Synthesis and evaluation of novel rhodacyanine dyes that exhibit antitumor activity.
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.
Kawakami
M
M
Ashigara Research Laboratories, Fuji Photo Film Company, Ltd., Kanagawa, Japan.
Koya
K
K
Ukai
T
T
Tatsuta
N
N
Ikegawa
A
A
Ogawa
K
K
Shishido
T
T
Chen
L B
LB
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002999:Clone Cells; D004396:Coloring Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003868:Dequalinium / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004396:Coloring Agents; D011744:Pyrimidinones; C003954:merocyanine dye; D012236:Rhodanine; D003868:Dequalinium