Synthesis and Cytotoxic Activity of Ethyl 2-Amino-1-Benzamido-4-Oxo-5-(2-Oxo-2-Arylethylidene)-4,5-Dihydro-1H-Pyrrole-3-Carboxylates

Recyclization of 5-aryl-2,3-dihydro-2-furandione 3-benzoylhydrazones (I) induced by cyanoacetic ester produced ethyl 2-amino-1-benzamido-4-oxo-5-(2-oxo-2-arylethylidene)-4,5-dihydro-1H-pyrrole-3-carboxylates (IIa-g). The biological activity of the synthesized compounds, which possessed low toxicities, was investigated. Ethyl 2-amino-1-benzamido-5-[2-(4-chlorophenyl)-2-oxoethylidene]-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate (IIf) and the 5-[2-(3,4-dimethoxyphenyl)-2-oxoethylidene] analog (IIc) exhibited the greatest cytotoxicities against several connective-tissue tumor cell lines, namely, gastrointestinal stromal tumors (GISTs), osteosarcoma U2OS, and leiomyosarcoma SK-LMS-1. Ethyl 2-amino-1-benzamido-4-oxo-5-[2-oxo-2-(p-tolyl)ethylidene]-4,5-dihydro-1H-pyrrole-3-carboxylate (IIa) suppressed significantly tumor growth of GIST, LMS, and OS cell lines. Its activity against GIST cells at 10 mu M was comparable with that of imatinib (1 mu M) and, at lower concentrations (2.5 and 5 mu M), with those of doxorubicin (0.25 mu g/mL) and etoposide (40 mu M), and exceeded significantly those of taxol (1 mu M) and hydroxyurea (1 mM). The cytotoxicities of most of the studied compounds at 10 mu M against SK-LMS-1 and U2OS cells in vitro were significantly greater than all reference drugs (doxorubicin, taxol, etoposide, etc.).