Bis-cyclic butenolides, 5-arylated 2(5H)-furanones 6a - c, 7a, b and the 3(2H)-pyridazones 9a - d were prepared by using the aldehyde form of muco halogen acids in electrophilic substitution reactions and in an aldol-like condensation reaction. The cytotoxicity of these simple and bis-cyclic butenolides have been evaluated in tissue culture studies on MAC 13 and MAC 16 murine colon cancer cell lines. The butyl furanone 3 displayed the highest cytotoxicity of 3 microM, as one selected example of a series of dichlorinated pseudoesters. The 5-arylated 2(5H)-furanones 6 and 7 did not show a structure-activity relationship (SAR) depending on the substitution pattern of the aromatic system. An IC50 (concentration inhibiting growth by 50%) was found within a range of 30-50 and 40-50 microM for the MAC 13 and MAC 16 cell lines, respectively. The pyridazine series 9 showed a maximum in-vitro activity for the p-methoxydrivative 9b, having an IC50 of 17 in MAC 13 and 11 microM in MAC 16 cell lines. Selected examples of each series and further novel 2(5H)-furanones such as the hydrazone 5 and the hydantoin 8 have been screened in-vivo in mice and the data are presented. For the pyridazines 9a - d, the in-vitro cytotoxicity correlated with an in-vivo inhibition of tumour growth. The ring expansion of the 5-membered 2(5H)-furanone ring system such as 6a into the 6-membered 3(2H)-pyridazone 9b led to an agent with improved antineoplastic properties. On the resistant MAC 16 cell line the pyridazone 9b displayed 52% tumour inhibition in mice at a dose of 50 mg kg(-1) compared with 27% for the 5-FU standard.
Analogues of new lead structures, such as amido-2(5H)-furanones, bisarylated acrylic acids and 3(2H)-pyridazones, were prepared from mucochloric acid. Initially, these simple butenolides and analogues have been evaluated in tissue culture studies and subsequently, selected examples were tested in vivo on MAC 16 murine colon cancer cell lines. Bis-arylated methacrylic acids showed in addition to a moderate cytotoxicity an inhibition of tumor growth in vivo in mice. The xylene derivative MXAA displayed at 20mg/kg a 25% inhibition compared to 27% for the control (5-FU). The acetamido-furanone AAF 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 DCPYR, had a manifold higher in vitro activity, than the known arylated pyridazones and most interestingly this correlated well with the observed in vivo activity. Pyridazine DCPYR showed 53% inhibition of tumour growths in vivo in mice at a 50mg/kg dose and less weight loss was observed for this best agent compared to the anti-metabolite 5-FU, which served as standard. Abstract
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