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.

Phomopsichin A–D; Four New Chromone Derivatives from Mangrove Endophytic Fungus Phomopsis sp. 33#

“…Compound 5 was identified as phomoxanthone A ( 5 , Figure 1) by comparison of its spectral data with that of the literature [16,17]; both compound 5 and phomoxanthone A had the same NMR, MS, ECD data (Figure S27, in Supplementary Materials) and specific rotation data.…”

“…Compounds 1 – 4 showed no cytotoxic activity against MDA-MB-435 breast cancer cells. It was reported that phomoxanthone A ( 5 ) has strong pro-apoptotic activity and immunostimulatory activity [17], so we did not consider its cytotoxicity assays in the study.…”

Metabolites from Combretum dolichopetalum and its associated endophytic fungus Nigrospora oryzae — Evidence for a metabolic partnership

“…In the course of our ongoing research on bioactive natural products from endophytic fungi and their associated host plants [7][8][9][10], we became interested in the African rain forest tree Combretum dolichopetalum Engl. and Diels (Combretaceae), a plant which is hitherto chemically unexplored but is reported to posses hepatoprotective [11], antiulcer [12] and antidiabetic activities [13] and is used traditionally for the treatment of gastrointestinal disorders [14].…”

Absolute configuration and anti-tumor activity of torrubiellin B

“…[8][9][10] We and others have repeatedly shown that Mangrove associated endophytes are valuable sources of new bioactive metabolites such as the anti-tumor metabolite phomoxanthone A isolated from the Mangrove endophyte Phomopsis longicolla, which was found to strongly inhibit tumor cells. 11 Mangroves are prone to numerous stress factors such as changing levels of salinity, periodical flooding, and a high incidence of herbivores and of pathogenic microbes. Apparently these factors have shaped not only the secondary metabolites of the hosts but also those of their associated endophytes.…”