Macrocyclic Trichothecene Mycotoxins from a Deadly Poisonous Mushroom, Podostroma cornu-damae

Abstract

Three new macrocyclic trichothecenes (1−3) and five known related compounds (4−8) were isolated from the MeOH extract of a plate culture of the fungus Podostroma cornu-damae, a deadly poisonous mushroom. Miophytocen D (1) is a rearranged macrocyclic type D trichothecene, featuring a bicyclo-[6.5]dodecahydrocyclopenta[b]chromene scaffold, and the structures of new compounds (1−3) were delineated by the combination of 1D and 2D NMR spectroscopic experiments and HRESIMS, modified Mosher's esterification, and quantum chemical ECD calculations. The isolated compounds (1−8) were evaluated for cytotoxicity against four human breast cancer cell lines (Bt549, HCC70, MDA-MB-231, and MDA-MB-468). Compounds 4, 6, and 8 exhibited significant cytotoxic effects against the breast cancer cell lines, with IC 50 values in the range of 0.02−80 nM, which is stronger than doxorubicin, the positive control, and a structure−activity relationship was suggested.Podostroma cornu-damae is a lethal toxic mushroom belonging to the Hypocreaceae family and contains fatal trichothecenes, a large family of chemically related mycotoxins that present a potential threat to public health throughout the world. 1 The mushroom, which is widely distributed in Japan, China, and East Asia, is known as the red deer's horn mushroom due to its exceptional deer-horn-like appearance. 2 Because the shape of P. cornu-damae resembles immature Ganoderma lucidum and Cordyceps medicinal mushrooms, fatal poisonings have occurred accidentally from misunderstandings involving these mushrooms. 2,3 In Japan, 13 cases of accidental intoxication of P. cornu-damae were reported from 1983 to 2008, including two deaths after ingesting only a few centimeters of its fruiting body. 2,3 In Korea, of two people who ate boiled fungus, one person died because of multiorgan failure in spite of aggressive medical intervention, and the other improved after conservative management for one month. 1,4 The early symptoms of poisoning are vomiting, dehydration, and diarrhea. After approximately 3 days, anuria, hypotension, polypnea, leukopenia, thrombocytopenia, and disturbance of consciousness have been reported. 2,3 There is only one report on the chemical investigation of toxic metabolites from P. cornu-damae, 5 where satratoxin H 12′,18′-diacetate, satratoxin H 12′-acetate, and satratoxin H 13′-acetate have been identified as new macrocyclic trichothecenes. All of the isolated macrocyclic

Toxicological analysis of satratoxins, the main toxins in the mushroom Trichoderma cornu-damae, in human serum and mushroom samples by liquid chromatography–tandem mass spectrometry

“…For both samples, in the transitions for satratoxin H, an unknown peak was observed at 20.5 min (Fig. 6a, b) and this was thought to be 12′-epi-satratoxin H [30] or isosatratoxin H [31] since these are the only currently known isomers of satratoxin H. However, we ultimately could not identify this peak because of the limited amount of mushroom samples. The standard addition calibration equations for satratoxins in mushroom samples are shown in Table S5.…”

Recent Advances on Macrocyclic Trichothecenes, Their Bioactivities and Biosynthetic Pathway

“…[ 7 , 10 , 28 ]. Macrocyclic trichothecenes are produced by the genera Myrothecium [ 29 , 30 , 31 ], Podostroma [ 32 ], Stachybotrys [ 33 ], Calcarisporium [ 34 ], Cercophora [ 35 ], Cylindrocarpon [ 36 ], Dendrodochium [ 37 ], Phomopsis [ 38 ], and Verticinimonosporium [ 39 ]. It is worth noting that Baccharis , belonging to the Asteraceae family, is the only plant genus that can produce trichothecenes [ 40 ].…”

“…Generally, 10,13-cyclotrichothecane macrolides have been proved to be less cytotoxic than the trichothecenes with the epoxide at C-12, C-13 [ 46 , 47 , 48 ]. Roridin F ( 21 ) and satratoxin I ( 22 ) discovered from Podostroma cornu-damae , a deadly poisonous mushroom, are not complete macrolides, because the macrocyclic ester bridge between C-4 and C-15 are not closed; however, they might be transformed into roridin E and satratoxin H, respectively, through a one-step esterification [ 32 ]. Chartarene D ( 23 ) is the only macrocyclic trichothecene isolated from Stachybotrys during the past decade [ 33 ].…”

“…Compounds 6 , 9 , 14 – 17 were evaluated for their in vitro cytotoxicities against K562 and SW1116, and the relatively large differences in IC 50 values suggested that the slight changes of the substituent group have obvious effects on the biological selectivity of macrocyclic trichothecenes against cancer cell lines [ 44 ]. There have been some studies suggesting that the breakage of the macrocyclic ring could dramatically decrease the cytotoxicity [ 45 , 54 ], and it was supported by the fact that roridin F ( 21 ) and satratoxin I ( 22 ) without macrocyclic ring were almost inactive against cancer cell lines (data not included in Table 2 ) [ 32 ]. All these data indicated that even small alterations in the molecular structure can lead to a substantial change in biological activity or selectivity against cancer cell lines [ 41 , 59 ].…”

Discovery of Dihydrophaseic Acid Glucosides from the Florets of Carthamus tinctorius

“…To acquire the optimal conformation of 1a/1b, computational DFT calculations were performed [23][24][25][26][27]. Detailed information is provided in the section of computational analysis in Supplementary Materials.…”