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-oxothi azolidin-2 -ylidene]methyl]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.