Pro-Apoptotic and Immunostimulatory Tetrahydroxanthone Dimers from the Endophytic Fungus Phomopsis longicolla

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• 作者：David R枚nsberg ; Abdessamad Debbab ; Attila M谩ndi ; Vera Vasylyeva ; Philip B枚hler ; Bj枚rn Stork ; Laura Engelke ; Alexandra Hamacher ; Richard Sawadogo ; Marc Diederich ; Victor Wray ; WenHan Lin ; Matthias U. Kassack ; Christoph Janiak ; Stefanie Scheu ; Sebastian Wesselborg ; Tibor Kurt谩n ; Amal H. Aly ; Peter Proksch
• 刊名：Journal of Organic Chemistry
• 出版年：2013
• 出版时间：December 20, 2013
• 年：2013
• 卷：78
• 期：24
• 页码：12409-12425
• 全文大小：749K
• 年卷期：v.78,no.24(December 20, 2013)
• ISSN：1520-6904

文摘

Four tetrahydroxanthone dimers (<b>1b>鈥?b>4b>) and four biogenetically related monomers (<b>5b>鈥?b>8b>), including the new derivatives <b>4b>鈥?b>6b>, were isolated from the endophyte Phomopsis longicolla. The absolute configurations of <b>2b>鈥?b>4b> were established for the first time by TDDFT electronic circular dichroism calculations, and that of phomoxanthone A (<b>1b>) was revised by X-ray crystallography. Phomoxanthone A (<b>1b>) 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鈥揳ctivity studies of isolated compounds and derivatives obtained by semisynthesis (<b>9ab>鈥?b>11b>) 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.