Furanonaphthoquinone analogs possessing preferential antitumor activity compared to normal cells

The 50% growth inhibition toxicity (IC50 at 72 h) of 16 synthetic and 2 phytochemical natural analogs of furanonaphthoquinones (naphtho[2,3-b]furan-4,9-dione; FNQ) and 2 analogs of isofuranonaphthoquinones was assayed in vitro in respect to established human cervical cancer and lung adenocarcinoma cells in comparison with human uterine endocervical, tracheal and bronchiolar epithelial cells and fibroblasts. Prostate, cholangio, colon, laryngeal, and tongue carcinoma cell lines and two osteosarcoma cell lines were also used for the assay. The IC50 ratio of normal cells to cancer cells was estimated in order to represent preferential antitumor activity. Two analogs, 2-methylnaphtho[2,3-b]furan-4, 9-dione (FNQ3) and 2-methyl-5(or 8)-hydroxynaphtho[2,3-b]furan-4, 9-dione (FNQ13) showed 10.4 to 14.1 IC50 ratios for all carcinoma cells used, indicating a wide spectrum. Among different carcinomas, there was no difference or variety in the IC50 ratio of a single analog. A moderate IC50 ratio (3.1-4.7) was also found in nine analogs, but seven others were equally cytotoxic (less than 2.6) to both cancer and normal cells. Two isofuranonaphthoquinone derivatives were ineffective, but a thieno derivative was equally cytotoxic to all cells tested. On the basis of the IC50 ratio data and the structure of the furanonaphthoquinones, the following structural activity (selectivity) relationship can be postulated: (i) the presence of an alkyl group at position 2 enhances the IC50 ratio, particularly the methyl group; (ii) a hydroxyl group at position 5 or 8 enhances the IC50 ratio; and (iii) methylation of the phenolic hydroxyl group leads to a decrease of potency. These results indicate that FNQ3, 13, and some other analogs are more preferentially cytotoxic to human tumor cells than to normal cells, unlike mitomycin-C, adriamycin, carboplatin, and methotrexate which are cytotoxic to the both. In nude mouse xenograft tests, FNQ3 demonstrated a significant antitumor activity with T/C% values of 16. 6 to 41.6 against several human carcinoma and osteosarcoma cells.