Furanonaphthoquinone analogs possessing preferential antitumor activity compared to normal cells

Citation
Ki. Hirai et al., Furanonaphthoquinone analogs possessing preferential antitumor activity compared to normal cells, CANCER DET, 23(6), 1999, pp. 539-550
Citations number
40
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology
Journal title
CANCER DETECTION AND PREVENTION
ISSN journal
0361-090X → ACNP
Volume
23
Issue
6
Year of publication
1999
Pages
539 - 550
Database
ISI
SICI code
0361-090X(1999)23:6<539:FAPPAA>2.0.ZU;2-E
Abstract
The 50% growth inhibition toxicity (IC50 at 72 h) of 16 synthetic and 2 phy tochemical natural analogs of furanonaphthoquinones (naphtho[2,3-b]furan 4, 9-dione; FNQ) and 2 analogs of isofuranonaphthoquinones was assayed in vitr o in respect to established human cervical cancer and lung adenocarcinoma c ells in comparison with human uterine endocervical, tracheal rind bronchiol ar 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 esti mated 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)hydroxynap htho[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 carcinoma s, 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 cel ls. Two isofuranonaphthoquinone derivatives were ineffective, but a thieno derivative was equally cytotoxic to all cells tested. On the basis of the I C50 ratio data and the structure of the furanonaphthoquinones, the followin g structural activity (selectivity) relationship can be postulated: (i) the presence of an alkyl group at position 2 enhances the IC50 ratio, particul arly the methyl group; (ii) a hydroxyl group at position 5 or 8 enhances th e IC50 ratio; and (iii) methylation of the phenolic hydroxyl group leads to a decrease of potency. These results indicate that FNQ3, 13, and some othe r analogs are more preferentially cytotoxic to human tumor cells than to no rmal cells, unlike mitomycin-C, adriamycin, carboplatin, and methotrexate w hich are cytotoxic to the both. In nude mouse xenograft tests, FNQ3 demonst rated a significant antitumor activity with T/C% values of 16.6 to 41.6 aga inst several human carcinoma and osteosarcoma cells.