Structure−Activity of Novel Rhodacyanine Dyes as Antitumor Agents

Abstract

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.

Synthesis and Anticancer Activity of Indolin‐2‐one Derivatives Bearing the 4‐Thiazolidinone Moiety

“…Therefore, we tentatively concluded that the electronic influences of the substituent in the phenyl ring appear to play an important role in activity, and this behavior depends on the cancer cell lines to which they are In the present study, the coupling between indolin-2-one and 5-benzylidene-4-thiazolidinone systems led to several compounds with better anticancer activity than the previously reported analogues [15,23,24]. Two neutral conjugate systems integrated at the 4-thiazolidinone moiety may contribute to the anticancer activity of these compounds, which has already been partially confirmed by anticancer activity of the rhodacyanine dyes [25].…”

A theoretical study on the ground and excited state behaviors of TTBC related carbocyanine dyes

“…In the last decades, interests in cyanine dyes [1] are rapidly increasing due to their wide application areas such as sensitizers in photographic industry [2], laser dyes [3,4], anti-tumor agent [5], non-linear optics [6], optical disk as recording media [7] and fluorescence probe for biological molecules [8].…”

π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms

“…The properties of 7 are comparable with quinine (1) and chloroquine (2) treatment (entries 4, 5). MKT-077 (7a) [17][18][19] was developed as a potential antitumor agent by FUJIFILM Co. based on the DLC hypothesis, originally proposed by Chen. 20) He proposed that π-delocalized lipophilic cations (DLCs) could penetrate the hydrophobic barriers of the plasma and mitochondria membrane under a cross-membrane negative potential.…”