VOL. 57 NO. 6, JUNE 2004 THE JOURNAL OF ANTIBIOTICS pp. 400 — 402 In Vitro and In Vivo Antimalarial Activities of In vitro activities against Plasmodium falciparum strains
a Carbohydrate Antibiotic, Prumycin, against
K1 (drug-resistant) and FCR3 (drug-sensitive), and
cytotoxicity against human diploid embryonic cell line
Drug-resistant Strains of Plasmodia
MRC-5, were measured as described previously1). Rodent
malaria-derived strains for in vivo 4-days suppressive
testing, P. berghei N (drug-sensitive) and P. yoelii ssp. NS
In the course of our program to discover antimalarial
(chloroquine-resistant) were used to assess in vivo efficacy
antibiotics active against drug-resistant parasites, by
as reported previously1,2). Prumycin was dissolved in water,
screening soil microorganisms and antibiotic library of the
while other test compounds were solubilized in 10%
Kitasato Institute for Life Sciences, we previously reported
DMSO-Tween 80 aqueous solution. The formulated
on various microbial metabolites exhibiting potent
samples were administered subcutaneously (s.c.) to mice
antimalarial properties1ϳ4). Now, we find that prumycin5ϳ7),
two hours after infection with parasites (Day 0), and then
a compound in the antibiotic library of our institute, has
once a day for 3 days (Days 1ϳ3). On the day after the last
potent and moderately selective antimalarial activity in vitro
treatment (Day 4), thin blood films were made from the tail
and in vivo. We report here the antimalarial profiles of
blood of the mice, and the parasitaemia was determined as
prumycin and its derivatives (Fig. 1) in comparison with
those of clinically used antimalarial drugs, and also present
Table 1 shows the in vitro antimalarial activities of
some conclusions on structure-activity relationships.
prumycin, its derivatives and some standard antimalarial
Prumycin was purified from the cultured broth of
drugs. Prumycin and a -prumycin had similar activity to
Streptomyces sp. strain No. F-10285,6). The derivatives
choroquine against the drug-resistant K1 strain of P.
(2ϳ4) were synthesized according to our previous report7). falciparum, but were less potent than the clinically used
Benzyl 4-amino-2-(benzyloxycarbonyl) amino-2,4-
antimalarials artemether, artemisinin and artesunate.
dideoxy-a -L-arabinopyraside (5) was a generous gift of
Furthermore, prumycin and a -prumycin showed similar
Nippon Kayaku Co. LTD., (Japan). The compounds (6ϳ8)
activities against the drug-sensitive FCR3 strain of P.
were prepared from 5 with the protected amino acids
(DCC, CH Cl , r.t.), followed by deprotections. 3ϳ8) against the K1 strain were Ͼ12.5 mg/ml.
Structures of prumycin and its derivatives. VOL. 57 NO. 6 THE JOURNAL OF ANTIBIOTICS
derivatives and the antimalarial drugs against K1
activities of prumycin, artemether, artesunate and
and FCR3 strains of Plasmodium falciparum.
chloroquine against P. berghei N and P. yoelii ssp. NS.
We then investigated the cytotoxicities of prumycin and a -
It is known that prumycin has inhibitory activities against
prumycin against MRC-5 cells and found them to be,
phytopathogenic fungi such as Sclerotinia sclerotiorum and
respectively, 3.6 and 1.2 m g/ml. Prumycin and a -prumycin
Botorytis cineria5,6), and against tumor cells8ϳ11), and that
showed moderate to low selectivity indexes, with ratios in
its mode of anti-fungal action in growing cells of B. cineria
the ranges of 22.5ϳ3.5 and 21.3ϳ8.6 for the MRC-5
involves selective inhibition of protein synthesis12).
cells/K1 strain and MRC-5 cells/FCR3 strain, respectively.
Furthermore, we previously reported that it inhibits both
The lack of antimalarial activity of prumycin derivatives
protein synthesis and DNA synthesis in cultured HeLa S3
(3ϳ8) in comparison to prumycin provides interesting
cells8). However, the finding of the antimalarial activities of
information on structure-activity relationships. Thus
prumycin and its derivative is novel and the above data are
introduction of a methyl group on the hydroxyl (to give 3)
the first report of such properties.
and acetylating the two primary amino groups (resulting in
4) destroys activity. Furthermore, replacement of the
in mice) of prumycin were 144 and 155 mg/kg, respectively.
L-alanine group on the amino moiety at C-4 with,
However, we did observe toxicity (loss of weight, mortality)
respectively, L-glycine (6), L-proline (7), and L-isoleucine
when the compound was delivered by the s.c. route
(8) also destroys activity. These results suggest that a free
at Ͼ30 mg/kgϫ4. These effects are being investigated
anomer at C-1, amino groups at C-2, and the methyl group
at L-alanine all play an important role in the antimalarial
The above results reveal that prumycin is a promising
lead compound for a new type of antimalarial drug. Further
Further studies are necessary to extend the structure-
investigation of the antimalarial potential of prumycin is in
activity relationships of prumycin-related antimalarial
Table 2 shows a preliminary comparison of the in vivo
subcutaneous antimalarial activities of prumycin and the
standard antimalarial drugs. Prumycin had moderate
This work was supported, in part, by funds from the
activity against both rodent malaria-derived P. berghei N
UNICEF/UNDP/World Bank/WHO Special Program forResearch and Training in Tropical Diseases (grants ID
and P. yoelii ssp. NS, but was less effective than the
A10124), and Grants-in-Aid for Scientific Research (A) from
clinically used antimalarials artemether and artesunate.
the Ministry of Education, Culture, Sports, Science and
value of prumycin (27.8 mg/kg) against the
Technology, Japan. A part of work was supported by The 21st
chloroquine-resistant strain (P. yoelii ssp. NS) was much
Century COE program, the Ministry of Education, Culture,Sports, Science and Technology, Japan. We are grateful to Dr.
lower than that of chloroquine (Ͼ100 mg/kg), and was
THE JOURNAL OF ANTIBIOTICS JUNE 2004
K. HATA, JPMW Coordination Center, for valuable discussion.
the microbial metabolites. J. Antibiotics 56: 322ϳ324,
We also thank Mr. Y. KATO and Ms. M. SUZUKI, the Kitasato
Institute, for the antimalarial assay, Dr. J. NAMATAME, Kitasato
OTOGURO, K.; H. UI, A. ISHIYAMA, M. KOBAYASHI, H.
Institute for Life Sciences, Kitasato University, for technical
TOGASHI, Y. TAKAHASHI, R. MASUMA, H. TANAKA, H.
¯ MURA: In vitro and in vivo
antimalarial activities of a non-glycoside 18-member
macrolide antibiotic, borrelidin, against drug-resistant
strains of Plasmodia. J. Antibiotics 56: 727ϳ729, 2003
¯ MURA, M. KATAGIRI, K. ATSUMI, J. AWAYA,
S. HIGASHIKAWA, K. YASUI, H. TERADA & S. KUYAMA: A
new antifungal antibiotic, prumycin. J. Antibiotics 24:
¯ MURA, S.; M. KATAGIRI, J. AWAYA, K. ATSUMI, R. O¯IWA,
T. HATA, S. HIGASHIKAWA, K. YASUI, H. TERADA & S.
KUYAMA: Production and isolation of a new antifungal
antibiotic, prumycin, and taxonomic studies ofStreptomyces sp., strain No. F-1028. Agr. Biol. Chem.
Research Center for Tropical Diseases, The Kitasato Institute,
† Kitasato Institute for Life Sciences, Kitasato University,
¯ MURA, S.; M. KATAGIRI, K. ATSUMI, T. HATA, A. A.
5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
JAKUBOWSKI, E. B. SPRINGS & M. TISHILER: Structure ofprumycin. J. Chem. Soc., Perkin Trans. I. 1974:
OKUBO, S.; N. NAKAMURA, K. ITO, H. MARUMO, M. TANAKA & S. O
¯ MURA: Antitumor activity of prumycin. J.
OKUBO, S.; N. NAKAMURA, M. MORIMOTO, K. MINEURA,H. MARUMO & S. O
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* Corresponding author: otoguro@lisci.kitasato-u.ac.jp
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