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-pyrrole3-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 M was comparable with that of imatinib (1 M) and, at lower concentrations (2.5 and 5 M), with those of doxorubicin (0.25 g/mL) and etoposide (40 M), and exceeded significantly those of taxol (1 M) and hydroxyurea (1 mM). The cytotoxicities of most of the studied compounds at 10 M against SK-LMS-1 and U2OS cells in vitro were significantly greater than all reference drugs (doxorubicin, taxol, etoposide, etc.).