Mode of action of epoxyphomalins A and B and characterization of related metabolites from the marine-derived fungus Paraconiothyrium sp.
Epoxyphomalins A (1) and B (2) are highly potent cytotoxic fungal metabolites. During the course of purifying larger quantities of 1 and 2 from Paraconiothyrium sp. fermentation extracts, three new epoxyphomalins (3-5) were isolated and characterized, showing modifications to the oxidation pattern of the cyclohexene moiety or of C-9 of the decalin system. IC(50) values for cytotoxicity against a panel of 36 human tumor cell lines were determined for all new compounds. Compound 4 was found to be cytotoxic particularly toward prostate PC3M (IC(50) = 0.72 μM) and bladder BXF 1218 L (IC(50) = 1.43 μM) cancer cell lines. In addition, inhibition of chymotrypsin-, caspase-, and trypsin-like activity of purified 20S proteasomes was determined for epoxyphomalins A (1) and B (2). The results indicate that compounds 1 and 2 exert their cytotoxic effect through potent inhibition of the 20S proteasome.
Department of Botany, University of Khartoum, Khartoum, Sudan.
Ietidal E
IE
Mohamed
Stefan
S
Kehraus
Anja
A
Krick
Gabriele M
GM
König
Gerhard
G
Kelter
Armin
A
Maier
Heinz-Herbert
HH
Fiebig
Markus
M
Kalesse
Nisar P
NP
Malek
Harald
H
Gross
D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001203:Ascomycota / Q000737:chemistry*; D061945:Caspase Inhibitors; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008297:Male; D008386:Marine Biology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D061988:Proteasome Inhibitors
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D018942:Macrolides; D061988:Proteasome Inhibitors; C545922:epoxyphomalin A; C545923:epoxyphomalin B; C555082:epoxyphomalin C; C555083:epoxyphomalin D; C555084:epoxyphomalin E