Evaluation of the anticancer activities of two fungal polycyclic ethanones, alternethanoxins A and B, and two of their derivatives.
Alternethanoxins A (1) and B (2) are fungal phytotoxins that are produced by Alternaria sonchi and have been recently characterized as new polycyclic ethanones. Triacetyl (3) and dimethyl (4) derivatives of compound 1 were evaluated together with alternethanoxins for their in vitro growth inhibitory activities in five human and one mouse cancer cell lines in comparison to the reference compound temozolomide (TMZ). Compounds 1-4 and TMZ displayed similar growth inhibitory activities, and these anticancer activities were equivalent in cancer cell lines that display certain levels of resistance to pro-apoptotic stimuli and those that are sensitive to pro-apoptotic stimuli. Of the six cancer cell lines under study, the human esophageal cancer cell line OE21 was the most sensitive to the four polycyclic ethanones. Computer-assisted phase-contrast microscopy (quantitative videomicroscopy) revealed that compounds 1, 2 and 4 displayed cytostatic rather than cytotoxic growth inhibitory effects, while compound 3 appeared to have cytotoxic effects. Thus, this study creates a stimulus for further structure-activity investigations with respect to the anticancer activities of compounds belonging to the alternethanoxin group. The observed toxicity does not seem to be affected by the stereochemistry of C-6 of the B ring, the presence of a hydroxy group at C-1 or the presence of a furan ring joining rings A and C in alternethanoxin B. The anticancer activity (cytostatic versus cytotoxic) of this type of compound could be affected by the chemical moieties present at the hydroxy groups at C-4 and C-6, as was observed for the cytostatic and cytotoxic activities of derivatives 4 and 3, respectively.
Laboratoire de Toxicologie, Institut de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Marina
M
Bury
Biancavaleria
B
Punzo
Alexander
A
Berestetskiy
Benjamin
B
Lallemand
Jacques
J
Dubois
Florence
F
Lefranc
Véronique
V
Mathieu
Anna
A
Andolfi
Robert
R
Kiss
Antonio
A
Evidente
D000528:Alternaria / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009183:Mycotoxins / Q000302:isolation & purification / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009183:Mycotoxins; D011083:Polycyclic Compounds