Synthesis and biological evaluation of meta-carborane-containing phenoxyacetanilides as inhibitors of hypoxia-inducible factor (HIF)-1 transcriptional activity

Article abstract of DOI:10.1016/j.jorganchem.2015.05.029

meta-Carboranylphenoxyacetanilides were synthesized by copper catalyzed coupling reaction of meta-carborane and phenyl iodides. The synthesized compounds were evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a ce

Full text of DOI:10.1016/j.jorganchem.2015.05.029

Journal of Organometallic Chemistry xxx (2015) 1e7
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis and biological evaluation of meta-carborane-containing
phenoxyacetanilides as inhibitors of hypoxia-inducible factor (HIF)-1
transcriptional activity
,
, *
Guangzhe Li a, Soyoko Azuma b, Hidemitsu Minegishi a b, Hiroyuki Nakamura a
a Chemical Resources Laboratory, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan
b Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
meta-Carboranylphenoxyacetanilides were synthesized by copper catalyzed coupling reaction of meta-
carborane and phenyl iodides. The synthesized compounds were evaluated for their ability to inhibit
hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter gene assay. Among the com-
pounds synthesized, meta-carborane containing phenoxyanilides 2d and 2h, which have an isobutyl
group on meta-carborane, exhibited significant inhibition of hypoxia-induced HIF-1 transcriptional ac-
Received 30 March 2015
Received in revised form
17 May 2015
Accepted 18 May 2015
Available online xxx
tivity toward HeLa cell-based reporter gene assay with the IC50 values of 0.73 and 0.55 mM, respectively.
Dedicated to Professor Russell N. Grimes on
the occasion of his 80th anniversary.
© 2015 Elsevier B.V. All rights reserved.
Keywords:
meta-Carborane
Hypoxia inducible factor
Transcription
Inhibitor
1. Introduction
[12], aspirin and indomethacin analogs [13,14], nicotinamide phos-
phoribosyltranferase inhibitors [15], carbonic anhydrase inhibitors
[16], purinergic P2X7 receptor antagonists [17], combretastatin an-
alogs [18], and manassantin analogs [19].
Recently much attention has been focused on carboranes as
pharmacophores in pharmaceutical drug design [1,2]. Especially
dicarba-closo-dodecaboranes, having three isomers: 1,2-, 1,7-, and
1,12-dicarba-closo-dodecaboraneare referred to as ortho-, meta- and
para-carbaborane, are extremely hydrophobic and regarded stable
under chemical and physical conditions [3]. The van der Waals vol-
ume of these carboranes is a range of from 141 to 148 Å3 and the
volume is compatible to that of adamantane (136 Å3) and almost
twice the volume of benzene [1,4]. Carboranes have been widely
used as boron sources for boron neutron capture therapy (BNCT)
agents [5e7]. The first attempts to use carboranes as a pharmaco-
phore have been initiated by Endo and coworkers, who introduced
the 1-(4-hydroxyphenyl)carborane core as a steroidal framework
[8,9]. Since their reports, various compounds have been synthesized
based on the carborane pharmacophore strategy including folic acid
analogs [10], antifolates [11], flufenamic acid and diflunisal analogs
We recently reported ortho-carborane-containing hypoxia
inducible factor (HIF)-1
synthesized based on the corresponding adamantane derivative
LW6 (Fig. 1) [23,24]. HIF-1 is a transcription factor that regulates
angiogenesis, invasion, metastasis, glucose uptake, and cell survival
during cancer development [25e28]. Although HIF-1 undergoes
a inhibitors (1aec) [20e22] that were
a
a
an oxygen-dependent degradation under aerobic conditions, it is
stabilized and translocate into the nucleus to form a heterodimeric
complex with a constitutively expressed subunit HIF-1b. This a/b
heterodimeric complex binds to specific nucleotide sequences
(hypoxia response elements) with co-activators, such as p300 and
CBP to activate various hypoxia responsive genes and over-
expression of HIF-1
tance to treatment of cancer patients [29]. Therefore, HIF-1
a
is associated with poor prognosis and resis-
is
a
considered to be one of the potential targets for antitumor agents
[30]. Previously, we examined the effects of substituents at a R2
group on HIF-1 transcriptional activity and found that an ethyl
group (1b) was the most suitable for the inhibitory activity of HIF-1
* Corresponding author.
E-mail address: hiro@res.titech.ac.jp (H. Nakamura).
http://dx.doi.org/10.1016/j.jorganchem.2015.05.029
0022-328X/© 2015 Elsevier B.V. All rights reserved.
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G. Li et al. / Journal of Organometallic Chemistry xxx (2015) 1e7
Fig. 1. Design of meta-carborane containing phenoxyacetanilides 2 based on the structures of LW6 and ortho-carborane derivatives 1.
transcription [22]. In this paper, we synthesized meta-carbor-
anylphenoxyacetanilides and evaluated their inhibitory effects on
HIF-1 transcriptional activity.
substituted meta-carboranes 5bed were also synthesized from
4a. Lithiation of 4a with n-BuLi proceeded in tetrahydrofuran (THF)
at ꢁ10 ꢀC and the resulting lithiated carborane reacted with alkyl
iodides to give the corresponding di-substituted meta-carboranes
4bed. Deprotection of a methoxy group on 4bed was carried out
using boron tribromide to give 1-alkyl-7-(4-hydroxyphenyl)-meta-
carboranes 5bed in 40e74% yields in two steps.
2. Results and discussions
2.1. Chemistry
We next synthesized 1-(3-hydroxyphenyl)-meta-carboranes in
a similar manner to the synthesis of 1-(4-hydroxyphenyl)-meta-
carboranes. As shown in Scheme 2, C-arylation of meta-carborane 3
with 3-iodoanisole proceeded in the presence of CuCl and pyridine
to give 1-(3-methoxyphenyl)-meta-carborane 6a [9], which was
converted to the phenoxy derivatives 7a [9] or 7bed through di-
substituted meta-carboranes 6bed.
Scheme 3 shows the synthesis of meta-carboranylphenox-
yacetanilides 2aeh. The pinacol ester of boronic acid moiety was
introduced into 4-bromo-2-nitrophenol benzyl ether 8 by the
Suzuki-Miyaura diboron coupling and the resulting phenyl boronic
ester 9 was converted to the corresponding aniline 10 under the
We first synthesized 1-(4-hydroxyphenyl)-meta-carboranes as
shown in Scheme 1. The C-arylation of meta-carborane through its
copper derivative was developed by Wade and coworkers [31].
meta-Carborane 3 was treated with n-BuLi in dimethoxyethane
(DME) at 0 ꢀC to give the corresponding lithiated carborane, which
reacted with CuCl to generate the C-copper derivative of meta-
carborane. Coupling reaction of the copper derivative with 4-
iodoanisole proceeded in the presence of pyridine under refluxed
conditions to give 1-(4-methoxyphenyl)-meta-carborane 4a [8].
The methoxy group of 4a was deprotected by boron tribromide to
give 1-(4-hydroxyphenyl)-meta-carborane 5 [8] in 91% yield. Di-
Scheme 1. Reagents and conditions: (a) (i) n-BuLi, DME, 0 ꢀC, 30 min, (ii) CuCl, r.t.,1.5 h, (iii) 4-iodoanisole, pyridine, reflux, 48 h, 26%; (b) (i) n-BuLi, THF, ꢁ10 ꢀC, 30 min, (ii)
R1I, ꢁ10 ꢀC, 1.5 h; (c) BBr3, CH2Cl2, r.t., overnight, 40e91%.
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G. Li et al. / Journal of Organometallic Chemistry xxx (2015) 1e7
3
Scheme 2. Reagents and conditions: (a) (i) n-BuLi, DME, 0 ꢀC, 30 min, (ii) CuCl, r.t.,1.5 h, (iii) 3-iodoanisole, pyridine, reflux, 48 h, 28%; (b) (i) n-BuLi, THF, ꢁ10 ꢀC, 30 min, (ii) R1I,
1.5 h; (c) BBr3, CH2Cl2, r.t., overnight, 55e96%.
reductive conditions. Acylation of 10 with bromoacetyl bromide
gave bromacetylanilide 11 [22]. Alkylation of 1-(4-hydroxyphenyl)-
meta-carboranes 5aed and 1-(3-hydroxyphenyl)-meta-carboranes
7aed with bromacetylanilide 11 proceeded in THF at room tem-
perature under basic conditions and the benzyl group of the
resulting phenoxy ethers was deprotected by hydrogenesis to give
the meta-carboranylphenoxyacetanilides 2aeh.
were tested for their ability to inhibit hypoxia-induced HIF-1
transcriptional activity in HeLa cells under hypoxia (1% oxygen)
using dual luciferase reporter gene assay expressing hypoxia
response element (HRE)-dependent firefly luciferase reporter
construct (HRE-Luc) and constitutively expressing CMV-driven
renilla luciferase reporter [32]. The compound concentrations
required to inhibit the hypoxia-induced HIF-1 transcriptional ac-
tivity by 50% (IC50) were summarized in Table 1. Although the
previously reported phenoxyacetanilide 1a [20] showed potent
2.2. Biological evaluation
inhibitory activity (IC50 ¼ 4.10
m
M), the corresponding pinacol ester
1c was more potent (IC50 ¼ 2.72
mM). Since the pinacol ester de-
The synthesized meta-carboranylphenoxyacetanilides 2aeh
rivatives were easy for purification and stable in a DMSO solution,
the pinacol esters of meta-carborane derivatives were evaluated for
their ability to inhibit hypoxia-induced HIF-1 transcriptional ac-
tivity. The meta-carborane derivative 2a showed the similar
inhibitory activity to its ortho-derivative 1c (IC50 ¼ 2.28
mM). Sub-
stituents of the R1 group, such as methyl (2b), ethyl (2c), and i-butyl
(2d) groups, affected the inhibitory potency against the hypoxia-
induced HIF-1 transcription and the IC50 values were 1.52, 0.83,
and 0.73
mM, respectively. Next, inhibitory potency of 1-(3-
hydroxyphenyl)-meta-carborane derivatives 2e-h were evaluated.
Compound 2e, which has no substituent at the R1 group, exhibited
the IC50 of 4.80 mM, whereas the sterically larger substituents of the
R1 group, such as methyl (2f), ethyl (2g), and i-butyl (2h) groups,
increased their inhibitory activity. Especially, i-butyl-substituted
meta-carboranylphenoxyacetanilide 2h exhibited significant
inhibitory activity against the hypoxia-induced HIF-1 transcription
and the IC50 was 0.55 mM.
3. Conclusions
We succeeded in synthesis of meta-carborane containing phe-
noxyacetanilides 2 based on the structures of LW6 and ortho-car-
borane derivatives 1. The C-arylation of meta-carborane through its
copper derivative developed by Wade and coworkers is a key for
the synthesis of 2, although the yields were not satisfactory
(26e28%). The effect of compounds 1 and 2 on hypoxia-induced
HIF-1 transcriptional activity was examined using a cell-based
dual luciferase reporter gene assay in HeLa cells under hypoxia.
Among the compounds synthesized, meta-carborane containing
phenoxyanilides 2d and 2h exhibited significant inhibitory activity
toward hypoxia-induced HIF-1 transcription with the IC50 values of
Scheme 3. Reagents and conditions: (a) pinacolatodiboron, PdCl2, dppf, AcOK,
dioxane, reflux, overnight, 91%; (b) Fe, NH4Cl, EtOHeH2O, reflux, 2 h, 60%; (c) bro-
moacetyl bromide, pyridine, DMAP, r.t., overnight, 90%; (d) 5 or 7, NaH, THF, r.t., 2 h; (e)
H2, Pd/C, MeOH-THF, r.t., overnight.
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G. Li et al. / Journal of Organometallic Chemistry xxx (2015) 1e7
Table 1
Inhibition of HIF-1 transcriptional activity on HeLa cell-based HRE and CMV dual luciferase assaya.
Compound
IC50
(
mM)
SD
1a: R2 ¼ B(OH)2
1c: R2 ¼ B(pin)
4.10
2.72
0.91
0.36
2a: R1 ¼ H
2.28
1.52
0.83
0.73
0.52
0.32
0.12
0.01
2b: R1 ¼ Me
2c: R1 ¼ Et
2d: R1 ¼ i-Bu
2e: R1 ¼ H
4.80
1.34
1.29
0.55
0.80
0.29
0.44
0.03
2f: R1 ¼ Me
2g: R1 ¼ Et
2h: R1 ¼ i-Bu
a
The drug concentration required to inhibit the relative light units by 50% (IC50) was determined from semi-logarithmic doseeresponse plots and the results represent
means standard deviation (SD) of triplicate samples.
0.73 and 0.55
mM, respectively. These compounds are more potent
4.2. Synthesis of 1-(4-methoxyphenyl)-1,7-dicarba-closo-
than ortho-carboranylphenoxyacetanilides (1aec) that were pre-
viously synthesized. Both compounds have an isobutyl group
substituted at R1 position of meta-carborane, revealing that a ste-
rically bulky group is essential for their significant inhibitory
potency.
dodecaborane 4a
To a solution of meta-carborane 3 (4.78 g, 33 mmol) in 150 mL of
dry ethylene glycol dimethyl ether (DME) was added a 1.6 M so-
lution of n-BuLi in n-hexane (20.6 mL, 33 mmol) dropwise at 0 ꢀC
under N2. After the mixture was stirred for 30 min, CuCl (5.94 g,
60 mmol) was added. The mixture was further stirred at room
temperature for 1.5 h. Pyridine (21 mL) and 4-iodoanisole (7.02 g,
30 mmol) were added and the resulting mixture was refluxed for
48 h. After the removal of the solvent with a rotary evaporator
under reduced pressure, the residue was diluted with water and
extracted three times with ethyl acetate. The combined organic
layer was washed with saturated aqueous NaCl solution, dried over
anhydrous MgSO4, and concentrated. The residue was purified by
silica gel column chromatography using hexane/AcOEt (100:1) as
an eluent to give 4a (1.93 g, 26%) as a colorless solid: 1H NMR
4. Experimental section
4.1. General procedures
All reactions were carried out under nitrogen atmosphere us-
ing standard Schlenk techniques. Most chemicals and solvents
were analytical grade and used without further purification. 1H
NMR and 13C NMR spectra were recorded on a Bruker biospin
AVANCE III HD500 (500 MHz) spectrometer. Tetramethylsilane (
0.00) was used as internal standard for 1H NMR. 13C NMR was
referenced to the residual solvent (CDCl3, 77.0). IR spectra were
d
(500 MHz; CDCl3):
3.78 (s, 1H), 3.04 (s, 1H).
d
7.33 (d, J ¼ 9.0 Hz, 2H), 6.76 (d, J ¼ 9.0 Hz, 2H),
d
measured on a JASCO FT/IR-4100 spectrophotometer. Melting
points were determined with a As one ATM-01 melting point
apparatus. High-resolution mass spectra were measured on a
Bruker microTOF II spectrometer. Analytical thin layer chroma-
tography (TLC) was performed on a glass plates (Merck Kieselgel
60 F254, layer thickness 0.2 mm). Visualization was accompanied
by UV light (254 nm), I2 and KMnO4. Column chromatography was
performed on silica gel (FUJI SILYSIA CHEMICAL LTD. silica gel PSQ
60B). Compounds 4a, 5a, 6a, 7a have been already reported, thus
identified by comparison with the reported 1H NMR spectral data
[8,9].
4.3. Synthesis of 1-(4-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane 5a
Compound 4a (500.6 mg, 2 mmol) was dissolved in CH2Cl2 so-
lution (10 mL), and a 1.0 M solution of BBr3 in CH2Cl2 (6 mL,
6 mmol) was added to the solution dropwise at 0 ꢀC under N2. The
resulting mixture was stirred overnight at room temperature. The
reaction was quenched by water and the mixture was extracted
three times with ethyl acetate. The combined organic layer was
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G. Li et al. / Journal of Organometallic Chemistry xxx (2015) 1e7
5
washed with saturated aqueous NaCl solution, dried over anhy-
drous MgSO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography with hexane/CH2Cl2 (2:1) to
give 5a (429.5 mg, 91%) as a colorless solid: 1H NMR (500 MHz;
33 mmol) and 3-iodoanisole (7.02 g, 30 mmol) using the procedure
described for 4a to give 6a (1.63 g, 28%) as a colorless solid: 1H NMR
(500 MHz; CDCl3):
1.0 Hz, 1H), 6.97 (t, J ¼ 2.0 Hz, 1H), 6.82 (dd, J ¼ 8.0 Hz, 2.0 Hz, 1H),
d
7.15 (t, J ¼ 8.0 Hz, 1H), 7.01 (dd, J ¼ 8.0 Hz,
CDCl3):
d
7.29 (d, J ¼ 9.0 Hz, 2H), 6.69 (d, J ¼ 9.0 Hz, 2H), 4.90 (s, 1H),
3.78 (s, 3H), 3.03 (s, 1H).
3.04 (s, 1H).
4.5.1. Synthesis of 1-(3-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane 7a
4.4. General procedure for synthesis of carboranylphenols 5bed
Compound 7a was synthesized from 6a (500.6 mg, 2 mmol)
using the procedure described for 5a to give 7a (453.1 mg, 96%) as a
To a solution of carboranylanisole 4a (500.6 mg, 2 mmol) in
15 mL of dry THF was added a 1.6 M solution of n-BuLi in n-hexane
(1.9 mL, 3 mmol) dropwise at ꢁ10 ꢀC under N2. After the mixture
was stirred for 30 min at ꢁ10 ꢀC, alkyl iodide (3 mmol) was added
to the reaction media. The reaction mixture was continuously
stirred for 1.5 h and then the reaction was quenched by saturated
NH4Cl aqueous solution. The mixture was extracted three times
with ethyl acetate and the combined organic layer was washed
with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and concentrated. The resulting crude products 4bed was
subsequently dissolved in CH2Cl2 solution (10 mL), and a 1.0 M
solution of BBr3 in CH2Cl2 (6 mL, 6 mmol) was added dropwise at
colorless solid: 1H NMR (500 MHz; CDCl3):
d
7.11 (t, J ¼ 8.0 Hz, 1H),
7.00 (d, J ¼ 8.0 Hz, 1H), 6.91 (t, J ¼ 2.0 Hz, 1H), 6.76 (dd, J ¼ 8.0 Hz,
2.0 Hz, 1H), 5.03 (s, 1H), 3.04 (s, 1H).
4.5.2. Synthesis of 1-methyl-7-(3-hydroxyphenyl)-1,7-dicarba-
closo-dodecaborane 7b
Compound 7b was synthesized from 6a (500.6 mg, 2 mmol) and
methyl iodide (0.19 mL, 3 mmol) using the procedure described for
5b to give 7b (279.2 mg, 56%) as a colorless solid: Mp. 79e80 ꢀC
(CH2Cl2/Hexane); 1H- NMR (500 MHz; CDCl3):
d
7.10 (t, J ¼ 8.0 Hz,
1H), 6.99 (d, J ¼ 8.0 Hz, 1H), 6.91 (t, J ¼ 2.0 Hz, 1H), 6.75 (dd,
0
ꢀC. The mixture was stirred overnight at room temperature. The
J ¼ 8.0 Hz, 2.0 Hz, 1H), 5.49 (s, 1H), 1.75 (s, 3H); 13C NMR (125 MHz,
reaction was quenched by water and the mixture was extracted
three times with ethyl acetate. The combined organic layer was
washed with saturated aqueous NaCl solution, dried over anhy-
drous MgSO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography with hexane/CH2Cl2 (2:1) to
give 5bed as a colorless solid.
CDCl3): d 155.0, 136.9, 129.5, 120.4, 115.6, 115.2, 78.1, 70.6,53.4, 24.6;
IR (NaCl) 3347, 2941, 2598, 1600, 1589, 1493, 1447, 1283, 1189 cmꢁ1
;
HRMS (ESI) m/z Calcd for C9H17B10O [MꢁH]þ: 249.2282. Found:
249.2289.
4.5.3. 1-Ethyl-7-(3-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane 7c
4.4.1. 1-Methyl-7-(4-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane 5b
Compound 7c was synthesized from 6a (500.6 mg, 2 mmol) and
ethyl iodide (0.24 mL, 3 mmol) using the procedure described for 5c
to give 7c (290.7 mg, 55%) as a colorless oil: 1H- NMR (500 MHz;
Compound 5b was synthesized using methyl iodide (0.19 mL,
3 mmol) in 74% yield (370.2 mg) as a colorless solid: mp.
CDCl3):
d
7.10 (t, J ¼ 8.0 Hz, 1H), 7.00 (d, J ¼ 8.0 Hz, 1H), 6.91 (t,
127e128 ꢀC (CH2Cl2/Hexane); 1H NMR (500 MHz; CDCl3):
d
7.28 (d,
J ¼ 2.0 Hz, 1H), 6.75 (dd, J ¼ 8.0 Hz, 2.0 Hz, 1H), 5.30 (s, 1H), 2.04 (q,
J ¼ 8.5 Hz, 2H), 6.68 (d, J ¼ 8.5 Hz, 2H), 5.12 (s, 1H), 1.76 (s, 3H); 13
C
J ¼ 7.5 Hz, 2H), 1.00 (t, J ¼ 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3):
NMR (125 MHz, CDCl3):
d
155.7, 129.2, 128.0, 115.0, 78.4, 70.6, 24.6;
d 155.1, 137.0, 129.5, 120.5, 115.6, 115.2, 77.1, 30.4, 14.2; IR (NaCl)
IR (NaCl) 3302, 2976, 2596, 1518, 1180 cmꢁ1; HRMS (ESI) m/z Calcd
for C9H17B10O [MꢁH]þ: 249.2282. Found: 249.2278.
3334, 2978, 2938, 2600,1589,1447, 1283,1186 cmꢁ1; HRMS (ESI) m/
z Calcd for C10H19B10O [MꢁH]þ: 263.2439. Found: 263.2441.
4.4.2. 1-Ethyl-7-(4-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane 5c
4.5.4. 1-Isobutyl-7-(3-Hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane 7d
Compound 5c was synthesized using ethyl iodide (0.24 mL,
Compound 7d was synthesized from 6a (500.6 mg, 2 mmol) and
isobutyl iodide (0.35 mL, 3 mmol) using the procedure described
for 5d to give 7d (419.0 mg, 72%) as a colorless oil: 1H- NMR
3 mmol) in 40% yield (214.8 mg) as a colorless solid: mp. 94e95 ꢀC
1
(CH2Cl2/Hexane); H NMR (500 MHz; CDCl3):
d
7.28 (d, J ¼ 9.0 Hz,
2H), 6.68 (d, J ¼ 9.0 Hz, 2H), 5.04 (s, 1H), 2.05 (q, J ¼ 7.5 Hz, 2H), 1.00
(500 MHz; CDCl3):
d
7.10 (t, J ¼ 8.0 Hz, 1H), 7.00 (d, J ¼ 8.0 Hz, 1H),
(t, J ¼ 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d
155.7, 129.2, 128.1,
6.91 (t, J ¼ 2.0 Hz, 1H), 6.75 (dd, J ¼ 8.0 Hz, 2.0 Hz, 1H), 5.53 (s, 1H),
115.0, 77.5, 30.5, 14.2; IR (NaCl) 3277, 2599, 1516, 1244 cmꢁ1; HRMS
1.89 (d, J ¼ 6.0 Hz, 2H),1.66e1.73 (m,1H), 0.91 (d, J ¼ 7.0 Hz, 6H); 13
C
(ESI) m/z Calcd for
C
10H19B10
O
[MꢁH]þ: 263.2439. Found:
NMR (125 MHz, CDCl3): d 155.1, 137.0, 129.5, 120.5, 115.6, 115.2, 77.1,
263.2434.
30.4, 14.2; IR (NaCl) 3335, 2959, 2934, 2602, 1600, 1589, 1447,
1189 cmꢁ1
291.2753. Found: 291.2759.
;
HRMS (ESI) m/z Calcd for C12H23B10
O
[MꢁH]þ:
4.4.3. 1-Isobutyl-7-(4-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane 5d
Compound 5d was synthesized using isobutyl iodide (0.35 mL,
4.6. General procedure for synthesis of 2aeh
3 mmol) in 70% yield (410.0 mg) as a colorless solid: Mp. 97e98 ꢀC
(CH2Cl2/Hexane); 1H -NMR (500 MHz; CDCl3):
d
7.27 (d, J ¼ 9.0 Hz,
To a dry THF solution (10 mL) of carboranylphenols 5aed or
7aed (0.5 mmol) was added 60% NaH (30 mg, 0.75 mmol) at 0 ꢀC
under N2, and the mixture was stirred for 30 min at room tem-
perature. Then bromoacetanilide 11 (334.5 mg, 0.75 mmol) was
added to the reaction media and let stirring continue for 2 h. The
reaction was quenched by saturated NH4Cl aqueous solution and
the mixture was extracted three times with ethyl acetate. The
combined organic layer was washed with saturated aqueous NaCl
solution, dried over anhydrous MgSO4, and concentrated in vacuo.
The resulting crude product was subsequently dissolved in MeOH/
THF (6mL/2 mL) solution and 50% Pd/C was added. The mixture was
2H), 6.67 (d, J ¼ 9.0 Hz, 2H), 5.40 (s, 1H), 1.90 (d, J ¼ 6.0 Hz, 2H),
1.66e1.74 (m, 1H), 0.91 (d, J ¼ 6.5 Hz, 6H); 13C NMR (125 MHz,
CDCl3):
d 155.5, 129.2, 128.2, 115.0, 77.6, 75.9, 45.9, 32.0, 23.3; IR
(NaCl) 3310, 2959, 2936, 2594, 1516, 1232, 841 cmꢁ1; HRMS (ESI) m/
z Calcd for C12H23B10O [MꢁH]þ: 291.2753. Found: 291.2748.
4.5. Synthesis of 1-(3-methoxyphenyl)-1,7-dicarba-closo-
dodecaborane 6a
Compound 6a was synthesized from meta-carborane 3 (4.78 g,
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G. Li et al. / Journal of Organometallic Chemistry xxx (2015) 1e7
stirred overnight at room temperature under hydrogen atmo-
sphere. The palladium catalysts were removed by Celite pad
filtration and solvent was removed in vacuo, resulting residue was
purified by silica gel column chromatography with hexane/ethyl
acetate (2:1) give to 2aeh as a colorless solid.
15% yield (69.6 mg) as a colorless solid: Mp. 259e260 ꢀC (CH2Cl2/
Hexane); 1H- NMR (500 MHz; CDCl3):
9.38 (s, 1H), 8.50 (s, 1H),
d
7.63 (dd, J ¼ 8.0 Hz, 1.0 Hz, 1H), 7.45 (d, J ¼ 1.5 Hz, 1H), 7.26 (t,
J ¼ 8.0 Hz, 1H), 7.17 (d, J ¼ 8.0 Hz, 1H), 7.12 (t, J ¼ 2.0 Hz, 1H), 7.06 (d,
J ¼ 8.0 Hz, 1H), 6.91 (dd, J ¼ 8.0 Hz, 2.0 Hz, 1H), 4.66 (s, 2H), 3.10 (s,
1H), 1.35 (s, 12H); 13C NMR (125 MHz, CDCl3):
d 167.6, 156.3, 151.9,
4.6.1. 3-[(4-(1,7-Dicarba-closo-carboranyl)phenoxyacetylamino)-
4-hydroxybenzene boronic acid pinacol ester 2a
137.2, 134.7, 130.0, 129.0, 124.0, 122.3, 120.0, 115.6, 114.2, 83.9, 77.5,
67.0, 55.1, 24.8; IR (NaCl) 3395, 3266, 2978, 2925, 2602, 1355 cmꢁ1
;
Compound 2a was synthesized using 5a (118.2 mg, 0.5 mmol) in
HRMS (ESI) m/z Calcd for C22H34B11NO5Na [MþNa]þ: 534.3438.
15% yield (56.4 mg) as a colorless solid: mp. 268e269 ꢀC (CH2Cl2/
Found: 534.3435.
Hexane); 1H NMR (500 MHz; CDCl3):
d 9.36 (s, 1H), 8.46 (s, 1H), 7.62
(d, J ¼ 8.0 Hz, 1H), 7.42 (d, J ¼ 8.0 Hz, 2H), 7.41 (s, 1H), 7.05 (d,
4.6.6. 3-[(3-(1-Methyl-1,7-dicarba-closo-carboranyl)
phenoxyacetylamino)-4-hydroxybenzene boronic acid pinacol ester
2f
J ¼ 8.0 Hz, 1H), 6.88 (d, J ¼ 8.0 Hz, 2H), 4.65 (s, 2H), 3.08 (s, 1H), 1.34
(s, 12H); 13C NMR (125 MHz, CDCl3):
d 167.6, 156.9, 151.8, 134.7,
129.8, 129.6, 129.0, 124.0, 120.0, 114.5, 83.9, 77.6, 67.0, 55.1, 24.8; IR
Compound 2f was synthesized using 7b (125.2 mg, 0.5 mmol) in
(NaCl) 3372, 3056, 2979, 2923, 2604, 1664, 1562, 1509, 1353 cmꢁ1
;
27% yield (61.2 mg) as a colorless solid: Mp. 233e234 ꢀC (CH2Cl2/
HRMS (ESI) m/z Calcd for C22H34B11NO5Na [MþNa]þ: 534.3438.
Hexane); 1H NMR (500 MHz; CDCl3):
d 9.39 (s, 1H), 8.51 (s, 1H), 7.63
Found: 534.3439.
(dd, J ¼ 8.0 Hz, 1.5 Hz, 1H), 7.46 (d, J ¼ 1.5 Hz, 1H), 7.25 (t, J ¼ 8.0 Hz,
1H), 7.15 (d, J ¼ 8.0 Hz, 1H), 7.12 (t, J ¼ 2.0 Hz, 1H), 7.06 (d, J ¼ 8.5 Hz,
1H), 6.90 (dd, J ¼ 8.0 Hz, 2.0 Hz, 1H), 4.66 (s, 2H), 1.80 (s, 3H), 1.35 (s,
4.6.2. 3-[(4-(1-Methyl-1,7-dicarba-closo-carboranyl)
phenoxyacetylamino)-4-hydroxybenzene boronic acid pinacol ester
2b
12H); 13C NMR (125 MHz, CDCl3):
d 167.6, 156.3, 151.9, 137.4, 134.8,
129.9, 129.0, 124.0, 122.3, 120.0, 115.6, 114.1, 83.9, 77.8, 70.7, 67.0,
Compound 2b was synthesized using 5b (125.2 mg, 0.5 mmol) in
24.8, 24.7; IR (NaCl) 3382, 3092, 2977, 2598, 1659, 1555, 1354 cmꢁ1
;
25% yield (56.6 mg) as a colorless solid: Mp. 252e253 ꢀC (CH2Cl2/
HRMS (ESI) m/z Calcd for C23H36B11NO5Na [MþNa]þ: 548.3595.
Hexane); 1H NMR (500 MHz; CDCl3):
d
9.35 (s, 1H), 8.48 (s, 1H), 7.61
Found: 548.3594.
(dd, J ¼ 8.0 Hz, 1.5 Hz, 1H), 7.44 (d, J ¼ 1.0 Hz, 1H), 7.41 (d, J ¼ 9.0 Hz,
2H), 7.04 (d, J ¼ 9.0 Hz, 1H), 6.87 (d, J ¼ 9.0 Hz, 2H), 4.64 (s, 2H), 1.78
4.6.7. 3-[(3-(1-Ethyl-1,7-dicarba-closo-carboranyl)
phenoxyacetylamino)-4-hydroxybenzene boronic acid pinacol ester
2g
(s, 3H), 1.34 (s, 12H); 13C NMR (125 MHz, CDCl3):
d 167.6, 156.8,
151.8, 134.7, 129.9, 129.6, 129.0, 124.0, 119.8, 114.5, 83.9, 77.9, 70.6,
67.0, 24.8, 24.7; IR (NaCl) 3384, 3254, 2978, 2925, 2597, 1510,
1358 cmꢁ1; HRMS (ESI) m/z Calcd for C23H36B11NO5Na [MþNa]þ:
548.3595. Found: 548.3592.
Compound 2g was synthesized using 7c (132.2 mg, 0.5 mmol) in
22% yield (52.7 mg) as a colorless solid: Mp. 192e193 ꢀC (CH2Cl2/
Hexane); 1H NMR (500 MHz; CDCl3):
d 9.38 (s, 1H), 8.52 (s, 1H), 7.62
(dd, J ¼ 8.0 Hz,1.5 Hz,1H), 7.47 (s,1H), 7.25 (t, J ¼ 8.0 Hz,1H), 7.15 (d,
J ¼ 8.0 Hz, 1H), 7.12 (t, J ¼ 2.0 Hz, 1H), 7.05 (d, J ¼ 8.5 Hz, 1H), 6.90
(dd, J ¼ 8.0 Hz, 2.0 Hz, 1H), 4.65 (s, 2H), 2.08 (q, J ¼ 7.5 Hz, 2H), 1.35
4.6.3. 3-[(4-(1-Ethyl-1,7-dicarba-closo-carboranyl)
phenoxyacetylamino)-4-hydroxybenzene boronic acid pinacol ester
2c
(s, 12H), 1.03 (t, J ¼ 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 167.6,
Compound 2c was synthesized using 5c (132.2 mg, 0.5 mmol) in
156.3,151.9,137.4,134.8,129.9,129.0,124.0,122.3,120.0,115.6,114.1,
83.9, 77.8, 70.7, 67.0, 24.8, 24.7; IR (NaCl) 3391, 3260, 2978, 2919,
2599, 1543 cmꢁ1; HRMS (ESI) m/z Calcd for C24H38B11NO5Na
[MþNa]þ: 562.3752. Found: 562.3753.
26% yield (60.3 mg) as a colorless solid: Mp. 225e226 ꢀC (CH2Cl2/
Hexane); 1H NMR (500 MHz; CDCl3):
d 9.36 (s, 1H), 8.47 (s, 1H), 7.62
(dd, J ¼ 8.0 Hz, 1.0 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J ¼ 9.0 Hz, 2H), 7.05
(d, J ¼ 8.0 Hz, 1H), 6.87 (d, J ¼ 9.0 Hz, 2H), 4.64 (s, 2H), 2.07 (q,
J ¼ 7.5 Hz, 2H), 1.34 (s, 12H), 1.02 (t, J ¼ 7.5 Hz, 3H); 13C NMR
4.6.8. 3-[(3-(1-Isobutyl-1,7-dicarba-closo-carboranyl)
phenoxyacetylamino)-4-hydroxybenzene boronic acid pinacol ester
2h
(125 MHz, CDCl3):
d 167.6, 156.8, 151.8, 134.7, 130.0, 129.5, 129.0,
124.0, 119.9, 114.5, 83.9, 67.0, 30.5, 24.8, 14.3; IR (NaCl) 3386, 2978,
2600, 1607, 1510, 1354 cmꢁ1
C
;
HRMS (ESI) m/z Calcd for
Compound 2h was synthesized using 7d (146.2 mg, 0.5 mmol)
24H38B11NO5Na [MþNa]þ: 562.3752. Found: 562.3760.
in 23% yield (56.4 mg) as a colorless solid: Mp. 170e171 ꢀC (CH2Cl2/
Hexane); 1H- NMR (500 MHz; CDCl3):
d 9.38 (s, 1H), 8.52 (s, 1H),
4.6.4. 3-[(4-(1-Isobutyl-1,7-dicarba-closo-carboranyl)
phenoxyacetylamino)-4-hydroxybenzene boronic acid pinacol ester
2d
7.62 (dd, J ¼ 8.0 Hz, 1.5 Hz, 1H), 7.46 (d, J ¼ 1.0 Hz, 1H), 7.25 (t,
J ¼ 8.5 Hz, 1H), 7.15 (d, J ¼ 6.0 Hz, 1H), 7.11 (t, J ¼ 2.0 Hz, 1H), 7.05 (d,
J ¼ 8.5 Hz, 1H), 6.90 (dd, J ¼ 8.0 Hz, 2.0 Hz, 1H), 4.65 (s, 2H), 1.93 (d,
J ¼ 6.0 Hz, 2H), 1.69e1.76 (m, 1H), 0.93 (d, J ¼ 6.5 Hz, 6H). 13C NMR
Compound 2d was synthesized using 5d (146.2 mg, 0.5 mmol)
in 21% yield (51.8 mg) as a colorless solid: Mp. 190e191 ꢀC (CH2Cl2/
(125 MHz, CDCl3):
d 167.6, 156.3, 151.9, 137.5, 134.7, 129.8, 129.0,
Hexane); 1H NMR (500 MHz; CDCl3):
d
9.35 (s, 1H), 8.48 (s, 1H), 7.61
124.0, 122.3, 119.9, 115.6, 114.1, 83.9, 76.1, 67.0,46.0, 28.7, 24.9, 23.4;
IR (NaCl) 3387, 3274, 2978, 2927, 2602, 1434, 1355 cmꢁ1; HRMS
(ESI) m/z Calcd for C26H42B11NO5Na [MþNa]þ: 590.4066. Found:
590.4066.
(dd, J ¼ 8.0 Hz, 1.5 Hz, 1H), 7.44 (d, J ¼ 1.5 Hz, 1H), 7.41 (d, J ¼ 9.0 Hz,
2H), 7.04 (d, J ¼ 8.0 Hz, 1H), 6.86 (d, J ¼ 9.0 Hz, 2H), 4.63 (s, 2H), 1.91
(d, J ¼ 6.0 Hz, 2H), 1.68e1.75 (m, 1H), 1.34 (s, 12H), 0.93 (d,
J ¼ 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3):
d 167.6, 156.7, 151.7,
134.6, 130.0, 129.5, 129.0, 124.0, 119.9, 114.5, 83.9, 77.1, 67.0,
46.0,28.7, 24.8, 23.4; IR (NaCl) 3384, 3273, 2978, 2929, 2601, 1510,
1355 cmꢁ1; HRMS (ESI) m/z Calcd for C26H42B11NO5Na [MþNa]þ:
590.4066. Found: 590.4066.
4.7. Cell culture
Cells were cultured under 5% CO2 at 37 ꢀC in RPMI 1640 medium
(Wako pure Pure Chemicals, Osaka, Japan) supplemented with 10%
fetal bovine serum (FBS, HyClone, Logan, UT), 100 U/ml mL peni-
4.6.5. 3-[(3-(1,7-Dicarba-closo-carboranyl)phenoxyacetylamino)-
4-hydroxybenzene boronic acid pinacol ester 2e
cillin and 100 mg/ml mL streptomycin (Invitrogen, Carlsbad, CA). For
subsequent experiments, the cells were seeded at a density of
Compound 2e was synthesized using 7a (118.2 mg, 0.5 mmol) in
2.5 ꢂ 105 cells/ml/well in a 12-well TC plate (Greiner Japan, Tokyo,
Please cite this article in press as: G. Li, et al., Journal of Organometallic Chemistry (2015), http://dx.doi.org/10.1016/j.jorganchem.2015.05.029

G. Li et al. / Journal of Organometallic Chemistry xxx (2015) 1e7
7
Japan), and incubated at 37 ꢀC for 12 h. Hypoxic condition was
achieved by replacing cells to 1% O2, 95% N2 and 5% CO2 in a mul-
tigas incubator (Astec, Fukuoka, Japan).
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4.8. HIF-1 transcriptional activity on HeLa cell-based HRE and CMV
dual luciferase assay
HeLa cells expressing HRE-dependent firefly luciferase reporter
construct (HRE-Luc) and constitutively expressing CMV-driven
Renilla luciferase reporter with SureFECT Transfection Reagent
were established with Cignal™ Lenti Reporter (SABiosciences,
Frederick, MD) according to the manufacturer's instructions. The
consensus sequence of HRE was 50-TACGTGCT-30 from the eryth-
ropoietin gene. Cells stably expressing the HRE-reporter gene were
selected with puromycin. The cells were incubated for 12 h with or
without drugs under the hypoxic condition (1% oxygen). After
removal of the supernatant, the luciferase assay was performed
using a Luciferase Assay System (Promega, Madison, WI) according
to the manufacturer's instructions.
[17] S.M. Wilkinson, H. Gunosewoyo, M.L. Barron, A. Boucher, M. McDonnell,
P. Turner, D.E. Morrison, M.R. Bennett, I.S. McGregor, L.M. Rendina, M. Kassiou,
The first CNS-active carborane: A novel P2X7 receptor antagonist with anti-
depressant activity, ACS Chem. Neurosci. 5 (2014) 335e339.
[18] H. Nakamura, L. Tasaki, D. Kanoh, S. Sato, H.S. Ban, Diaryl-substituted ortho-
carboranes as
a new class of hypoxia inducible factor-1alpha inhibitors,
Dalton Trans. 43 (2014) 4941e4944.
[19] H. Minegishi, T. Matsukawa, H. Nakamura, Synthesis and biological evaluation
of diaryl-substituted carboranes as inhibitors of hypoxia inducible factor
(HIF)-1 transcriptional activity, ChemMedChem 8 (2013) 265e271.
[20] K. Shimizu, M. Maruyama, Y. Yasui, H. Minegishi, H.S. Ban, H. Nakamura,
Boron-containing phenoxyacetanilide derivatives as hypoxia-inducible factor
(HIF)-1alpha inhibitors, Bioorg. Med. Chem. Lett. 20 (2010) 1453e1456.
[21] H.S. Ban, K. Shimizu, H. Minegishi, H. Nakamura, Identification of HSP60 as a
primary target of o-carboranylphenoxyacetanilide, an HIF-1alpha inhibitor,
J. Am. Chem. Soc. 132 (2010) 11870e11871.
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scien-
tific Research on Innovative Areas “Chemical Biology of Natural
Products” (26102721) from The Ministry of Education, Culture,
Sports, Science and Technology, Japan.
[22] H. Nakamura, Y. Yasui, M. Maruyama, H. Minegishi, H.S. Ban, S. Sato, Devel-
opment of hypoxia-inducible factor (HIF)-1alpha inhibitors: effect of ortho-
carborane substituents on HIF transcriptional activity under hypoxia, Bioorg.
Med. Chem. Lett. 23 (2013) 806e810.
[23] K. Lee, J.H. Lee, S.K. Boovanahalli, Y. Jin, M. Lee, X. Jin, J.H. Kim, Y.-S. Hong,
J.J. Lee, (Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-
inducible factor-1 inhibitors, J. Med. Chem. 50 (2007) 1675e1684.
[24] M.-S. Won, N. Im, S. Park, S.K. Boovanahalli, Y. Jin, X. Jin, K.-S. Chung, M. Kang,
K. Lee, S.-K. Park, H.M. Kim, B.M. Kwon, J.J. Lee, K. Lee, A novel benzimidazole
analogue inhibits the hypoxia-inducible factor (HIF)-1 pathway, Biochem.
Biophys. Res. Commun. 385 (2009) 16e21.
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