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A total of 23 newly-synthesized 2-aminomethylene-3(2H)-benzofuranone and structurally-related compounds were compared for their cytotoxic activity against both normal (human gingival fibroblast HGF) and tumor cells (human oral squamous cell lines HSC-2, HSC-3 and human salivary gland tumor cells HSG). There was a significant variability of drug sensitivity among the oral tumor cell lines. In general, HSC-2 cells were the most sensitive, followed by HSG cells, while HSC-3 cells were the most resistant. HGF normal cells were highly resistant to all compounds, suggesting their tumor-specific cytotoxic action. The cytotoxic activity of the compounds with morpholine, 1-methylpiperazine or piperidine structure was generally elevated by the introduction of fluorine, but not chlorine and methoxy functional groups, to the benzofuranone structure, whereas that of compounds attached by 1-phenylpiperazine or 1-(2-pyridyl)piperazine was rather reduced. The most active compounds induced internucleosomal DNA fragmentation in human promyelocytic leukemia HL-60 cells, but not in HSG, further confirming that oral tumor cell lines are resistant to DNase digestion.

A total of 11 newly synthesized benzothiepins and structurally-related compounds were investigated for cytotoxic activity against both normal and tumor cells. All these compounds showed higher cytotoxic activity against three human oral tumor cell lines (HSC-2, HSC-3, HSG) than against normal human gingival fibroblast (HGF), suggesting tumor-specific cytotoxic action. In general, 3,4-dihydro-1-benzothiepin-5(2H)-ones [1-6] showed higher cytotoxic activity than 2,3-dihydro-1-benzothiepins [7-11]. Compounds 4 (4-bromo-3,4-dihydro-2-(2-oxo-2-phenylethyl)-1-benzothiepin-5(2H)-one), 5 (4-bromo-3,4-dihydro-2-(2-oxopropyl)-1-benzothiepin-5(2H)-one) and 6 (4-bromo-3,4-dihydro-2-[1-(methoxycarbonyl)-1-methylethyl]-1-benzothiepin-5(2H)-one), showed higher cytotoxic activity than compounds 1, 2 and 3, respectively, which had Cl instead of Br at C-4 position. Agarose gel electrophoresis demonstrated that these compounds induced large DNA fragments in oral tumor cells, whereas they produced smear pattern of smaller DNA fragments in human promyelocytic leukemia cells HL-60. These data suggest the medicinal efficacy of benzothiepins.

A total of 24 benzoylimidazoles and structurally-related compounds were investigated for their cytotoxic activity against oral tumor cells and normal gingival fibroblast. Compound 23 (5-(2-hydroxylbenzoyl)-2-phenylimidazole) showed the highest cytotoxic activity against both human oral tumor cell lines (human squamous cell carcinoma HSC-2, human salivary gland tumor HSG) and normal human gingival fibroblast (HGF). Compounds 7 (2-(2-hydroxybenzoyl)benz imidazo[2,1-b]thiazole), 14 (1,3-diethyl-5-(2-hydroxybenzoyl)-4-imidazoline-2-thione) and 18 (5-(2-hydroxy-4-methoxybenzoyl)-3-methyl-2-methylimino-4-thiazoline) showed slightly lower cytotoxic activity, but higher tumor-specific cytotoxic action. The cytotoxic activity of compound 23 was significantly reduced by CuCl2, but not by CoCl2, FeCl3, or by antioxidants (N-acetyl-L-cysteine, sodium ascorbate, catalase). Compound 23 did not show any detectable oxidation potential (determined by NO monitor). Agarose gel electrophoresis demonstrated that compound 23 induced DNA fragmentation in human promyelocytic leukemia cells HL-60, but not in HSG cells. These data suggested that the response to compound 23 might be different from cell to cell.

Among 11 benzothiepins/benzoxepins, 4-chloro-3,4-dihydro-2-(2-oxo-2-phenylethyl)-1-benzothiepin-5-(2H)-one [1] showed the highest cytotoxicity against human oral squamous cell carcinoma HSC-2 cells, followed by 2,3-dihydro-2-(2-oxopropyl)-2-phenyl-1-benzoxepin [2]. Popular antioxidants, such as N-acetyl-L-cysteine and sodium ascorbate significantly reduced the cytotoxic activity of [1] but not that of [2]. Compound [1] induced internucleosomal DNA fragmentation in human promyelocytic leukemic HL-60 cell line, but produced large DNA fragmentation in human oral tumor cell lines (HSC-2, HSG). Compounds [1] and doxorubicin additively reduced the viable cell number of HSC-2 cells. These data, taken together with their tumor specific action, demonstrate for the first time, the medicinal efficacy of benzothiepins/benzoxepins.