Eremophilane Sesquiterpenes and Polyketones Produced by an Endophytic Guignardia Fungus from the Toxic Plant Gelsemium elegans

Abstract

A cultured endophytic fungus, Guignardia mangiferae, isolated from the toxic plant Gelsemium elegans yielded five new sesquiterpenes (1−5), two new polyketones (6 and 7), and two known terpene polyketones (8 and 9). Their structures were elucidated using spectroscopic methods. On the basis of circular dichroism, the absolute configurations of the new compounds were determined. Compounds 1, 3, 4, and 9 inhibited lipopolysaccharide-induced NO production in BV2 cells with IC 50 values of 15.2, 6.4, 4.2, and 4.5 μM, respectively (positive control curcumin, IC 50 = 3.9 μM). M icroglia are a type of glial cell that are the resident macrophages of the central nervous system (CNS). Activation of microglia plays a critical role in the neural inflammatory process by releasing a variety of inflammatory mediators including nitric oxide (NO). 1,2 Thus, secondary metabolites that inhibit NO production may have antineuroinflammatory effects.Gelsemium elegans Benth., historically used in traditional Chinese medicine as an analgesic and antispasmodic and as a remedy for certain kinds of skin ulcers, 3 can be lethal to humans and livestock due to its toxic alkaloid content. 4 We have previously discovered some bisindole alkaloids with potential antineuroinflammatory activity by suppressing lipopolysaccharide (LPS)-induced NO production in BV2 microglial cells from G. elegans. 2 We have continued this research program on the discovery of bioactive secondary metabolites with NO production inhibition from endophytic fungi associated with the toxic plant G. elegans.Guignardia mangiferae is an endophytic fungus isolated from the leaves of G. elegans. A series of bioactive secondary metabolites including the cytotoxic tricycloalternarenes, 5,6 the cytotoxic vermistatin derivatives, 7 and the phytotoxic dioxolanone-type secondary metabolites 8 have been reported from Guignardia fungi. In our study, five new eremophilane sesquiterpenes named guignarderemophilanes A−E (1−5), two new benzyl derivatives named guignardene A (6) and guignarlactone A (7), and two known metabolites (8 and 9) were isolated from G. mangiferae. The compounds obtained were assayed for their inhibitory activity on NO production. Compounds 1, 3, 4, and 9 inhibited LPS-induced NO production in BV2 cells with IC 50 values of 15.2, 6.4, 4.2, and 4.5 μM, respectively (positive control curcumin, IC 50 = 3.9 μM). None of the compounds were active against the HCT-8, HCT-116, Bel-7402, BGC-823, A549, and A2780 cell lines. Herein, we report the structural elucidation and bioactivity of 1−9. ■ RESULTS AND DISCUSSIONThe fungus G. mangiferae was cultured in potato dextrose agar (PDA) medium (100 L). The filtrate of the culture was loaded onto a macroporous resin column and eluted with water and 95% alcohol, respectively. The alcohol elution, after concentration, was fractionated by chromatography, and compounds were purified by preparative HPLC, to afford compounds 1−9.

Identification of a Unique Azaphilone Produced by Chaetomium globosum Isolated from Polygonatum sibiricum

“…Chaetomium globosum belongs to the widely studied Chaetomiaceae family and is rich in structurally diverse compounds . Fungal polyketones are of considerable importance in medical research and agricultural application . Azaphilone is one of the polyketide family produced by numerous species of ascomycetes and basidiomycetes with various bioactivities such as cytotoxic, antimicrobial and other biological activities .…”

Total Synthesis of the Polyoxygenated Sesquiterpenes Guignarderemophilanes C and D

“…Neither of these compounds have been synthesized yet and there is no reported preparative strategy addressing this unusual trihydroxylated A‐ring motif. Recently, two natural products with a 1 α ,2 β ,3 β ‐trihydroxylated scaffold have been isolated for the first time from the fungus Guignardia mangiferae , and named guignarderemophilanes C ( 1 ) and D ( 2 ) . The fungus Guignardia mangiferae is an endosymbiont of plants such as Gelsemium elegans , whose extracts are used in traditional Chinese medicine as nervous relaxant and for the treatment of pain .…”

“…The fungus Guignardia mangiferae is an endosymbiont of plants such as Gelsemium elegans , whose extracts are used in traditional Chinese medicine as nervous relaxant and for the treatment of pain . Both eremophilanes showed neural anti‐inflammatory activity by inhibiting the LPS‐induced NO production in BV2 cells with IC 50 values of 6.4 and 4.2 μ m , respectively . Therefore, guignarderemophilanes C and D may potentially serve as lead compounds for developing treatment options for neurodegenerative diseases.…”

“…Recently, two natural products with a 1a,2b,3b-trihydroxylated scaffold have been isolated for the first time from the fungus Guignardia mangiferae, and named guignarderemophilanes C (1) and D (2). [9] The fungus Guignardia mangiferae is an endosymbiont of plants such as Gelsemium elegans, whose extracts are used in traditional Chinese medicine as nervous relaxant and for the treatment of pain. [10] Both eremophilanes showed neural anti-inflammatory activity by inhibiting the LPS-induced NO production in BV2 cells with IC 50 values of 6.4 and 4.2 lM, respectively.…”

“…[10] Both eremophilanes showed neural anti-inflammatory activity by inhibiting the LPS-induced NO production in BV2 cells with IC 50 values of 6.4 and 4.2 lM, respectively. [9] Therefore, guignarderemophilanes C and D may potentially serve as lead compounds for developing treatment options for neurodegenerative diseases.…”