Antimelanoma activity of 1,3,4-thiadiazolium mesoionics: a structure-activity relationship study.
The effect of a series of 4-phenyl-5-(2'-Y, 4'-X or 4'-X-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chlorides was evaluated against B16-F10 murine melanoma cells in vitro and against tumors resulting from implanted B16-F10 cells in C57BL/6 mice. These compounds differ from each other only at the cinnamoyl ring substituent (MI-J, X=OH; MI-2,4diF, X=Y=F; MI-4F, X=F and MI-D, X=NO2). The results were compared with those obtained for MI-D, which has already been shown to be a potent and promising drug against melanoma. On exposure of B16-F10 cells to MI-D, MI-2,4diF and MI-4F, all of them at the same micromolar concentration (50 microM) decreased the cell viability to 8, 50 and 22%, respectively, while MI-J did not show any significant effect under the same conditions. However, low doses such as 10 microM MI-D were sufficient to impair cell growth over 72 h, but for MI-2,4diF and MI-4F the effect on B16-F10 proliferation was only observed at a concentration of 25 microM. Furthermore, MI-4F had a slightly better effect than MI-2,4diF in vitro; its effect on tumor growth in vivo was not significant. MI-D inhibited tumor growth by 77%. The greater effectiveness of MI-D compared with MI-2,4diF, MI-4F and MI-J against B16-F10 melanoma cells is probably due to its stronger electron-withdrawing group (NO2), which increases the positive charge on the mesoionic ring and allows extensive conjugation of the side-chain with the exocyclic moiety. This seems to be important for degree of anti-tumor activity of these compounds.
Senff-Ribeiro
Andrea
A
Department of Biochemistry, Federal University of Paraná, Curitiba, PR, Brazil.
Echevarria
Aurea
A
Silva
Edson F
EF
Veiga
Silvio S
SS
Oliveira
Maria B M
MB
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D013830:Thiadiazoles; C058949:1,3,4-thiadiazole