Bis(pentafluorosulfanyl)phenyl azide as an expeditious tool for click chemistry toward antitumor pharmaceuticals

Article abstract of DOI:10.1002/cmdc.201400059

The inclusion of fluorine in pharmaceutical agents is a well- established means of improving their druglike properties. Different substituents have been used to introduce fluorine, including trifluoromethyl and trifluoromethylthio groups; however, the pentafluorosulfanyl remains relatively underutilized although it is considered to be a super trifluoromethyl group. Here, a series of pentafluorosulfanyl-containing 1,4-disubstituted-1,2,3-triazoles were synthesized by click reaction from alkynes and 3,5-bis(pentafluorosulfanyl) phenyl azide in excellent yields. Their biological activities were evaluated against human leukemic monocyte lymphoma U937 cells. In particular, 1-(3,5-bis(pentafluorosulfanyl)phenyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole exhibited potent efficacy in cell viability assays at a concentration of 60 μM and was shown to activate caspase-3 activity, indicating induction of apoptosis. An analogous fluorenol-substituted triazole also exhibited promising cytotoxic effects against U937 cells, with an IC₅₀ value of 6.29 μM. Given these preliminary results, these pentafluorosulfanyl-containing triazoles represent useful building blocks for the further development of novel antitumor agents. Fluoro power! (5-Azido-1,3-phenylene)bis(pentafluoro- λ⁶-sulfane) is introduced as a powerful tool for the synthesis of pentafluorosulfanyl-containing arenes using click chemistry. A series of 13 pentafluorosulfanylarene-triazoles was synthesized and evaluated against a human leukemic monocyte lymphoma cell line. The results indicate their potential as building blocks for the further development of pentafluorosulfanyl-containing antitumor agents.

Full text of DOI:10.1002/cmdc.201400059

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DOI: 10.1002/cmdc.201400059
Bis(pentafluorosulfanyl)phenyl Azide as an Expeditious
Tool for Click Chemistry toward Antitumor
Pharmaceuticals
Yu-Dong Yang,[a] Etsuko Tokunaga,[a] Hidehiko Akiyama,[b] Norimichi Saito,[c] and
Norio Shibata*[a]
The inclusion of fluorine in pharmaceutical agents is a well-
established means of improving their druglike properties. Dif-
ferent substituents have been used to introduce fluorine, in-
cluding trifluoromethyl and trifluoromethylthio groups; howev-
er, the pentafluorosulfanyl remains relatively underutilized al-
though it is considered to be a “super” trifluoromethyl group.
Here, a series of pentafluorosulfanyl-containing 1,4-disubstitut-
ed-1,2,3-triazoles were synthesized by click reaction from al-
kynes and 3,5-bis(pentafluorosulfanyl)phenyl azide in excellent
yields. Their biological activities were evaluated against human
leukemic monocyte lymphoma U937 cells. In particular, 1-(3,5-
bis(pentafluorosulfanyl)phenyl)-4-(4-fluorophenyl)-1H-1,2,3-tri-
azole exhibited potent efficacy in cell viability assays at a con-
centration of 60 mm and was shown to activate caspase-3 activ-
ity, indicating induction of apoptosis. An analogous fluorenol-
substituted triazole also exhibited promising cytotoxic effects
against U937 cells, with an IC50 value of 6.29 mm. Given these
preliminary results, these pentafluorosulfanyl-containing tria-
zoles represent useful building blocks for the further develop-
ment of novel antitumor agents.
into organic compounds, especially (hetero)aromatics, which
are highly important moieties in pharmaceuticals and agro-
chemicals, has been widely researched.[3,4] On the other hand,
the pentafluorosulfanyl (SF5) group has been less extensively
investigated, despite its attractive properties.
The SF5 moiety is thermally, hydrolytically and chemically
stable and is considered to be
a “super-trifluoromethyl
group”.[1a,5] In fact, the SF5 group is not just a larger version of
the trifluoromethyl group, it shows higher lipophilicity, which
in turn may enhance the ability of the parent compound to
pass through lipid membranes and improve the vivo absorp-
tion rate (pp =1.23 for SF5; pp =0.88 for CF3). In addition, the
geometries of these two functional groups are completely dif-
ferent—the SF5 group presents a pyramidal electron density,
while the CF3 group displays an inverted cone of density—and
as such, the former may exhibit distinct biological proper-
ties.[1a,5e] An increasing number of studies have reported that
improved bioactivity was obtained when an SF5 group was in-
corporated, such as the SF5 analogues of mefloquine and fipro-
nil.[5j,6] Consequently, it remains an important research goal to
develop new approaches to introduce the SF5 group into or-
ganic molecules, and furthermore, to explore the potential of
the SF5 group to enhance the biological properties of these
molecules.
It is now well known that the introduction of a fluorine atom
or fluorinated functional group into organic compounds is
highly likely to enhance the metabolic stability, lipophilicity
and further improve the bioactivity of the parent molecules.[1]
Thus, fluorine chemistry is of interest to pharmaceutical and
agrochemical industries, and the development of novel meth-
ods to introduce fluorine is quite attractive in current organic
chemistry research.[2] About 30–40% of agrochemicals and
20% of pharmaceuticals on the market are estimated to con-
tain fluorine in the structures. In recent years, the introduction
of a trifluoromethyl (CF3) or a trifluoromethylthio (CF3S) group
There are only limited direct methods to incorporate the SF5
group into organic molecules. Therefore, we are interested in
the practical use of pentafluorosulfanyl-aromatics as versatile
building blocks in synthesis and the development of new bio-
logically active compounds.[5i,6c,7] Moreover, a large number of
1,3-dichloro-aromatics are frequently encountered in parts of
structures of biologically active compounds, in particular, agro-
chemicals, the 1,3-bis(pentafluorosulfanyl)aromatics are highly
likely to have unique biological activity due to the structural
similarity. Recently, we reported the preparation of (3,5-bis(-
pentafluoro-l6-sulfanyl)phenyl)boronic acid (1) and its utility as
an organocatalyst.[5h] A boronic acid should also be attractive
as a pentafluorosulfanyl-aromatic building block under the
Suzuki–Miyaura coupling reaction.[8] As a part of our research
program toward the design and synthesis of biologically active
organofluorine compounds, we were interested in previously
unknown (5-azido-1,3-phenylene)bis(pentafluoro-l6-sulfane) (2)
as a new tool for click chemistry (Figure 1).
[a] Y.-D. Yang, E. Tokunaga, Prof. N. Shibata
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
[b] Prof. H. Akiyama
Department of Clinical Hematology, Faculty of Medical Technology
Fujita Health University School of Health Sciences
Toyoake, Aichi 470-1192 (Japan)
[c] N. Saito
Click chemistry,[9] named by Sharpless in 2001,[9c] is a Huis-
gen-type 1,3-dipolar cycloaddition reaction between azides
and alkynes in the presence of copper catalysts to provide
1,2,3-triazoles. Several modifications of click chemistry have
Pharmaceutical Division, Ube Industries, Ltd
Seavans North Bldg, 1-2-1 Shibaura, Minato-ku, Tokyo 105-8449 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201400059.
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Table 1. CuI-catalyzed synthesis of 1,4-disubtituted 1,2,3-triazoles (3) from al-
kynes 6 (1.0 equiv) and 3,5-bis(pentafluorosulfanyl)phenyl azide 2 (1.05 equiv).
Figure 1. Versatile pentafluorosulfanylarene-containing building
blocks. Aryl boronic acid 1 (previous work) for Suzuki–Miyaura cou-
pling reaction and aryl azide 2 for click chemistry (this work).
Compd
t
Yield
R
Compd t
Yield
R
3a
20 min Quant.
20 min Quant.
20 min 97%
3h
3i
20 min 95%
20 min 98%
been disclosed, and all the reactions have become power-
ful tools for drug discovery due to the wide scope of sub-
strates, and high rate and yield of the reaction. Further-
more, the resulting 1,2,3-triazoles are important pharma-
cophores that are metabolically stable and are capable of
hydrogen bonding, which would both promote binding
to biomolecular targets and enhance solubility.[10] Further-
more, although 1,2,3-triazole-containing compounds are
not found in nature, they can be synthesized simply by
copper(I)-catalyzed cycloaddition of alkynes and azides.[11]
Given the above rationale, it is reasonable to surmise
that the bioactivity of 1,2,3-triazoles could be enhanced
and that more effective pharmaceuticals or pharmaco-
phores might be developed through incorporation of SF5
groups in the designed compounds. In particular, these
3b
3c
3d
3e
3j
3k
3l
20 min Quant.
20 min Quant.
20 min 94%
4 h
8 h
98%
93%
SF5-substituted
1,2,3-triazole-containing
compounds
3 f
8 h
1 h
92%
83%
3m
4 h
98%
should exhibit improved cell membrane permeability. In-
terestingly, these compounds are also attractive due to
their potential use as energetic materials.[12] Herein, we
report the preparation of (5-azido-1,3-phenylene)bis(pen-
tafluoro-l6-sulfane) (2) and its utility for the synthesis of
1,4-disubstituted 1,2,3-triazoles 3 containing SF5-arenes.
The effects of compounds 3 on cell viability (annexin V
and propidium iodide) and proliferation (MTT assay), and
their ability to induce apoptosis (caspase-3 activity) were
evaluated.
3g
[a] Reagents and conditions: Sodium ascorbate (6 mol%), CuSO4·H2O (3 mol%),
PhCO2H (20 mol%), tBuOH/H2O (1:2), RT. Reaction times and yields are given in
the table body.
reactivity.[11a] Both aromatic and aliphatic alkynes were tolerat-
ed under the same condition, and all the products were afford-
ed in excellent yields albeit a longer reaction time was needed
when electron-withdrawing substituents were attached to the
benzene ring.[15]
Novel 3,5-bis(pentafluorosulfanyl)phenyl azide 2 was synthe-
sized from aryl bromide 4 via aniline derivative 5 in two steps
(Scheme 1). First, copper(I)-catalyzed coupling of aryl bromide
4 with ammonia in the presence of l-hydroxy proline and po-
tassium carbonate in dimethyl sulfoxide with heating furnished
5 in 79%.[13] The reaction of aryl amine 5 with tert-butyl nitrite,
followed by the addition of trimethylsilyl-azide in acetonitrile,
provided desired aryl azide 2 in 89%.[14]
With these pentafluorosulfanyl-containing 1,4-disubstituted-
1,2,3-triazoles in hand, their bioactivity was next investigated.
The annexin V–fluorescein isothiocyanate (FITC) kit is
a common tool used to detect the ability of compounds to
induce cell death. Triazoles 3 were evaluated for their ability to
induce cell death in human leukemic monocyte lymphoma
U937 cells. Arabinofuranosyl cytidine (Ara-C), a known chemo-
therapy agent used in the treatment of acute leukemia, was
evaluated in parallel for comparison. Ara-C exhibited 61.9% ef-
ficiency when evaluated at a concentration of 40 mm (Figure 2).
However, phenyl-substituted triazole 3a only exhibited very
poor activities at a concentration of 60 mm. The addition of
a methyl group on the phenyl substituent slightly increased
the efficiency of the compounds (3b, 3c and 3d), and the po-
sition of the methyl showed a significant influence on the ac-
tivities. 2’-Methyl phenyl triazole 3d exhibited a 16.6% efficien-
cy. Substitution of the 2’-methyl to a 2’-trifluoromethyl group
The copper(I)-catalyzed cycloaddition of alkynes 6 to 2 was
next investigated (Table 1). Despite the uniqueness of the two
SF5 moieties on the aromatic group, azide 2 showed very nice
Scheme 1. Synthesis of 2. Reagents and conditions: a) CuI (0.3 equiv), l-hy-
droxy proline (0.6 equiv), K2CO3 (4.4 equiv), NH3·H2O, DMSO, 608C, 90 h,
79%; b) tBuONO (1.2 equiv), TMSN3 (1.5 equiv), CH3CN, 2 h, 89%.
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Figure 3. The effect of triazole concentration on human leukemic monocyte
lymphoma cell viability. Briefly, U937 cells (2ꢁ105 cells per mL) were incubat-
ed with test compound at 60 mm (&) or 100 mm (&) for 24 h.
Figure 2. Pentafluorosulfanyl-containing 1,4-disubstituted-1,2,3-triazoles
induced cell death in human leukemic monocyte lymphoma cells. Briefly,
U937 cells (2ꢁ105 cells per mL) were incubated with test compound at
60 mm for 24 h. For comparison, arabinofuranosyl cytidine (Ara-C) was evalu-
ated at 40 mm in parallel. Cells were stained with annexin V and propidium
iodide (PI).
Table 2. Cytotoxicity of selected 1,4-disubstituted 1,2,3-triazoles against
(3e) lead to very disappointing result, while 4’-fluorophenyl tri-
azole 3 f exhibited an efficiency of 30.9% to inhibit cell growth
at a concentration of 6ꢁ10À5 m. Triazoles with aliphatic sub-
stituents (3g–j) instead of aromatic rings were less potent.
However, fluorenol-substituted triazole 3k exhibited compara-
tively good activity (16.7%). Heteroaromatic rings such as 3’-
thienyl and 2’-pyridyl were also tested and found to be less
effective.
a human leukemic monocyte lymphoma cell line (U937).[a]
Compd
IC50 [mm]
3d
3 f
3k
Ara-C
137Æ7
145Æ3
6.29Æ0.83
0.163Æ0.021
[a] IC50 values were determined using an MTT assay (for details, see Sup-
porting Information); data represent the mean Æstandard deviation of
three independent experiments.
We then studied the bioactivity of these triazoles at a higher
concentration (Figure 3). Triazoles 3d, 3 f and 3k were found
to exhibit an antiproliferative effect in a dose-dependent
manner. The 4’-fluorophenyl-substituted triazole (3 f) gave the
best result of 45.8% when evaluated at a concentration of
100 mm.
The patterns of apoptosis of some triazoles are shown in
Figure 4. All of the evaluated triazoles clearly induced apopto-
sis, represented by a shift of cells from the bottom left quad-
rant (viable cells) to the bottom right quadrant (early apoptotic
cells) and the top right quadrant (late apoptotic or necrotic
cells) after incubation for 24 hours, although the level of apop-
tosis induced by Ara-C was greater.
(Figure 5). The results showed that triazole 3 f only slightly en-
hanced the activity of caspase-3, however, 2’-methyl-phenyl-
substituted triazole 3d increased the activity by 1.68-fold com-
pared with the untreated control. Finally, triazole 3k induced
3.40-times more activity than the untreated control, although
it was still less efficient than Ara-C (4.75-fold activation at
40 mm).
In conclusion, a series of pentafluorosulfanyl-containing 1,4-
disubstituted 1,2,3-triazoles were prepared via a click reaction
using alkynes and 3,5-bis(pentafluorosulfanyl)phenyl azide.
Their effects on cell viability, proliferation and the induction of
apoptosis were evaluated. Some of the triazoles exhibited
good activity against the human leukemic monocyte lympho-
ma cell line used for their evaluation, and compound 3k in
particular showed good results in all of the assays. These tria-
zoles are potential building blocks for the development of
novel pentafluorosulfanyl-containing antitumor pharmaceuti-
The IC50 values of triazoles 3d, 3 f and 3k are shown in
Table 2. Although compounds 3d and 3k exhibited very weak
potency compared with Ara-C, hydroxy-containing triazoles 3k
gave an IC50 value of 6.29 mm, which is 1/39 times more potent
than Ara-C.
Caspase-3 has been identified as a key executioner caspase
in the apoptosis pathway, and it’s activation leads to pro-
grammed cell death.[16] As such, triazoles 3d, 3 f and 3k were
evaluated for their ability to activate caspase-3 activity
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Figure 4. Flow cytometric assay results. U937 cells were analyzed after 24 h of incubation with test compound at 100 mm. Cells were stained with annexin V
and propidium iodide (PI).
cals, and investigations to this end are underway in our labora-
tory.
Experimental Section
Details of the synthetic protocols, characterization data for novel
compounds, and the biological methods used to evaluate these
compounds are provided in the Supporting Information.
Acknowledgements
This study was financially supported in part by the Platform for
Drug Discovery, Informatics, and Structural Life Science, Grants-
in-Aid for Scientific Research on Innovative Areas (“Advanced Mo-
lecular Transformations by Organocatalysts”; 24105513) and Sci-
entific Research (B) (25288045) from the Japanese Ministry of
Education, Culture, Sports, Science and Technology (MEXT), and
ACT-C from the Japan Science and Technology Agency (JST), Ex-
ploratory Research (25670055).
Figure 5. Capase-3 activity. The efficiencies were based on the untreated
result. U937 cells (1ꢁ104 cells per mL) were incubated with test compound
at 60 mm for 24 h. For comparison, arabinofuranosyl cytidine (Ara-C) was
evaluated at 40 mm in parallel.
Keywords: antitumor agents
pentafluorosulfanyl group · triazoles
·
apoptosis
·
necrosis
·
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Received: January 26, 2014
Published online on March 3, 2014
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