Synthesis and Evaluation of Novel Rhodacyanine Dyes That Exhibit Antitumor Activity

Abstract

Rhodacyanine dyes and several analogous delocalized lipophilic cations (DLCs) were synthesized and evaluated as novel antitumor agents. Rhodacyanine dye consists of two heteroaromatic rings such as thiazoles at both termini of the conjugate systems and 4-oxothiazolidine (rhodanine) in the middle of it. Compounds with such a unique double-conjugate structure were found to inhibit the growth of several tumor cell lines, such as colon carcinoma CX-1, and to exhibit relatively low toxicity against normal kidney cell line CV-1 (e.g., IC50(CX-1) = 50 nM, IC50(CV-1) = 17.3 microM; selectivity index = 346 for compound 5). These compounds were also found to be efficacious in the tumor-bearing nude mice model (e.g., against human melanoma LOX; T/C (%) = 168 for compound 5). Structural modifications on rhodacyanine, including deletion of a heteroaromatic ring involved in the merocyanine conjugate system and replacement of rhodanine with a structurally related moiety such as 4-oxoimidazolidine or 4-oxo-1,3-dithiolane, resulted in a loss of the selectivity and/or the activity. Our current structure-activity studies imply that the double-conjugate system with a rhodanine moiety is essential for the selective activity of rhodacyanine dyes, and we find this class of compounds as unique antitumor agents candidates.

Regioselective synthesis, structure and behavior in solutions of novel phosphorylated thiazolidin‐4‐ones

“…1, Table 1) are close to the typical values for thizolidine-4-one derivatives [6,7,[11][12][13]. In particular, the thiazolidin-4-one cycle is planar and both C(2) C(8) and C(5) C(6) bond lengths are equal to 1.344(4)Å.…”

“…1). The latter type of intramolecular interaction is also typical for the thiazolidin-4-one derivatives [6,7,11]. The nature of the such X S· · ·O contacts is usually explained in terms of the charge transfer from the oxygen lone pair (Lp O ) to the antibonding orbital of the X S bond ( * X S ) [12,13] which is in line with the specific direction of this contact in 3a [C(2)S(1)O (5) is 164.8 (2) • ].…”

“…It was suggested that E,Z-isomers are stabilized in nonpolar solvents (CDCl 3 ; R is COOEt or CONR 2 ) by the formation of the intramolecular hydrogen bond [8,9]. In contrast, the S· · ·O contact stabilizes Z,Z-isomers in such solvents as ethanol or DMSO-d 6 . However, the data and assignment of the configuration for the compounds in the [8] and [9] conflict with each other.…”

Synthesis and Evaluation of β-Carbolinium Cations as New Antimalarial Agents Based on π-Delocalized Lipophilic Cation (DLC) Hypothesis

“…b-Hydroxyethyl substituent for R 5 group also lead decrease in activity (6pa versus 6pb). It was observed that counter anion (X Ϫ ) affected antiplasmodial properties to some extent (runs 9,11,12). The difference might be caused by the solubility of the substances in aqueous media.…”

“…[9][10][11] Namely, lipophilic cations possessing a delocalized positive charge (DLCs) penetrate the hydrophobic barriers of the plasma and mitochondria membrane in response to the negative inside transmembrane potentials. The higher mitochondrial membrane potentials of carcinoma cells compared to normal cells induce the selective transfer of DLCs into carcinoma mitochondria.…”