CH2Cl2, r.t.; (v) c-HBr, AcOH, r.t.; (vi) ClP(O)(OEt)2, CHCl3, 0–
5 °C; (vii) 15, CH2Cl2, r.t.; (viii) c-HBr, AcOH, r.t.
cyclization. To authenticate the assignments of the piper-
idine framework made on the basis of NMR spectral data,
an X-ray structural study of 9b was undertaken to confirm
the basic structure shown in Figure 2.
at d = 54.1–54.6 ppm in the 13C NMR spectra for the
methine (C-1) unit furnished by the acetal 15. The
methine unit signals at d = 4.51–4.56 ppm in the 1H NMR
spectra of the starting acetal 15 move downfield upon
Table 1 Summary of Selected Physical and Spectral Properties of the Piperidines 7, 9, 10, 12, 13, and 14
4
3
Ar
N
Y
1
2'
α
1'
Entry Compd
Y
Mp (°C)a Yield (%)b NMR (1H/13C)
IR
(BH, cm–1)
C(1)
C(3)
C(4)
C(a)
C(1¢) C(2¢)
1
2
3
7a
7b
9a
SO3H
SO3H
123–125 54
2583
4.74–4.77 (m) 3.45–3.54 (m) 3.00–3.13 (m)
64.0 4.82 (br s)
72.6
54.5
41.8
39.5
24.9
170–177 70
2589
4.58–4.63 (m) 3.35–3.42 (m) 2.98 (dd),
2.83–2.95
24.3
64.6 5.33 (br s)
73.7
54.6
42.0
3.09 (dd)
40.1
P(O)(OEt) 133–135 42
2604
4.09 (dd),
4.67 (dd)
53.4
3.11–3.22 (m), 2.97–3.05 (m) 2.88–2.93 (m) 63.2 5.49 (br s)
3.49 (ddd)
42.9
36.6
26.7
72.8
Synlett 2006, No. 2, 275–278 © Thieme Stuttgart · New York

LETTER
N-Functionalized o-Carboranylmethyl Benzopiperidines
277
Table 1 Summary of Selected Physical and Spectral Properties of the Piperidines 7, 9, 10, 12, 13, and 14 (continued)
4
3
Ar
N
Y
1
2'
α
1'
Entry Compd
Y
Mp (°C)a Yield (%)b NMR (1H/13C)
IR
(BH, cm–1)
C(1)
C(3)
C(4)
C(a)
C(1¢) C(2¢)
4
5
6
7
8
9b
P(O)(OEt2 145–147 45
2591
4.65 (dd)
53.6
3.10 (m),
3.50 (ddd)
42.8
2.89–2.91 (m) 2.46–2.51 (m) 63.1 5.46 (br s)
36.8
25.9
72.9
10a
10b
13
P(O)(OH2 291–294 42
2583
4.61–4.69 (m) 3.12–3.17 (m) 2.93–3.05 (m)
54.5
64.8 54.0 (br s)
74.2
41.7
40.7
25.9
P(O)(OH2 295–296 45
2591
4.59–4.63 (m) 3.35–3.42 (m) 2.99 (dd),
54.6
2.84–2.96
24.8
64.9 5.44 (br s)
74.3
41.6
3.15 (dd)
39.8
P(O)(OEt2 106–107 48
2606
4.77 (dd)
52.3
3.07–3.18 (m), 2.82 (dd),
3.55–3.61 (m) 2.95–3.03 (m) 23.7
42.0 37.4
2.51–2.63 (m) 63.1 5.55
72.6
14
P(O)(OH2 270–270 42
2591
4.69–4.78 (m) 2.91–3.12 (m) 2.50–2.80 (m)
41.4
64.8 5.34 (br s)
74.1
54.5
40.8
21.9
a Melting points are uncorrected.
b Purified yields
Contrary to our expectation, the water solubility of the
tested samples was not improved. However, in an in vitro
study, compounds 7a and 10b were found to accumulate
markedly in B-16 melanoma cells (Table 2).
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This work was supported by Grant No. (F01-2003-000-00202-0)
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Table 2 Cytotoxicity (IC50) and Boron Uptake
Entry
Compd
B-16a
mg/mL
18
Boron uptakeb
M
mg B/106 cells
0.41
SD
0.047
0.098
0.012
1
7a
4.33 × 10–5
4.33 × 10–5
2
10b
18
1.00
BPA
0.083
a B-16: B-16 melanoma cell.
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LETTER
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Synlett 2006, No. 2, 275–278 © Thieme Stuttgart · New York