Irregularly Bridged Epipolythiodioxopiperazines and Related Analogues: Sources, Structures, and Biological Activities.

Epipolythiodioxopiperazines (ETPs) are a class of biologically active fungal secondary metabolites characterized by a bridged polysulfide piperazine ring. Regularly, the sulfide functionality is attached in the α-positions of the dioxopiperazine scaffold. However, ETPs possessing irregular sulfur bridges have rarely been explored. This review summarizes that 83 compounds of this subtype have been isolated and characterized since the discovery of gliovirin in 1982. Herein, particular emphasis is given to the isolation, chemistry, and biological activity of this subtype. For a better understanding, a relevant summary focusing on the source microorganisms and their taxonomy is provided and will help elucidate the fascinating chemistry and biology of these unusual ETPs.

Cyclic heptapeptides from the soil-derived fungus Clonostachys rosea.

Three new cyclic heptapeptides (1-3) together with three known compounds (4-6) were isolated from a solid rice culture of the soil-derived fungus Clonostachys rosea. Fermentation of the fungus on white beans instead of rice afforded a new γ-lactam (7) and a known γ-lactone (8) that were not detected in the former extracts. The structures of the new compounds were elucidated on the basis of 1D and 2D NMR spectra as well as by HRESIMS data. Compounds 1 and 4 exhibited significant cytotoxicity against the L5178Y mouse lymphoma cell line with IC50 values of 4.1 and 0.1 µM, respectively. Compound 4 also displayed cytotoxicity against the A2780 human ovarian cancer cell line with an IC50 value of 3.5 µM. The preliminary structure-activity relationships are discussed.

Synthesis and bioactivity of diketopiperazine PJ147 and its derivatives from Gliocladium sp. YUP08.

Concise total synthesis of diketopiperazine PJ147, obtained from mycelium of Gliocladium sp. YUP08, has been achieved in seven steps with 43.5% overall yield. Biological evaluation of PJ147 exhibited strong inhibiting activity against A375-S2, Hela, P388, A-549, HL-60, and BEL-7420 cell lines. Thus, eight derivatives of PJ147 with high water solubility were also synthesized to facilitate the in vivo bioassay of this kind of diketopiperazines.

An antimicrobial diketopiperazine alkaloid and co-metabolites from an endophytic strain of Gliocladium isolated from Strychnos cf. toxifera.

From an endophytic strain of Gliocladium sp. isolated from the Amazonian plant Strychnos cf. toxifera, we obtained the diketopiperazine alkaloid cyclo-(glycyl-L-tyrosyl)-4,4-dimethylallyl ether (1), the steroids ergosterol (2), ergosterol peroxide (3), cerevisterol (4) and the citric acid (5). The AcOEt extract of the fermented broth by Gliocladium sp. showed potent activity against the cancer cell lines MDA-MB435 (human breast cancer cells), HCT-8 (human colorectal cancer cells) and SF-295 (human glioblastoma cancer cells). Compound 1 exhibited a strong antimicrobial activity against Micrococcus luteus at a concentration of 43.4 µM.

Cytotoxic piperazine-2,5-dione derivatives from marine fungus Gliocladium sp.

Two new piperazine-2,5-dione derivatives, gliocladride A (1) and B (2), along with deoxymycelianamide (3) were isolated from the mycelial mass of marine fungus Gliocladium sp. Their structures were established on the basis of spectral data, and the stereochemical assignments were made by chiral HPLC analysis of the hydrolyzed compounds and optical rotation comparison with known compound. Their cytotoxic activity was tested on three cancer cell lines, HL-60, U937 and T47D by MTT assay. As a result, gliocladride A (1) and B (2) showed moderate cytotoxic activity against the three cell lines with IC50 values from 11.60 microg/ml to 52.83 microg/ml, while deoxymycelianamide (3) showed strong cytotoxic activity against U937 cell line with IC50 values of 0.785 microg/ml.

Bioactive p-terphenyl derivatives from a Cordyceps-colonizing isolate of Gliocladium sp.

Gliocladinins A (1) and B (2), two new p-terphenyl derivatives, have been isolated from solid cultures of an isolate of Gliocladium sp. that colonizes Cordyceps sinensis. The structures of these compounds were determined mainly by analysis of their NMR spectroscopic data. In standard disk assays, compounds 1 and 2 showed modest antimicrobial activity against Staphylococcus aureus (ATCC 6538). In addition, these compounds displayed inhibitory effects on the growth of two human tumor cell lines, HeLa and HCT116.

A new piperazine-2,5-dione from the marine fungus Gliocladium sp.

A new piperazine-2,5-dione, named gliocladride, was isolated from marine fungus Gliocladium sp. The structure was established on the basis of spectral data, and the stereochemical assignments were made by 1H NMR spectrum and chiral HPLC of the hydrolyzed compound. Gliocladride showed a cytotoxic effect with an IC50 value of 3.86 microg/ml against human A375-S2 melanoma cell line.

Bioactivity profiling using HPLC/microtiter-plate analysis: application to a New Zealand marine alga-derived fungus, Gliocladium sp.

Using HPLC/microtiter-plate-based generation of activity profiles the extract of a marine alga-derived fungus, identified as Gliocladium sp., was shown to contain the known strongly cytotoxic metabolite 4-keto-clonostachydiol (1) and also clonostachydiol (2) as well as gliotide (3), a new cyclodepsipeptide containing several D-amino acids. The absolute configuration of 1 was elucidated by reduction to 2, and two further oxidized derivatives of clonostachydiol (5, 6) were prepared and evaluated for biological activity.

Secalonic acid D; A cytotoxic constituent from marine lichen-derived fungus Gliocladium sp. T31.

Secalonic acid D (SAD) was isolated as the major secondary metabolite of the marine lichen-derived fungus Gliocladium sp. T31. Its structure was established on the basic of physico-chemical and spectroscopic data. This is the first report on the isolation of SAD from this fungus, as well as its inhibitory effect on K562 cell cycle and its cytotoxicity against several tumor cell lines in vitro.

Cladionol A, a polyketide glycoside from marine-derived fungus Gliocladium species.

A new polyketide glycoside, cladionol A (1), was isolated from the cultured broth of a fungus Gliocladium sp., which was separated from sea grass Syringodium isoetifolium, and the structure was elucidated by spectroscopic data. The relative stereochemistry of C-2-C-3 was assigned by mainly J-based configuration analysis, while those of two sugar units were elucidated to be beta-mannopyranoside and arabitol on the basis of NOESY data and/or 1H-1H couplings. Furthermore, the absolute configuration of the mannose moiety was determined as the D-form on the basis of chiral HPLC analysis of a benzoyl derivative of the acid hydrolysate of 1. Cladionol A (1) exhibited modest cytotoxicity.