Antitumor activity of some microbial and chemical transformation products of anguidine (4,15-diacetoxyscirpene-3-ol)

Claridge, C. A.; Schmitz, H; Bradner, William T.

doi:10.1007/bf00258292

Cited by 12 publications

(7 citation statements)

References 3 publications

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“…The difference in the relative cytotoxicity of compounds 5 vs 6 suggested that the stereochemistry of 12′-OH also plays a role in potency. In vivo studies for trichothecene mycotoxins as antitumor chemotherapy drugs have been reported during the late 1970s and early 1980s; , unfortunately, they failed due to varied toxicity. Optimization of higher efficacy and lower toxicity of trichothecene mycotoxins might have significant potential for use as a chemotherapeutic agent in cancer treatment, and our SAR findings provide the derivatization information to develop the potential trichothecene mycotoxins.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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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

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Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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“…The structures of major toxins include zearalenone, zearalene, deoxynivalenol, nivalenol, T-2 toxin, and diacetoxyscirpenol (Figure 3) [75]. As far as anguidine analogues are concerned (Figure 3B), the in vivo antitumor activity in mice was measured upon treatment by triacetoxyscirpenol, the three diacetoxyscirpenols, the three monoacetoxyscirpenols, and scirpenetriol [81].…”

Section: Fusarium Toxinsmentioning

confidence: 99%

Janus-Faced Molecules against Plant Pathogenic Fungi

Bánfalvi

2021

IJMS

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The high cytotoxicity of the secondary metabolites of mycotoxins is capable of killing microbes and tumour cells alike, similarly to the genotoxic effect characteristic of Janus-faced molecules. The “double-edged sword” effect of several cytotoxins is known, and these agents have, therefore, been utilized only reluctantly against fungal infections. In this review, consideration was given to (a) toxins that could be used against plant and human pathogens, (b) animal models that measure the effect of antifungal agents, (c) known antifungal agents that have been described and efficiently prevent the growth of fungal cells, and (d) the chemical interactions that are characteristic of antifungal agents. The utilization of apoptotic effects against tumour growth by agents that, at the same time, induce mutations may raise ethical issues. Nevertheless, it deserves consideration despite the mutagenic impact of Janus-faced molecules for those patients who suffer from plant pathogenic fungal infections and are older than their fertility age, in the same way that the short-term cytotoxicity of cancer treatment is favoured over the long-term mutagenic effect.

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“…15) Trichothecenes inhibit protein synthesis by binding to the 60S ribosomal subunit in eukaryotic cells. 16) Inhibitors of protein synthesis have been known to trigger apoptosis of tumor cells.…”

Section: )mentioning

confidence: 99%

4-Acetyl-12,13-epoxyl-9-trichothecene-3,15-diol Isolated from the Fruiting Bodies of Isaria japonica YASUDA Induces Apoptosis of Human Leukemia Cells (HL-60).

Hong

et al. 2001

Biological & Pharmaceutical Bulletin

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The fruiting bodies of Isaria fungi have been traditionally used in Korea to treat cancer. An apoptosis-inducing compound, 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol, was isolated from the methanol extract of fruiting bodies of Isaria japonica YASUDA by bioassay-guided fractionation. The apoptosis of the human leukemia cells (HL-60) by the compound was accessed by propidium iodide-staining flow cytometric analysis, and apoptosis-inducing activity at IC 50 concentration (10 nmol/l) was further confirmed by a nuclear morphological change, a ladder pattern of internucleosomal DNA fragmentation, and an activation of caspase-3.Key words Isaria japonica YASUDA; human HL-60 leukemia cell; 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol; apoptosis japonica were inoculated into potato dextrose agar, and incubated at 25°C until the fungal colony grow to 5 cm in diameter. It usually took 10 d, and the colony turned gray. The cultures were then refrigerated at approximately 4°C, and used as stock cultures. In the second culture, a 1 l flask, containing 500 ml of culture medium, which had been sterilized at 121°C for 20 min and then cooled to 15°C, was inoculated with four 5-mm agar plugs taken from stock cultures. The flask culture was aerated by agitation on an orbital shaker at 140 rpm for a period of 3 d at 25°C, then at 160 ppm for 4 d. The culture medium consists of potato (200 g/l) and sugars (30 g/l). All cultures were conducted in the dark room. The third fermentation was carried out in the pupae of the silkworm (100 g). The fermentation media were autoclaved at 121°C for 40 min. After the media had cooled to 15°C, they were inoculated with 5 ml of spore inoculum and incubated for 8 d at 25°C in the dark room. After 8 d of cultivation, the culture condition was changed to 60% humidity for 10 d in the dark room, then 80% humidity at 20°C in 2000 lux of brightness for 30 d. After incubation, the fruiting bodies of the fungi were harvested, and extracted with MeOH for further chemical and biological investigations.Isolation and Structure Determination of 4-Acetyl-12,13-epoxy-9-trichothecene-3,15-diol The air-dried fruiting bodies (226 g) from the fermentation of I. japonica were extracted with methanol (MeOH) for 48 h. The MeOH extract was concentrated, suspended in H 2 O, and sequentially partitioned with n-hexane, CH 2 Cl 2 , and ethyl acetate (EtOAc). The EtOAc-soluble fraction (247.5 mg) was subjected to C18 flash column chromatography with a stepwise gradient of 30 to 100% (v/v) MeOH in H 2 O. The fractions eluting at 30% and 40% MeOH in H 2 O (36.8 mg) were combined, and subjected to preparative reversed-phase HPLC using a gradient from 15 to 35% CH 3 CN in H 2 O over 40 min, then 100% CH 3 CN for 10 min (Alltech HS Hyperprep 100 BDS C 18 (1.0ϫ25 cm; 8-mm particle size; 2 ml/min; UV detection at 210 nm)) to yield compound 1 (12.3 mg). The structure of compound 1 was identified as 4-acetyl-12,13-epoxy-9-trichothecene-3,15-diol (AEDT) by the comparison of MS and NMR data with those reported in the literature ...

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Antitumor activity of some microbial and chemical transformation products of anguidine (4,15-diacetoxyscirpene-3-ol)

Cited by 12 publications

References 3 publications

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

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

Janus-Faced Molecules against Plant Pathogenic Fungi

4-Acetyl-12,13-epoxyl-9-trichothecene-3,15-diol Isolated from the Fruiting Bodies of Isaria japonica YASUDA Induces Apoptosis of Human Leukemia Cells (HL-60).

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