Synthesis and notable antimalarial activity of acyclic peroxides, 1-(alkyldioxy)-1-(methyldioxy)cyclododecanes

Article abstract of DOI:10.1021/jm010473w

Of several bis(alkyldioxy)alkanes and the related acyclic peroxides prepared in this study, 1,1-bis(methyldioxy)cyclododecane showed the most notable antimalarial activity particularly in vivo (almost a half of that of artemisinin).

Full text of DOI:10.1021/jm010473w

1374
J . Med. Chem. 2002, 45, 1374-1378
Syn th esis a n d Nota ble An tim a la r ia l Activity of Acyclic P er oxid es,
1-(Alk yld ioxy)-1-(m eth yld ioxy)cyclod od eca n es
Yoshiaki Hamada,† Hidekazu Tokuhara,† Araki Masuyama,† Masatomo Nojima,*,† Hye-Sook Kim,‡ Kanako Ono,‡
Naoki Ogura,‡ and Yusuke Wataya‡
Department of Materials Chemistry & Frontier Research Center, Graduate School of Engineering, Osaka University, Suita,
Osaka 565-0871, J apan, and Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, J apan
Received October 16, 2001
Of several bis(alkyldioxy)alkanes and the related acyclic peroxides prepared in this study, 1,1-
bis(methyldioxy)cyclododecane showed the most notable antimalarial activity particularly in
vivo (almost a half of that of artemisinin).
Sch em e 1
In tr od u ction
Because malaria parasites are rapidly developing
multidrug resistance to the most common chemothera-
peutic alkaloidal drugs, interest in the antimalarial
properties of nonalkaloidal compounds such as arte-
misinin and the related endoperoxides is rapidly grow-
ing.1 In connection with this, we also have found that
3,3-dialkyl-substituted 1,2,4,5-tetroxocanes I-III show
moderate to remarkable antimalarial activities in vitro
(EC50: 0.025 µM, 0.0030 µM, and 0.16 µM, respectively),
while the 3-alkyl-substituted one (IV) is ineffective.2 In
contrast, only small attention has been paid to the
potential of acyclic peroxides.3 We report herein that
acyclic analogues of the endoperoxides I-IV with a
variety of functional groups can be conveniently pre-
pared by the dialkylation of bis(hydroperoxide)s 1.
Moreover, 1,1-bis(methyldioxy)cyclododecane (2a ), an
acyclic analogue of endoperoxide I, exerts a notable
antimalarial activity not only in vitro but also in vivo.
excellent yield depending on the nature of the alkyl
halides and of the promoter (Scheme 1). The reaction
of the bis(hydroperoxide)s 1b,c with MeI gave the
corresponding peroxides 2g,h in excellent yield (Scheme
2).
Syn th esis of Un sym m etr ica lly Su bstitu ted Bis-
(a lk yld ioxy)a lk a n es. Treatment of the bis(hydroper-
oxide) 1a with 1.2 equiv of alkyl iodides in the presence
of Ag2O gave in each case the monoalkylated products
4a -c in moderate yield. Subsequent methylation pro-
vided the unsymmetrically substituted peroxides 5a -
c. Similarly, the peroxide 5h was obtained from 1c
(Scheme 2). For the preparation of the iodoalkyl-
substituted peroxides 5d ,e, Ag2O-promoted reaction of
1-(methyldioxy)cyclododecyl hydroperoxide (4d ) with
diiodoalkanes was found to be effective. R-Alkoxyalkyl-
substituted peroxides 5f,g were prepared by the reac-
tions of the same starting material 4d and vinyl ethers6
(Scheme 2).
Resu lts a n d Discu ssion
Syn th esis of Sym m etr ica lly Su bstitu ted Bis-
(a lk yld ioxy)a lk a n es. We first examined the synthesis
of symmetrically substituted bis(alkyldioxy)alkanes.
Treatment of a bis(hydroperoxide) 1a with 3 equiv of
MeI in the presence of Ag2O4 in ethyl acetate gave the
expected 1,1-bis(methyldioxy)cyclododecane 2a in 83%
yield. Alternatively, the CsOH-promoted reaction5 in
DMF resulted in the formation of 2a (56%) together with
cyclododecanone 3 (12%). The bis(alkyldioxy)alkanes
2b-f with longer alkyl chains were obtained in poor to
The hydroxyalkyl-substituted peroxide 5j was pre-
pared by the procedure illustrated in Scheme 3. The key
step was the alkylation of bis(hydroperoxide) 1a with
2-(6-iodohexyloxy)tetrahydropyran. Subsequent oxida-
tion of 5j with J ones reagent gave the corresponding
* Corresponding author. Tel: +81-6-6879-7928. Fax: +81-6-6879-
7928. E-mail: nojima@ap.chem.eng.osaka-u.ac.jp.
† Osaka University.
‡ Okayama University.
10.1021/jm010473w CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/13/2002

Antimalarial Acyclic Peroxides
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1375
Sch em e 2
Sch em e 3
bis(methyldioxy)-substituted one 2a was the most prom-
ising. Regretfully, the activity of 2a (IC50 ) 0.086 µM)
was only one tenth of that of artemisinin (IC50 ) 0.01
µM), and the selectivity was significantly poor (17)
compared to than that of artemisinin (1000). However,
this is, to our knowledge, the first example to demon-
strate that acyclic peroxide has certainly a substantial
antimalarial activity. (b) The characteristics of 1-(bu-
tyldioxy)-1-(methyldioxy)cyclododecane (5b) were no-
table. The IC50 value (0.22 µM) was comparable to that
of 2a . Moreover, a better selectivity (91) was observed.
In contrast, the antimalarial activity of 1,1-bis(butyl-
dioxy)cyclododecane (2d ) was very low. These results
suggest that the minor change of the structure of
peroxides would exert a meaningful influence on the
nature of the medicinal action. Also, some functionalized
peroxides, 5e-g and 5i-l,o, showed significant activi-
ties. (c) When the antimalarial activities of a series of
bis(methyldioxy)alkanes 2a , 2g, and 2h were compared,
it was noted that the structure of the alkyl groups exerts
a remarkable influence. A similar trend was observed
for a series of R-methoxy-substituted peroxides, 10a ,
10d , and 10f. This implies that in the case of acyclic
peroxides the presence of the cyclododecane ring would
be an important factor for the appearance of a signifi-
cant antimalarial activity. (d) The effect of alkyl chain
observed for a series of R-methoxy-substituted peroxides
10a -c was very similar to that for 1,1-bis(alkyldioxy)-
carboxylic acid 5k . As an alternative way for the
synthesis of the similar acyclic peroxide having a
carboxylic acid group in the side chain, oxidation of the
unsaturated peroxide 5l with KMnO4 was undertaken
(Scheme 4). The carboxylic acid 5m was certainly
obtained albeit in a low yield of 26%, together with
cyclododecanone (36%) and the unreacted peroxide 5l
(26%). Ozonolysis of 5l in methanol, followed by dehy-
dration gave the corresponding ester 5o.
Syn th esis of r-Meth oxy-Su bstitu ted Dia lk yl P er -
oxid es. To obtain the acyclic peroxides with a different
structure, we next conducted the ozonolysis of alkenes
in methanol to give the R-methoxy-substituted hydro-
peroxides 9. By the subsequent Ag2O-promoted alkyla-
tion, R-methoxy-substituted peroxides 10a -f were pre-
pared (Scheme 4). These compounds would be considered
as the acyclic analogue of 1,2,4-trioxacycloalkanes.
An t im a la r ia l Act ivit y of Acyclic P er oxid es in
Vitr o. With a series of acyclic peroxides 2, 5, and 10 in
hand, we tested the antimalarial activities against P.
falciparum and cytotoxicities against FM3A cell (Table
1).7 The results are summarized as follows. (a) For a
series of symmetrically substituted peroxides 2a -f, the

1376 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Hamada et al.
Ta ble 1. In Vitro Antimalarial Activities of Peroxides against
P. falciparum and Cyctotoxicities against FM3A Cellsa
Sch em e 4
EC50 values (µM)
peroxide
P. falciparumb
FM3Ac
selectivityd
2a
0.086
0.20
1.8
1.5
10
17
50
7
2b
2c
12
2d
2.1
8.5
14
38
25
4
2e
1.6
9
25
1
>9
13
91
34
2f
1.5
2g
25
2h
4.8
>45
5a
1.3
17
5b
0.22
1.0
20
5c
34
5d
NAe
0.74
0.24
0.29
1.6
5e
86
7.3
12
116
30
41
9
5f
5g
5h
15
5i
5j
0.90
0.072
0.27
0.38
5.0
7.6
1.6
14
8
22
52
16
5k
5l
5m
5o
10a
10b
10c
10d
10e
10f
artemisinin
6.0
0.45
1.4
19
26
>37
0.23
0.080
0.23
0.62
NAe
8.6
6
238
113
>60
>48
>6
NAe
0.01
10
1000
a
In vitro antimalarial activities and cytotoxicities were deter-
mined by the previously reported protocol.7 Chloroquine sensi-
b
tive (FCR-3 strain). c Mouse mammary tumor FM3A cells in
d
culture as a control for mammalian cell cytotoxicity. Selectivity
) mean of EC50 value for FM3A cells/mean of EC50 value for P.
falciparum. e NA: no activity at 10 µM.
Ta ble 2. In Vivo Antimalarial Activities (ip and po) of
Peroxides against P. berghei Infected Mice
intraperitoneal
oral
ED50
,
ED90
,
ED50
,
ED90,
peroxides
mg/kga
mg/kga
mg/kga
mg/kga
artemisinin
5.4
13
32
20
64
80
60
68
13
30
89
60
2a
2b
41
cyclododecanes 2a -c. Thus, the IC50 value of 10a (0.080
µM) was comparable to that of 2a (0.086 µM). In
addition, the selectivity of 10a (238) was much better
than that of 2a (17). The same trend was observed
between the ethyl-substituted ones, 2b and 10b.
5b
35
5j
30
10a
10b
30
>100
a
Various concentrations of the test compounds were prepared
in olive oil. The test compounds were administered to groups of
five mice once a day starting on day 0 and continued on day 1,
day 2, and day 3. Parasitemia levels were determined on the day
following the last treatment (on day 4), and ED values of the
antimalarial activities indicated above were determined by the
previously reported protocol.7
An t im a la r ia l Act ivit y of Acyclic P er oxid es in
Vivo. In vivo antimalarial activities against P. berghei
NK 65 strain7 were then determined for the acyclic
peroxides, 2a ,b, 5b,j, and 10a ,b, which had shown
notable activities in vitro. Results shown in Table 2
indicate that the ED50 value of 1,1-bis(methyldioxy)-
cyclododecane (2a ) (ED50: 13 mg/kg) on intraperitoneal
administration (ip) was only twice of that of artemisinin
(ED50: 5.4 mg/kg). In contrast, 1-(methyldioxy)-1-meth-
oxycyclododecane (10a ), which had a similar activity
and a better selectivity in vitro, showed only moderate
activity in vivo (ED50: 30 mg/kg). A similar difference
of the activity in vivo was also observed between 2b and
10b. Thus, the ED50 value of bis(ethyldioxy)cyclodode-
cane (2b) was moderate (41 mg/kg), while 1-(ethyldioxy)-
1-methoxycyclododecane (10b) showed no activity against
P. berghei NK 65 strain. The activities of unsymmetri-
cally substituted peroxides 5b,j were found to be only
moderate. It is also interesting to note that the peroxide
2a was found to be orally active (ED50: 30 mg/kg) (Table
2).
On administration of the most active acyclic peroxide
2a (ip; 20 mg/kg; 4 days), malaria parasites could not
be observed in blood stream after the 4 day suppressive
test. Consistent with this, one (by administration of 20
mg/kg; 4 days) and two (50 mg/kg; 4 days) of five infected
mice were cured, and they had no cytotoxicities more
than 60 days.
Su m m a r y
We could demonstrate that some acyclic peroxides
show substantial antimalarial activity even in vivo. This
is certainly a new finding and suggests that further

Antimalarial Acyclic Peroxides
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1377
Subsequent elution with ether-hexane (25:75) gave the car-
boxylic acid 5k (150 mg, 32%).
investigation on the antimalarial activity for a wide
range of acyclic peroxides would be promising to find a
new candidate of antimalarial drugs.
6-[(1-Met h yld ioxy)cyclod od ecyld ioxy]h exa n oic a cid
1
(5k ): Mp 37-38 °C (from hexane-ether); H NMR δ 1.3-1.8
(m, 28 H), 2.37 (t, J ) 7.3 Hz, 2 H), 3.90 (s, 3 H), 4.08 (t, J )
6.3 Hz, 2 H), 11.06 (br s, 1 H); 13C NMR δ 19.21, 21.76, 22.14,
24.33, 25.55, 25.93, 25.99, 26.78, 27.42, 33.86, 63.00, 74.57,
113.15, 180.16. Anal. (C19H36O6) C, H.
Exp er im en ta l Section
Gen er a l P r oced u r e. 1H (270 MHz) and 13C NMR (67.5
MHz) spectra were obtained in CDCl3 with SiMe4 as standard.
The bis(hydroperoxide)s 1a -c were prepared by the reported
methods.2b,8 The detailed procedures for the determination of
antimalarial activities of peroxides in vitro and in vivo have
been previously described.7
CsOH-Med ia ted Syn th esis of 1,1-Bis(a lk yld ioxy)a l-
k a n es. The preparation of 2a is representative. To a stirred
solution of a bis(hydroperoxide), 1a (464 mg, 2.00 mmol), and
CsOH-H2O (672 mg, 4.00 mmol) in DMF (25 mL) was added
methyl iodide (568 mg, 4.00 mmol) via a syringe over 10 min
at 0 °C, and the mixture was stirred at room temperature for
16 h. To the reaction mixture was added ether (150 mL), and
the organic layer was washed with aqueous sodium thiosulfate,
aqueous NaHCO3, and saturated brine and dried over anhy-
drous MgSO4. After evaporation of the solvent under vacuum,
the residue was separated by column chromatography on silica
gel. Elution with ether-hexane (1.25:98.75) gave the peroxide
2a (296 mg, 57%). Subsequent elution with ether-hexane (2:
98) gave cyclododecanone (3) (44 mg, 12%).
Syn th esis of 3-[(1-Meth yld ioxy)cyclod od ecyld ioxy]-
p r op ion ic Acid (5m ). To a stirred solution of an alkene 5l
(129 mg, 0.43 mmol) and NaHCO3 (18.1 mg, 0.22 mmol) in
acetone (1 mL) was added KMnO4 (197 mg, 1.25 mmol)
dissolved in acetone (5 mL) at 0 °C. After 1 h, the mixture
was concentrated under vacuum, and the residue was dis-
solved in ether and washed with aqueous NaHSO3. After
filtration of MnO2 over Celite, the aqueous layer acidified by
1 N HCl (pH 4) was extracted with ether. The combined
organic layer was washed with saturated brine and dried over
anhydrous MgSO4. The residue was separated by column
chromatography on silica gel. Elution with ether-hexane (1:
99) gave the unreacted alkene (34 mg, 26%). Subsequent
elution with ether-hexane (2:98) gave cyclododecanone (28 mg,
36%). From the final fraction (elution with ether-hexane; 60:
40) was obtained the carboxylic acid 5n (36 mg, 26%).
3-[(1-Meth yld ioxy)cyclod od ecyld ioxy]p r op ion ic a cid
(5m ): Mp 69-70 °C (from ether-hexane); 1H NMR δ 1.2-1.8
(m, 22 H), 2.78 (t, J ) 6.3 Hz, 2 H), 3.88 (s, 3 H), 4.35 (t, J )
6.3 Hz, 2 H); 13C NMR δ 19.25 (2 C), 21.87 (2 C), 22.21 (2 C),
25.99 (2 C), 26.06, 26.79 (2 C), 33.26, 63.06, 70.01, 113.48,
177.25. Anal. (C16H30O6).
1,1-Bis(m eth yld ioxy)cyclod od eca n e (2a ): Mp 38-39 °C
1
(from hexane); H NMR δ 1.3-1.5 (m, 18 H), 1.63 (t, J ) 9.6
Hz, 4 H), 3.92 (s, 6 H); 13C NMR δ 19.30, 21.78, 22.44, 26.04,
26.09, 26.83, 63.18, 113.33. Anal. (C14H28O4) C, H.
P r ep a r a tion of F u n ction a lized P er oxid es, 5i-k . To a
solution of Ag2O (650 mg, 2.8 mmol) and the bis(hydroperoxide)
1a (928 mg, 4.0 mmol) in ethyl acetate (10 mL) was added a
solution of 1-iodo-6-(2-tetrahydropyranyloxy)hexane9 (1.25 g,
4.0 mmol) in ethyl acetate (5 mL) via a syringe over 5 min at
0 °C, and the reaction was continued at room temperature for
15 h. After filtration of the solid material over Celite, ether
(100 mL) was added to the filtrate, and the organic layer was
washed with 3% aqueous sodium thiosulfate (50 mL), aqueous
NaHCO3, and saturated brine and dried over anhydrous
MgSO4. After evaporation of the solvent under reduced pres-
sure, the residue was separated by column chromatography
on silica gel. From the first fraction (elution with ether-
hexane, 5:95) was obtained cyclododecanone (102 mg, 14%).
Subsequent elution with ether-hexane (12.5:87.5) gave 1-[6-
(2-tetrahydropyranyloxy)hexyldioxy]cyclododecyl hydroperox-
ide (4f) in 47% yield (780 mg). To a solution of Ag2O (232 mg,
1.00 mmol) and the hydroperoxide 4f (416 mg, 1.00 mmol) in
ethyl acetate (10 mL) was added a solution of methyl iodide
(284 mg, 2.00 mmol) in ethyl acetate (5 mL) via a syringe over
5 min at 0 °C, and the reaction was continued at room
temperature for 15 h. By column chromatography on silica gel
(elution with ether-hexane, 6:94), the desired peroxide 5i was
obtained in 78% yield (337 mg). Then, the peroxide 5i (215
mg, 0.5 mmol) in acetic acid (4 mL)-THF (2 mL)-H2O (1 mL)
was stirred at room temperature for 15 h. Then, the products
were separated by column chromatography on silica gel.
Elution with ether-hexane (10:90) gave the unreacted perox-
ide 5i (77 mg, 36%). Subsequent elution with ether-hexane
(27:73) gave the alcohol 5j (100 mg, 58%).
Ozon olysis of Met h oxym et h ylen ecyclod od eca n e in
Meth a n ol. To a solution of vinyl ether 8a (630 mg, 3 mmol)
in MeOH-ethyl acetate (35 mL, 3:4) was passed a slow stream
of ozone (1 equiv; flow for 9 min) at -70 °C. By evaporation of
the solvent under vacuum, followed by crystallization from
hexane, pure hydroperoxide 9a was obtained (620 mg, 90%).
1-Meth oxycyclod od eca n -1-yl h yd r op er oxid e (9a ): Mp
88-90 °C (from ether-hexane); 1H NMR δ 1.4-1.8 (m, 22 H),
3.31 (s, 3 H), 7.55 (s, 1 H); 13C NMR δ 19.61, 22.12, 22.55,
26.33, 27.93, 48.90, 110.17. Anal. (C13H26O3) C, H.
Ag2O-P r om oted Alk yla tion of r-Meth oxya lk yl Hyd r o-
p er oxid es. The preparation of peroxide 10a is representative.
To a solution of Ag2O (580 mg, 2.5 mmol) and 9a (575 mg, 2.5
mmol) in ethyl acetate (20 mL) was added a solution of methyl
iodide (710 mg, 5 mmol) in ethyl acetate (10 mL) via a syringe
over 5 min at 0 °C, and the reaction was continued at room
temperature for 15 h. By column chromatography on silica gel
(elution with ether-hexane, 1:49), peroxide 10a (430 mg, 70%)
was obtained.
1-Meth oxy-1-(m eth yld ioxy)cyclod od eca n e (10a ): An oil;
1H NMR δ 1.2-1.8 (m, 22 H), 3.31 (s, 3 H), 3.87 (s, 3 H); 13C
NMR δ 13.32, 21.89, 26.02, 26.11, 28.11, 48.56, 62.86, 109.11.
Anal. (C14H28O3) C, H.
Su p p or tin g In for m a tion Ava ila ble: Synthetic methods
of R-(alkyldioxy)alkyl hydroperoxide 4b and of unsymmetri-
cally substituted peroxides 5a , 5g, and 5o and the spectro-
scopic and elemental analysis data for all new compounds 2a -
h , 4a -g, 5a -o, 9a -c, and 10a -f are available free of charge
via the Internet at http://pubs.acs.org.
6-[(1-Meth yld ioxy)cyclod od ecyld ioxy]h exa n -1-ol (5j):
1
Refer en ces
An oil; H NMR δ 1.2-1.7 (m, 30 H), 1.95 (br s, 1 H), 3.63 (t,
J ) 6.6 Hz, 2 H), 3.90 (s, 3 H), 4.08 (t, J ) 6.6 Hz, 2 H); 13C
NMR δ 19.21, 21.78, 22.16, 25.45, 25.86, 25.95, 26.81, 27.69,
32.49, 32.63, 62.63, 63.02, 74.83, 113.15. Anal. (C19H38O5) C,
H.
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in acetone (5 mL) was added J ones reagent (prepared from
CrO3 (260 mg, 2.6 mmol), concentrated H2SO4 (0.23 mL), and
1.4 mL of H2O) at 0 °C, and the mixture was stirred at room
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