Applications of triphenylpyrylium salt-sensitized electron-transfer photo-oxygenation reactions to the synthesis of benzo-fused 1,4-diaryl-2,3- dioxabicyclo[2.2.2]octanes as new antimalarial cyclic peroxides

Article abstract of DOI:10.1007/s11164-012-0637-3

Benzo-fused 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes 4a-d (4a: Ar = C ₆H₅, 4b: Ar = p-FC₆H₄, 4c: Ar = p-MeC₆H₄, 4d: Ar = p-MeOC₆H₄) were synthesized by 2,4,6-tripheny

Full text of DOI:10.1007/s11164-012-0637-3

Res Chem Intermed (2013) 39:127–137
DOI 10.1007/s11164-012-0637-3
Applications of triphenylpyrylium salt-sensitized
electron-transfer photo-oxygenation reactions
to the synthesis of benzo-fused 1,4-diaryl-2,3-
dioxabicyclo[2.2.2]octanes as new antimalarial cyclic
peroxides
•
Masaki Kamata Jun-ichi Hagiwara
•
•
Tomoko Hokari Chiharu Suzuki Ryohta Fujino
•
•
•
Sayaka Kobayashi Hye-Sook Kim Yusuke Wataya
•
Received: 24 September 2011 / Accepted: 14 December 2011 / Published online: 23 June 2012
ꢀ Springer Science+Business Media B.V. 2012
Abstract Benzo-fused 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes 4a–d (4a: Ar =
C6H5, 4b: Ar = p-FC6H4, 4c: Ar = p-MeC6H4, 4d: Ar = p-MeOC6H4) were synthe-
sized by 2,4,6-triphenylpyrylium tetrafluoroborate (TPPBF4)-sensitized photoinduced
electron-transfer (PET)-promoted oxygenation reactions, and their in-vitro antimalarial
activity was evaluated. The results showed that these substances have sufficiently high
activity to enable them to serve as antimalarial lead compounds. In addition, TPPBF4-
biphenyl-cosensitized PET oxygenation was shown to be an efficient method for
introduction of an O–O moiety in the construction of antimalarial cyclic peroxides.
Keywords Photoinduced electron transfer Á Single electron transfer Á Photo-
oxygenation Á Triphenylpyrylium salt Á Cyclic peroxide Á Antimalarial activity
Introduction
Because malaria parasites rapidly develop resistance to antimalarial alkaloids, for
example chloroquine and mefloquine, the discovery that non-alkaloidal endoper-
oxides, for example artemisinin and related compounds can act as antimalarial
agents stimulated several synthetic and mechanistic studies [1–9]. In particular,
much effort has been devoted to the preparation and evaluation of structurally
M. Kamata (&) Á J. Hagiwara Á T. Hokari Á C. Suzuki Á R. Fujino Á S. Kobayashi
Faculty of Education, Department of Chemistry, Niigata University, Ikarashi,
Niigata 950-2181, Japan
e-mail: kamata@ed.niigata-u.ac.jp
H.-S. Kim Á Y. Wataya
Faculty of Pharmaceutical Sciences, Division of International Infectious Diseases Control, Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Tsushima Naka
1-1-1 Kita-Ku, Okayama City 700-8530, Okayama, Japan
e-mail: hskim@cc.okayama-u.ac.jp
123

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M. Kamata et al.
simple, more potent antimalarial cyclic peroxides. Posner reported that 1,4-diaryl-
2,3-dioxabicyclo[2.2.2]octanes 1a–b [10], 1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-
enes 2a–c [10], and 1,5-diaryl-6,7-dioxabicyclo[3.2.2]nonane 3d [11, 12] are potent
antimalarials (Scheme 1). Later, we also described the synthesis, mechanism of
degradation, and antimalarial activity of endoperoxides 1a–d [13], 2a–d [14–16],
and 3a–d [17].
During the course of ongoing investigation of the use of single-electron-transfer
(SET)-promoted reactions in synthetic organic chemistry [18–26] and the develop-
ment of new antimalarial cyclic peroxides [13, 14, 17], we became interested in
benzo-fused 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octane targets 4a–d with a similar
framework to 1 and 2. Although it has been reported that 4a can be synthesized by
9,10-dicyanoanthracene (DCA)-sensitized PET oxygenation of 1,2-bis(1-phenyleth-
enyl)benzene 5a via a cyclization and oxygenation process that is similar to that for
the preparations of 1 and 3 [27, 28], the yield of the reaction was relatively low
(\50 %). In addition, synthesis of other derivatives 4b–d and assessment of the
antimalarial activity of 4a–d have not been investigated. In previous work we
demonstrated that 3a–c can be efficiently prepared by 2,4,6-triphenylpyrylium
tetrafluoroborate (TPPBF4)-sensitized PET oxygenation of the corresponding 2,6-
diaryl-1,6-heptadienes and that these substances can be readily separated by
chromatography as a consequence of the ionic character of TPPBF4 [17]. These
observations stimulated our interest in the application of TPPBF4-sensitized PET
oxygenation reactions to conversion of 1,2-bis(1-arylethenyl)benzenes 5a–d to the
corresponding bicyclic peroxides 4a–d. Below, we describe the results of a recent
study that has led to concise syntheses of bicyclic peroxides 4a–d by TPPBF4-
sensitized PET oxygenation reactions, and evaluation of their antimalarial properties.
O
O
O
O
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
O
O
O
O
4
3
2
1
a: Ar = C6H5
b: Ar = p-FC6H4
c: Ar = p-MeC6H4
d: Ar = p-MeOC6H4
Ph
CN
-
BF4
Ph
+
Ph
O
CN
TPPBF4
DCA
Scheme 1 Synthesis of antimalarial bicyclic peroxides by TPPBF4-sensitized and DCA-sensitized PET
oxygenation reactions
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Applications of triphenylpyrylium salt-sensitized electron transfer
129
Results and discussion
1,2-Bis(1-arylethenyl)benzenes 5a–d were prepared by methylation of the corre-
sponding o-diaroylbenzenes 6a–d in THF, using the Tebbe reagent (Scheme 2). The
o-diaroylbenzenes 6a–d were prepared via Grignard addition of the corresponding
arylmagnesium bromides with phthaloyl chloride in THF [29]. The oxidation
potentials of 5a–d in CH3CN containing 0.1 M Et4NClO4 were determined, by use
OX
of cyclic voltammetry, to be ?1.49, ?1.44, ?1.38, and ?1.19 V (E vs. SCE),
1/2
respectively. The estimated reduction potential of the excited singlet state of
red
1/2
TPPBF4 (*E vs. SCE) is ca ?2.50 V [30]. Therefore, the calculated DGo values
for SET between 5a–d and the excited singlet state of TPPBF4 in CH3CN are -25,
-26, -27, and -32 kcal mol-1, respectively [22, 30–34]. Similarly the calculated
DGo values for SET between 5a–d and the excited singlet state of DCA
(*E = ? 1.90 V vs. SCE) in CH3CN are -11, -12, -13, and -18 kcal mol-1
,
red
1/2
respectively. Consequently, SET from 5a–d to the excited singlet states of TPPBF4
and DCA are highly exothermic.
PET oxygenation reactions were performed in dry CH3CN solutions of
5a–d (20 mM) and a sensitizer (TPPBF4: 2 mM or DCA: 0.2 mM) in the presence
or absence of biphenyl (Bip: 60 mM). The solutions were irradiated at 20 ꢁC under
an oxygen atmosphere using a 2-kW Xe lamp and a Toshiba L-39 filter ([390 nm).
The progress of each reaction was monitored by use of thin-layer chromatography
and further analyzed by use of 200 MHz 1H NMR spectroscopy (CDCl3). The
peroxides 4a–d were isolated by silica gel chromatography. As the results
summarized in Table 1 show, TPPBF4-sensitized PET oxygenation reactions of
hν/sens-Bip/O2
Ar
O
Ar
Ar
Ar
O
CH3CN
sens: DCA or TPPBF4
Bip: biphenyl
4
5
a: Ar = C6H5
b: Ar = p-FC6H4
c: Ar = p-MeC6H4
d: Ar = p-MeOC6H4
Tebbe reagent/THF
ArMgBr/N2
THF
Cl
Cl
Ar
Ar
O
O
O
O
6
Scheme 2 Synthesis of benzo-fused bicyclic peroxides 4a-d
123

130
M. Kamata et al.
5a–d produce the corresponding bicyclic peroxides 4a–d in moderate to good yield
(60–71 %, runs 3, 7, 11, and 15), with small amounts of o-diaroylbenzenes 6a–d,
whereas processes promoted by DCA as sensitizer are less efficient (36–58 %, runs
1, 5, 9, and 13) and generate appreciable amounts of 6a–d. On the basis of an
observation by Schaap that use of biphenyl (Bip) as cosensitizer leads to dramatic
enhancement of the efficiency of DCA-sensitized PET oxygenation reactions of
aryl-substituted oxiranes [26, 35–38], Bip was incorporated in the photo-oxygen-
ation mixture to improve the yields of 4a–d. We observed that TPPBF4–Bip-
cosensitized PET oxygenation reactions of 5a–d occur with significantly improved
yields (66–88 %, runs 4, 8, 12, and 16) to form 4a–d, with diminished production of
6a–d. Although yields of 4a–d are similarly improved when DCA–Bip-cosensiti-
zation conditions are used (44–68 %, runs 2, 6, 10, and 14), they did not exceed
those of the TPPBF4–Bip-cosensitized oxygenation reactions. The combined results
indicate that use of TPPBF4–Bip-cosensitization is the best method for synthesis of
4a–d, especially 4a–c, which have relatively weaker electron-donating aromatic
groups.
On the basis of the results of this and related studies [11–17, 22, 26–28, 30, 39–
41], it is possible to propose a mechanism for TPPBF4–Bip-cosensitized PET
oxygenation reactions leading to 4 as shown in Scheme 3. SET oxidation of 5 with
Table 1 PET oxygenation reactions of 1,2-bis(1-arylethenyl)benzenes 5
Run
Substratea
Sensitizera
Irradiation time (min)
Yield of products ( %)b
4
6
1
5a
5a
5a
5a
5b
5b
5b
5b
5c
5c
5c
5c
5d
5d
5d
5d
DCA
15
10
10
5
36
49
61
83
40
44
60
66
54
68
71
88
58
58
66
67
19
12
6
2
DCABip
TPPBF4
TPPBF4–Bip
DCA
3
4
3
5
15
10
15
5
11
11
6
6
DCABip
TPPBF4
TPPBF4–Bip
DCA
7
8
2
9
15
10
10
5
15
11
7
10
11
12
13
14
15
16
DCABip
TPPBF4
TPPBF4–Bip
DCA
4
15
10
3
9
DCABip
TPPBF4
TPPBF4–Bip
9
0
3
0
Oxygen-saturated acetonitrile solutions (10 mL) of 5 (0.20 mmol) containing the sensitizer or the sen-
sitizer with Bip were irradiated with a 2-kW Xe lamp (k [ 360 nm)
a
[5] = 20 mM; [TPPBF4] = 2.0 mM; [DCA] = 0.2 mM; [Bip] = 60 mM
b
Isolated yield by silica gel TLC. 5a–d were completely consumed
123

Applications of triphenylpyrylium salt-sensitized electron transfer
131
the excited singlet state of TPPBF4 leads to the corresponding cation radical 51•
,
which cyclizes to generate the o-xylylene cation radical 71• [27, 28]. Reaction of
71• with molecular oxygen (3O2) followed by back electron transfer from the pyryl
radical (TPP•) or electron transfer from 5 then affords 4. Under the irradiation
conditions, o-diaroylbenzene 6 is produced by SET from 4 to the excited singlet
state of TPPBF4 [42]. Our previous result that 4a was formed in the tris(4-
bromophenyl)aminium hexachloroantimonate-catalyzed oxygenation of 5a under
oxygen in the dark supports the participation of 3O2 in this TPPBF4-sensitized PET
oxygenation reaction [28]. The possibility of involvement of the oxygen anion
radical (O2-•) in the oxygenation process can be ruled out by taking into account the
redox properties of the excited TPPBF4 [30, 40, 43–46]. Electron transfer from
3
TPP• to O2 is calculated to be endothermic by approximately 20.1 kcal mol-1
using the reduction potentials (EO1/X2 ) of -0.43 and -1.30 V (vs. SCE in CH3CN)
respectively for TPPBF4 and 3O2. Thus, generation of O2-• by this electron-transfer
step is unfavorable. On the other hand, participation of singlet oxygen (1O2) in this
oxygenation process is also unfavorable, because generation of O2-• and 1O2 can be
ruled out as reported in the TPPBF4-sensitized PET oxygenation reaction of
adamantylideneadamantane [47]. The efficiency enhancement effect of addition of
OX
Bip (E = ? 1.86 V vs. SCE in CH3CN) to the reaction mixture, although not yet
1/2
fully elucidated owing to a lack of spectroscopic data, is likely to be a consequence
of the participation of Bip in electron transfer with the excited singlet state of
TPPBF4 that occurs in addition to electron transfer from 5 to generate the Bip cation
radical (Bip1•) [48]. This leads to a greater utilization of the excited state of
TPPBF4 in forming cation radical species that eventually produce the key reactive
intermediate 51•. Thus, under TPPBF4–Bip-cosensitized conditions 51• is effec-
tively generated by exothermic electron transfer from 5 to Bip1•. Under the DCA-
sensitized photoreaction conditions, oxygenation pathways similar to those involved
2•
1
in the TPPBF4–Bip-cosensitized process occur except that O2 and O2 are also
produced as reactive intermediates [48–50].
The in-vitro antimalarial activity of endoperoxides 4a–d against Plasmodium
falciparum (P. falciparum) and their cytotoxicity against mouse mammary tumor
FM3A cells (FM3A cells) were evaluated to clarify relationships that may exist
between activity and the nature of aromatic substituents (Table 2) [6, 7, 9]. The
results show that EC50 of 4a–d against P. falciparum are in the range 1.7 9 10-7 to
8.0 9 10-8 M, values that are higher than those of 1a–d (1.2 9 10-6–5.6 9
10-7 M) [13]. The nature of the benzo-substituent in 4a–d remarkably affects the
antimalarial activity of 4a–d; this may be a consequence of their enhanced
lipophilicity compared with 1a–d. In addition, 4c and 4d have fairly high
antimalarial activity and selectivity (cytotoxicity against FM3A cells/antimalarial
activity against P. falciparum: see ‘‘Experimental’’ section). The high antimalarial
activity and low toxicity of 4c and 4d may be the result of the presence of 1,4-
disubstituted electron-donating aromatic groups as compared with 4a and 4b. The
activity of 4a and 4b is somewhat lower and their selectivity is poor, owing to their
slightly high toxicity. Although the presence of a fluorine atom in 1 and 2 has been
reported to enhance antimalarial activities [10], the activity of 4b does not reflect
this effect. Finally, despite their structural and synthetic simplicity, the new series of
123

132
M. Kamata et al.
.
-
+.
TPP + BF4
+.
hν/TPPBF4
Ar
Ar
Ar
Ar
CH3CN
Ar
Ar
5
+.
+.
5
7
3O2
Ar
Ar
+e
O
O
6
hν/TPPBF4
.
-
TPP + BF4
5
hν/TPPBF4
+.
Bip
Bip
Bip
O
Ar
Ar
CH3CN
O
Bip: biphenyl
4
Scheme 3 A mechanism for the PET oxygenation reaction of 5
Table 2 In vitro antimalarial activity of cyclic peroxides 4 against P. falciparum (FCR-3 strain) and
cytotoxicity against FM3A cells
Substrate
EC50 (M)
Selectivityc
P. falciparuma
FM3A cellb
4a
1.3 9 10-7
1.7 9 10-7
8.0 9 10-8
1.1 9 10-7
1.0 9 10-6
5.6 9 10-7
5.0 9 10-7
1.2 9 10-6
1.0 9 10-8
1.0 9 10-6
3.0 9 10-6
1.9 9 10-5 (66 %)d
1.0 9 10-5
3.2 9 10-5
1.8 9 10-5
1.7 9 10-6
1.8 9 10-5
1.0 9 10-5
8
18
4b
4c
[238
91
4d
1ae
1be
1ce
1de
[32
[32
3
[15
1,000
Artemisininf
In vitro antimalarial activity and cytotoxicity are described in the ‘‘Experimental’’ section
a
Chloroquine-sensitive (FCR-strain)
b
Mouse mammary tumor FM3A cells in culture as a control for mammalian cell cytotoxicity
c
d
e
f
Selectivity = (mean of EC50 value for FM3A)/(mean of EC50 value for P. falciparum)
Growth percent at the concentration indicated
Ref. [13]
Ref. [7]
123

Applications of triphenylpyrylium salt-sensitized electron transfer
133
benzo-fused bicyclic peroxides 4a–d should serve as promising lead compounds in
efforts targeted at the design and preparation of new antimalarial drugs.
Conclusion
In conclusion, the results of the investigation described above demonstrate that
benzo-fused bicyclic peroxides 4a–d can be efficiently prepared by TPPBF4–Bip-
cosensitized PET oxygenation processes. The TPPBF4–Bip-cosensitized PET
oxygenation reaction should serve as a convenient method for synthesis of a
variety of antimalarial cyclic peroxides via concise sequences, because it enables
introduction of an O–O bond simultaneous with C–C bond-formation in some
dienes [17] or C–C bond cleavage in some cyclopropanes [51]. We are now
investigating further structural modifications of these substances and the Fe(II)-
promoted degradation of 4 with the purpose of clarifying the relationship that might
exist between reaction intermediates and antimalarial activity.
Experimental
General experimental procedures
All melting points are uncorrected. Elemental analysis was performed at the
Research and Analytical Center for Giant Molecules, Graduate School of Science,
1
Tohoku University. H and 13C NMR spectra were recorded on a Varian Gemini-
1
200 spectrometer (operating at 200 MHz for H and 50 MHz for 13C), with CDCl3
as solvent. Half-wave oxidation potentials were measured on a BAS cyclic
voltammograph CV-1B. CH3CN (Wako, special grade) for electrochemical
measurements and photoreactions was distilled twice over phosphorus(V) oxide
and once over calcium hydride. Triphenyl pyrilium tetrafluoroborate (TPPBF4) was
prepared by a method reported elsewhere [52] and recrystallized twice from
CH3CN. 9,10-Dicyanoanthracene (DCA, Wako) was recrystallized from CH3CN.
Photo-oxygenation of 1,2-bis(1-arylethenyl)benzenes 5a–d using SET
sensitizers
An oxygen-purged CH3CN (10 mL) solution of 5 (0.20 mmol) and a catalytic
amount of TPPBF4 (0.02 mmol) or DCA (0.002 mmol) in the presence or absence
of Bip (0.60 mmol) was irradiated (k [ 360 nm) by use of a 2-kW Xe lamp. The
resulting mixture was concentrated and the residue was subjected to silica gel TLC
separation (n-hexane–CH2Cl2) to afford the benzo-fused bicyclic peroxide 4 as a
major product and a small amount of o-diaroylbenzene 6. The structures of
4a–d were determined by analysis of their spectroscopic data and comparison of the
data with those reported for 4a [27].
123

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M. Kamata et al.
Compound 4a
Colorless needles; mp 192–194 ꢁC (CH3OH); IR (KBr, cm-1) m: 3090, 3060, 2970,
2884, 1606, 1498, 1248, 1045; 1H NMR (200 MHz, CDCl3), d: 2.27–2.52 (m, 2H),
2.71–2.96 (m, 2H), 6.68–6.78 (m, 2H), 7.18–7.28 (m, 2H), 7.35–7.70 (m, 10H); 13
C
NMR (50 MHz, CDCl3), d: 28.3 (t, 2C), 80.7 (s, 2C), 122.9 (d, 2C), 127.1 (d, 4C),
127.8 (d, 2C), 128.4 (d, 4C), 128.6 (d, 2C), 137.0 (s, 2C), 140.7 (s, 2C). Anal. calcd
for C22H18O2: C, 84.05; H, 5.77. Found: C, 83.71; H, 5.84. MS (EI) m/z 314 (M?,
2 %), 282 (100 %).
Compound 4b
Colorless needles; mp 222–224 ꢁC (C2H5OH); IR (KBr, cm-1) m: 3090, 2975, 2900,
1607, 1504, 1222, 1051; 1H NMR (200 MHz, CDCl3), d: 2.22–2.48 (m, 2H),
2.68–2.87 (m, 2H), 6.65–6.78 (m, 2H), 7.10–7.32 (m, 6H), 7.48–7.63 (m, 4H); 13C
NMR (50 MHz, CDCl3), d: 28.3 (t, 2C), 80.4 (s, 2C), 115.4 (d, 4C, JC–
= 21.8 Hz), 122.8 (d, 2C), 128.0 (d, 2C), 129.1 (d, 4C, JC–F = 8.3 Hz), 132.7 (d,
F
2C, JC–F = 3.1 Hz), 140.5 (s, 2C), 162.8 (s, 2C, JC–F = 247 Hz). Anal. calcd for
C22H16F2O2: C, 75.42; H, 4.60. Found: C, 75.20; H, 4.70. MS (EI) m/z 350 (M?,
1 %), 318 (100 %).
Compound 4c
Colorless prisms; mp 224–226 ꢁC (C2H5OH); IR (KBr, cm-1) m: 3010, 2945, 2905,
2830, 1607, 1508, 1238, 1038; 1H NMR (200 MHz, CDCl3), d: 2.25–2.45 (m, 2H),
2.42 (s, 6H), 2.73–2.86 (m, 2H), 6.68–6.78 (m, 2H), 7.16–7.32 (m, 6H), 7.40–7.48
(m, 4H): 13C NMR (50 MHz, CDCl3), d: 21.3 (q, 2C), 28.2 (t, 2C), 80.7 (s, 2C),
122.9 (d, 2C), 127.1 (d, 4C), 127.7 (d, 2C), 129.1 (d, 4C), 134.0 (s, 2C), 138.4
(s, 2C), 140.9 (s, 2C). Anal. calcd for C24H22O2: C, 84.18; H, 6.48. Found: C, 84.04;
H, 6.53. MS (EI) m/z 342 (M?, 2 %), 310 (100 %).
Compound 4d
Colorless needles; mp 206–208 ꢁC (C2H5OH); IR (KBr, cm-1) m: 3040, 3010, 2897,
1596, 1513, 1259, 1034; 1H NMR (200 MHz, CDCl3), d: 2.14–2.46 (m, 2H),
2.69–2.98 (m, 2H), 3.87 (s, 6H), 6.72–6.80 (m, 2H), 6.97–7.07 (m, 4H), 7.17–7.30
(m, 2H), 7.45–7.55 (m, 4H): 13C NMR (50 MHz, CDCl3), d: 28.1 (t, 2C), 55.3
(q, 2C), 80.5 (s, 2C), 113.7 (d, 4C), 122.9 (d, 2C), 127.6 (d, 2C), 128.7 (d, 4C),
128.9 (s, 2C), 141.0 (s, 2C), 159.7 (s, 2C). Anal. calcd for C24H22O4: C, 76.99; H,
5.92. Found: C, 76.64; H, 5.95. MS (EI) m/z 374 (M?, 8 %), 342 (100 %).
In vitro antimalarial activity of benzo-fused 1,4-diaryl-2,3-
dioxabicyclo[2.2.2]octanes 4a–d
Plasmodium falciparum (ATCC 30932, FCR-3 strain) was used in this study.
P. falciparum was cultivated by a modification of the method of Trager and Jensen
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Applications of triphenylpyrylium salt-sensitized electron transfer
135
[53] using a 5 % hematocrit of type A human red blood cells suspended in RPMI
1640 medium (Gibco, NY, USA) supplemented with heat-inactivated 1 % type A
human serum. The following procedures were used for assay of antimalarial
activity. Asynchronously cultivated P. falciparum were used. Different concentra-
tions of 4a–d in dimethyl sulfoxide were prepared. Each solution (5 lL) was added
to individual wells of a multidish, 24 wells. Erythrocytes with 0.3 % parasitemia
were added to each well containing 995 lL culture medium to give a final
hematocrit level of 3 %. The plates were incubated at 37 ꢁC for 72 h in a CO2–O2–
N2 incubator (5 % CO2, 5 % O2, and 90 % N2 atmosphere). To evaluate the
antimalarial activity of a test compound, we prepared thin blood films from each
culture and stained them with Giemsa (E. Merck, Germany). A total of 1 9 104
erythrocytes/1 thin blood film were examined under a microscope. All of the test
compounds were assayed in duplicate at each concentration. Drug-free control
cultures were run simultaneously. All data points are means from three experiments.
Parasitemia in controls reached between 4 and 5 % at 72 h. The EC50 value is the
concentration of the compound necessary to inhibit the increase in parasite density
at 72 h by 50 % of control.
Toxicity against mammalian cell line
Mouse mammary tumor FM3A cells (wild-type, subclone F28-7) were supplied by
the Japanese Cancer Research Resources Bank (JCRB). FM3A cells were
maintained in suspension culture at 37 ꢁC in a 5 % CO2 atmosphere in plastic
bottles containing ES medium (Nissui Pharmaceuticals, Japan) supplemented with
2 % heat-inactivated fetal bovine serum (Gibco, NY, USA). FM3A cells grew with
a doubling time of approximately 12 h. Before exposure to drugs, cell density was
adjusted to 5 9 104 cells/mL. A cell suspension of 995 lL was dispensed on to the
test plates, and compound at different concentrations suspended in dimethyl
sulfoxide (5 lL) was added to individual wells of a multidish, 24 wells. The plates
were incubated at 37 ꢁC in a 5 % CO2 atmosphere for 48 h. All of the test
compounds were assayed in duplicate at each concentration. Cell numbers were
measured by use of a CC-130 microcell counter (Toa Medical Electric, Japan). All
data points are means from three experiments. The EC50 value is the concentration
of the compound necessary to inhibit the increase in cell density at 48 h by 50 % of
control. Selectivity refers to the mean EC50 value for FM3A cells per the mean EC50
value for P. falciparum.
Acknowledgments We gratefully acknowledge financial support provided by The Uchida Energy
Science Promotion Foundation. We also thank Professor Eietsu Hasegawa (Department of Chemistry,
Faculty of Science, Niigata University), Professor Ryoichi Akaba (Department of Chemistry, Gunma
College of Technology), Professor Tsutomu Miyashi (Department of Chemistry, Graduate School of
Science, Tohoku University), Professor Yasutake Takahashi (Graduated School of Medicine and
Pharmaceutical Science for Education, University of Toyama), and Professor Hiroshi Ikeda (Department
of Chemistry, Graduate School of Engineering, Osaka Prefecture University) for their helpful comments
and assistance.
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