title: In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii.
abstract: The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.
authors.affiliation: Laboratoire de Toxicologie, Faculté de Pharmacie de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Le Calvé
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lallemand
authors.forename: Carmen
authors.initials: C
authors.lastname: Perrone
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Lenglet
authors.forename: Sabine
authors.initials: S
authors.lastname: Depauw
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Van Goietsenoven
authors.forename: Marina
authors.initials: M
authors.lastname: Bury
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vurro
authors.forename: Françoise
authors.initials: F
authors.lastname: Herphelin
authors.forename: Anna
authors.initials: A
authors.lastname: Andolfi
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zonno
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
authors.forename: François
authors.initials: F
authors.lastname: Dufrasne
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Antwerpen
authors.forename: Yves
authors.initials: Y
authors.lastname: Poumay
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.forename: Antonio
authors.initials: A
authors.lastname: Evidente
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
mesh_terms: D000478:Alkylation / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001203:Ascomycota / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D018715:Microscopy, Video; D009369:Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D006575:Heterocyclic Compounds, 3-Ring; C560346:phyllostictine A; D004247:DNA; D005978:Glutathione