Abstract
Each diastereomer of 10-thiophenyl- and 10-benzenesulfonyl-dihydroartemisinin was synthesized from artemisinin in three steps, and screened against chloroquine-resistance and chloroquine-sensitive Plasmodium falciparum. Three of the four tested compounds were found to be effective. Especially, 10β-benzenesulfonyl-dihydroartemisinin showed stronger antimalarial activity than artemisinin.
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Key words: Plasmodium falciparum, antimalarial activity, artemisinin, dihydroartemisinin, synthesis, natural product
The natural sesquiterpene endoperoxide artemisinin (
Fig. 1-1), which was isolated from
Artemisia annua L. (
Klayman, 1985), has become a potential lead compound in the development of an antimalarial (
Luo and Shen, 1987;
Jung, 1994;
Haynes and Vonwiller, 1997;
Vroman et al., 1999) and recently anticancer agents (
Beekman et al., 1997;
Jung et al., 2003;
Posner et al., 2003). The semi-synthetic, acetal-type, artemisinin derivatives (
Fig. 1-3), ether and ester derivatives of trioxane lactol dihydroartemisinin (
Fig. 1-2), were developed for their higher antimalarial efficacy and are now widely used to treat malarial patients (
Fig. 1) (
Brossi et al., 1988).
Although these acetal artemisinin derivatives showing potent antimalarial activity
in vitro, the acetal functional group at the C-10 position is responsible for chemical instability (
Jung and Lee, 1998), and toxicity (
Gordi and Lepist, 2004). Therefore, to improve bioavailability, it is important to discover novel artemisinin derivatives suitable to chemo-antimalarial therapy. In 1995, Venugopalan et al. reported a series of thioacetal type artemisinin derivatives, some of which have potent antimalarial activity in vivo.
In 1998, Posner et al. also reported that sulfide and sulfone endoperoxide from R-(+)-limonene (
Bachi et al., 1998) and sulfone trioxanes (
Posner et al., 1998;
Posner et al., 2000) have similar or less activity to natural artemisinin. However, because there is no report on C-10 sulfonyl artemisinin derivatives (
Fig. 2), we decided to investigate and report the synthesis and antimalarial activity of such derivatives.
TESTED COMPOUNDS
As seen in
Fig. 3, separable diastereomeric mixtures of 10α- (
Fig. 3-6) and 10β-thiophenyl-dihydroartemisinins (
Fig. 3-6) were prepared by reacting known dihydroartemisinin (
Fig. 1-2) (
Lin et al., 1987) with thiophenol (2eq) under the catalysis of BF
3Et
2O (1eq) at room temperature for 10 minutes (
Venugopalan et al., 1995;
Oh et al., 2004a,
2004b). The thioacetal products (
Fig. 3-6) were transformed to produce 10α- (
Fig. 3-7) and 10β-benzenesulfonyl-dihydroartemisinins (
Fig. 3-8), respectively, in good yields, by performing oxidation with H
2O
2/urea complex (UHP), trifluoroacetic anhydride (TFAA) and NaHCO
3 (
Varma and Naicker, 1999;
Caron et al., 2000).
Two culture-adapted strains of
P. falciparum were used: the chloroquine-sensitive strain FCR-8/West African, and chloroquine-resistant strain FCR-3/Gambia subline F-86 of
P. falciparum obtained from ATCC (
Nguyen-Dinh and Trager, 1980;
Jensen and Trager, 1978). The medium used was RPMI medium containing hypoxanthine and supplemented with HEPES buffer, sodium bicarbonate, human A serum, glutamine, gentamicin, and uninfected human O erythrocytes.
The assays were conducted
in vitro by a modification of the semiautomated microdilution technique of Desjardins et al. (
1979) and Delhaes et al. (
2002) based on radiolabeled [
3H]hypoxanthine incorporation. Drug testing was carried out in 96-well, microtiter plates. Stock solutions of each compound were prediluted in complete culture medium (RPMI 1640 supplemented with 10% pooled human A serum), and titrated in duplicate in serial twofold dilutions. The final concentrations ranged from 1.96-250 nmole L
-1 for artemisinin derivatives and artemisinin, and 11.2-1435nmole L
-1 for chloroquine. After the addition of a suspension of parasitized erythrocytes in complete culture medium (200µl per well, 0.7% initial parasitemia with a majority of ring stages, 1.8-2% haematocrit) and [H3]hypoxanthine (Amersham, UK, TRK74, 1µl per well), the test plates were incubated at 37℃ for 24 h in an atmosphere of 5% O
2, 5% CO
2, and 90% N
2. Growth of the parasites was estimated from the incorporation of radiolabeled [H
3]hypoxanthine into the parasites` nucleic acids, measured in a liquid scintillation spectrometer (Packard, USA). The 50% inhibitory concentration (IC50) values refer to the molar concentrations of drug causing a 50% reduction in [H
3]hypoxanthine incorporation, compared to drug-free control wells. IC50 values were estimated by linear regression analysis of log-dose-response curves.
In the screening of the two standard molecules, chloroquine and artemisinin, against chloroquine-resistance (50005 = FCR-3) and -sensitive (50028 = FCR-8) parasites, we could confirm the biological property of each cell line and the inhibitory activity of each drug (
Table 1). At first, two diastereomers, 10α-(
Fig. 3-5) and 10β-thiophenyl-dihydroartemisinins (
Fig. 3-6), had a similar inhibition activity with artemisinin. Interestingly, 10α- (
Fig. 3-7) and 10β-benzenesulfonyl-dihydroartemisinins (
Fig. 3-8) showed different inhibitory activity against each cell line according to the change of stereochemistry in the C-10 position of artemisinin. 10β-Diastereomer (
Fig. 3-8) was ten times more active than 10α-diastereomer (
Fig. 3-7). In particular, 10β-benzenesulfonyl-dihydroartemisinin (
Fig. 3-8) was two times more active than artemisinin and ninety times more than chloroquine. This preliminary screening of each thiophenyl- and benzenesulfonyl-dihydroartemisinin derivative indicated that 10β-sulfonyl-dihydroartemisinin derivative can be a potentially promising antimalarial drug against chloroquine-resistance parasites.
Notes
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This study was supported by a grant from the Korea Science and Engineering Foundation [R05-2002-000-00808-0(2002)]
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Fig. 1Structure of artemisinin and acetal-type artemisinin derivatives.
Fig. 2Structure of thioacetal artemisinin derivatives.
Fig. 3Synthesis of thioacetal artemisinin derivatives.
Table 1.Antimalarial activity of thiophenyl- and benzenesulfonyl-dihydroartemisinin against chloroquine-resistance (FCR-3) and -sensitive P. falciparum (FCR-8)
Table 1.
|
Compoundsa)
|
IC50 (nM)b)
|
|
FCR-3 |
FCR-8 |
|
Chloroquine |
611.6 ± 69.5 |
31.3 ± 0.49 |
|
Artemisinin |
17.2 ± 0.84 |
33.1 ± 9.47 |
|
5 |
23.2 ± 1.06 |
31.8 ± 5.23 |
|
6 |
34.7 ± 1.2 |
40.7 ± 10.25 |
|
7 |
89.1 ± 0 |
190.5 ± 84.14 |
|
8 |
6.8 ± 2.41 |
17.2 ± 7.35 |
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