Abstract
A B S T R A C T 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.
Highlights
Many cancer patients have metastatic disease at diagnosis and cannot be cured by modern cancer treatment
We designed a potential anti-metabolite with alkylating properties, an azaanalogue of uracil containing chemically reactive chlorine
General: Atmospheric pressure chemical ionisation mass spectrometry (APCI-MS) was carried out on a Hewlett-Packard 5989B quadrupole instrument connected to an APCI accessory
Summary
Many cancer patients have metastatic disease at diagnosis and cannot be cured by modern cancer treatment. Cancer suspect agents like epoxides, aziridines and N-nitroso compounds [1] served as a starting point for the development of anti-cancer agents in the past. Alkylating agents such as Chlorambucil and Cyclophosphamide, which are still in clinical use, contain reactive chlorine atoms as leaving groups [2]. Various butenolides such as Penicillin acid [3] and Basidalin [4] are furanone based natural products [5] and exhibit antitumour activity in the micromolar range. We designed a potential anti-metabolite with alkylating properties, an azaanalogue of uracil containing chemically reactive chlorine
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