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: David Rönsberg, Abdessamad Debbab, Attila Mándi, Vera Vasylyeva, Philip Böhler, Björn Stork, Laura Engelke, Alexandra Hamacher, Richard Sawadogo, Marc Diederich, Victor Wray, WenHan Lin, Matthias U Kassack, Christoph Janiak, Stefanie Scheu, Sebastian Wesselborg, Tibor Kurtán, Amal H Aly, Peter Proksch
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 78 Issue 24 Pg. 12409-25 (Dec 20 2013) ISSN: 1520-6904 [Electronic] United States
• PMID: 24295452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Xanthones

Topics

• Animals
• Antineoplastic Agents (chemistry, isolation & purification, pharmacology)
• Apoptosis (drug effects, immunology)
• Ascomycota (chemistry)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dimerization
• Dose-Response Relationship, Drug
• Humans
• Killer Cells, Natural (drug effects, immunology)
• Leukocytes, Mononuclear (drug effects, immunology)
• Macrophages (drug effects, immunology)
• Mice
• Models, Molecular
• Molecular Structure
• Quantum Theory
• Structure-Activity Relationship
• T-Lymphocytes (drug effects, immunology)
• Xanthones (chemistry, isolation & purification, pharmacology)