title: Pro-apoptotic and immunostimulatory tetrahydroxanthone dimers from the endophytic fungus Phomopsis longicolla.
abstract: Four tetrahydroxanthone dimers (1-4) and four biogenetically related monomers (5-8), including the new derivatives 4-6, were isolated from the endophyte Phomopsis longicolla. The absolute configurations of 2-4 were established for the first time by TDDFT electronic circular dichroism calculations, and that of phomoxanthone A (1) was revised by X-ray crystallography. Phomoxanthone A (1) showed the strongest pro-apoptotic activity when tested against a panel of human cancer cell lines, including cisplatin-resistant cells, whereas it was up to 100-fold less active against healthy blood cells. It was also the most potent activator of murine T lymphocytes, NK cells, and macrophages, suggesting an activation of the immune system in parallel to its pro-apoptotic activity. This dual effect in combating cancer cells could help in fighting resistance during chemotherapy. Preliminary structure-activity studies of isolated compounds and derivatives obtained by semisynthesis (9a-11) hinted at the location of the biaryl axis and the presence of acetyl groups as important structural elements for the biological activity of the studied tetrahydroxanthones.
authors.affiliation: Institut für Pharmazeutische Biologie und Biotechnologie, Heinrich-Heine-Universität , Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Rönsberg
authors.forename: Abdessamad
authors.initials: A
authors.lastname: Debbab
authors.forename: Attila
authors.initials: A
authors.lastname: Mándi
authors.forename: Vera
authors.initials: V
authors.lastname: Vasylyeva
authors.forename: Philip
authors.initials: P
authors.lastname: Böhler
authors.forename: Björn
authors.initials: B
authors.lastname: Stork
authors.forename: Laura
authors.initials: L
authors.lastname: Engelke
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hamacher
authors.forename: Richard
authors.initials: R
authors.lastname: Sawadogo
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.forename: Victor
authors.initials: V
authors.lastname: Wray
authors.forename: WenHan
authors.initials: W
authors.lastname: Lin
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Christoph
authors.initials: C
authors.lastname: Janiak
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
authors.forename: Tibor
authors.initials: T
authors.lastname: Kurtán
authors.forename: Amal H
authors.initials: AH
authors.lastname: Aly
authors.forename: Peter
authors.initials: P
authors.lastname: Proksch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001203:Ascomycota / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D044004:Xanthones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones