Abstrakt

Novel Anti-Cancer Agents Derived from Mucochloric Acid

Simon Dunn, Floren Low, Harjit Singh, Derek Kinchinaton, Michael J Tisdale, Carl H Schwalbe and Eric Lattmann

Analogues of a new lead structure were subsequently synthesized by alternative synthetic routes. Various pyrrols, 2(5H)-furanones, bisarylated acrylic acids and 3(2H)-pyridazones were prepared from muco halogen acids in an array of chemical reactions. The cytotoxicity of these simple butenolides and analogues have been evaluated in tissue culture studies on MAC 13 and MAC 16 murine colon cancer cell lines. Ketone 5 containing an aromatic moiety only occurred a cytotoxicity in vitro, while acyclic bisarylated methacrylic acids 7 showed in addition to a moderate cytotoxicity an inhibition of tumor growth in vivo in mice. The xylene derivative 7b displayed at 20mg /kg a 25 % inhibition compared to 27%for the control (5FU). The acetamido –furanone 8a displayed an IC50 of 18, 4 µM for the MAC 13 and MAC16 cell line, respectively and this translated into 26%inhibition of tumour growth in the transplanted MAC 16 cell line in mice. The unsubstituted pyridazine 9b, had amanifold higher in vitro activity, than the known arylated pyridazone 9a and most interestingly this correlated well with the observed in vivo activity. Pyridazine 9b showed 53% inhibition of tumour growths in vivo in mice at a 50 mg/kg dose and less weight loss was observed for this best agent compared to the anti-metabolite 5-FU, which served as standard.