- Rhodacyanine dyes as antimalarials. 1. Preliminary evaluation of their activity and toxicity
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The rhodacyanine dye MKT-077 (1), a potent antitumor agent, was found to possess strong in vitro activity against Plasmodium falciparum and a low cytotoxicity. Several new rhodacyanine dyes related to 1, containing a variety of linked heterocyclic moieties, were synthesized, and their antimalarial potencies were evaluated. The synthetic rhodacyanines were found to have EC50 values against P. falciparum in vitro in the range of 4-300 nM. Several compounds in this series have remarkable selective toxicity profiles (> 100).
- Takasu, Kiyosei,Inoue, Hiroshi,Kim, Hye-Sook,Suzuki, Makoto,Shishido, Tadao,Wataya, Yusuke,Ihara, Masataka
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p. 995 - 998
(2007/10/03)
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- Structure-activity of novel rhodacyanine dyes as antitumor agents
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We have previously reported that rhodacyanine dyes, such as 1 and 2, exhibited a potent inhibitory effect on the growth of several tumor cells and that 4-oxothiazolidine (rhodanine) was an essential moiety for antitumor activity. On the basis of our foregoing work, two types of rhodacyanine dyes, which categorized into class I and II depending on the methine length, were synthesized and evaluated as a novel antitumor agent. Attention was particularly focused on the structure-activity study of two heteroaromatic rings. In class I, where the A rings were conjugated to rhodanine via two methine groups, compounds 1, 20, 23, and 24 were found to be efficacious in tumor-bearing nude mice model study, but they did not have the chemical properties (stability, solubility) suitable for clinical use. In contrast, in class II, where the A rings were directly conjugated to rhodanine, compounds 13 and 25, which possessed a benzothiazole moiety for the A ring, exhibited the favorable biological and chemical properties. Therefore, we decided to have a benzothiazole moiety as the A ring and introduce various heterocyclic groups for the B ring. As a result, the pyridinium ring was selected as the optimal moiety for the B ring (compound 13). Further, the variation of counteranion had a profound effect on solubility in water without influence on antitumor activity. Chloride anion was selected as the favorable anion with respect to synthetic method as well as solubility in water. Our study finally led us to the identification of compound 3 (MKT 077, 1-ethyl-2-[[3- ethyl-5-(methylbenzothiazolin-2-ylidene)-4-oxothiazolidin-2- ylidene]pyridinium chloride) as the candidate for clinical trials and is currently subjected to further investigation as a potent antitumor agent in phase I clinical trial for the treatment of solid tumors.
- Kawakami, Masayuki,Koya, Keizo,Tatsuta, Toshinao,Noriaki, Ukai T.,Ikegawa, Akihiko,Ogawa, Keizo,Shishido, Tadao,Chen, Lan Bo
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p. 130 - 142
(2007/10/03)
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