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

被引：100

作者：

Roensberg, David ^{[1
]}

Debbab, Abdessamad ^{[1
]}

Mandi, Attila ^{[2
]}

Vasylyeva, Vera ^{[3
]}

Boehler, Philip ^{[4
]}

Stork, Bjoern ^{[4
]}

Engelke, Laura ^{[5
]}

Hamacher, Alexandra ^{[5
]}

Sawadogo, Richard ^{[6
]}

Diederich, Marc ^{[6
]}

Wray, Victor ^{[7
]}

Lin, WenHan ^{[8
]}

Kassack, Matthias U. ^{[5
]}

Janiak, Christoph ^{[3
]}

Scheu, Stefanie ^{[9
]}

Wesselborg, Sebastian ^{[4
]}

Kurtan, Tibor ^{[2
]}

Aly, Amal H. ^{[1
]}

Proksch, Peter ^{[1
]}

机构：

[1] Univ Dusseldorf, Inst Pharmazeut Biol & Biotechnol, D-40225 Dusseldorf, Germany

[2] Univ Debrecen, Dept Organ Chem, H-4010 Debrecen, Hungary

[3] Univ Dusseldorf, Inst Anorgan Chem & Strukturchem, D-40225 Dusseldorf, Germany

[4] Univ Dusseldorf, Univ Klinikum Dusseldorf, Inst Mol Med, D-40225 Dusseldorf, Germany

[5] Univ Dusseldorf, Inst Pharmazeut & Med Chem, D-40225 Dusseldorf, Germany

[6] Hop Kirchberg, Lab Mol & Cellular Biol Canc LBMCC, L-2540 Luxembourg, Luxembourg

[7] Helmholtz Ctr Infect Res, D-38124 Braunschweig, Germany

[8] Peking Univ, Hlth Sci Ctr, Natl Res Labs Nat & Biomimet Drugs, Beijing 100083, Peoples R China

[9] Univ Dusseldorf, Inst Med Mikrobiol & Krankenhaushyg, D-40225 Dusseldorf, Germany

来源：

JOURNAL OF ORGANIC CHEMISTRY | 2013年 / 78卷 / 24期

基金：

新加坡国家研究基金会;

关键词：

ABSOLUTE-CONFIGURATION; SECONDARY METABOLITES; ASPERGILLUS-ACULEATUS; CISPLATIN RESISTANCE; STRUCTURE VALIDATION; PHOMOXANTHONE-A; SECALONIC ACIDS; CANCER; DERIVATIVES; ENDOCROCIN;

D O I：

10.1021/jo402066b

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

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.

引用

页码：12409 / 12425

页数：17

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