Search Results (10)

The special metabolite of Fusarium spp. zearalenone (ZEN) exerts estrogenic effects on mammals, stimulates plant growth, stimulates sexual development in fungi, and inhibits fungal growth. These activities inspired hypotheses about the biological function of ZEN. We briefly review the discovery of ZEN and its implications. The main subject of this review is a critical assessment of the hypotheses that ZEN is a fungal hormone, a plant hormone, a virulence factor, or a fungal defense metabolite. Conceptual and technical issues related to testing these hypotheses, such as inadequate analytical methods, confusion of incidental effects with biological functions, and lack of normalization, are illuminated. Based on these considerations, gene knockout experiments, and on the effects of biotic interactions on ZEN synthesis, we argue that ZEN is a defense metabolite protecting Fusarium spp. against mycoparasites and competitors. Similar reasoning and published data suggest that the Fusarium metabolite fusaristatin A fulfils the same function. Fungi produce many macrolactones of resorcylic acid (RALs) and dihydroxyphenylacetic acid (DHPLs) with properties similar to ZEN. Their widespread occurrence, antifungal activity, and further considerations prompt us to hypothesize that the fundamental function of fungal RALs and DHPLs lies in defense and interference competition. Full article

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti-M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid lactone with an acetonide group at C-5′ and C-6′, exhibits a wide range of antimicrobial, antimalarial, and antifouling activities. To further explore the effect of this structural change at C-5′ and C-6′ on this compound’s activity, we synthesized a series of compounds with a structure similar to that of cochliomycin A, bearing ketal groups at C-5′ and C-6′. The R/S configuration of the diastereoisomer at C-13′ was further determined through an NOE correlation analysis of CH₃ or CH₂ at the derivative C-13′ position and the H-5′ and H-6′ by means of a 1D NOE experiment. Further comparative ¹H NMR analysis of diastereoisomers showed the difference in the chemical shift (δ) value of the diastereoisomers. The synthetic compounds were screened for their anti-microbial activities in vitro. Compounds 15–24 and 28–35 demonstrated promising activity against M. marinum, with MIC₉₀ values ranging from 70 to 90 μM, closely approaching the MIC₉₀ of isoniazid. The preliminary structure–activity relationships showed that the ketal groups with aromatic rings at C-5′ and C-6′ could enhance the inhibition of M. marinum. Further study demonstrated that compounds 23, 24, 29, and 30 had significant inhibitory effects on M. marinum and addictive effects with isoniazid and rifampicin. Its effective properties make it an important clue for future drug development toward combatting M. marinum resistance. Full article

Zearalenone and radicicol are resorcylic acid lactones produced by numerous plant pathogenic fungi. Zearalenone is a non-steroidal estrogen mimic that can cause serious reproductive issues in livestock that consume contaminated feed. Radicicol is a potent inhibitor of the molecular chaperone Hsp90, which, in plants, has an important role in coordinating the host’s immune response during infection. Here, we describe the identification and characterization of a soil-borne strain of the Gram-positive bacterium Aeromicrobium sp. capable of hydrolyzing the macrolide ring of resorcylic acid lactones, including zearalenone and radicicol. Proteomic analysis of biochemically enriched fractions from the isolated and cultured bacterium identified an α/β-hydrolase responsible for this activity. A recombinantly expressed and purified form of the hydrolase (termed RALH) was active against both zearalenone and radicicol. Interpretation of high-resolution mass spectrometry and NMR data confirmed the structures of the enzymatic products as the previously reported non-toxic metabolite hydrolyzed zearalenone and hydrolyzed radicicol. Hydrolyzed radicicol was demonstrated to no longer inhibit the ATPase activity of the Saccharomyces cerevisiae Hsp90 homolog in vitro. Enzymatic degradation of resorcylic acid lactones will enable insight into their biological functions. Full article

With the emergence of drug-resistant strains, the treatment of tuberculosis (TB) is becoming more difficult and there is an urgent need to find new anti-TB drugs. Mycobacterium marinum, as a model organism of Mycobacterium tuberculosis, can be used for the rapid and efficient screening of bioactive compounds. The 14-membered resorcylic acid lactones (RALs) have a wide range of bioactivities such as antibacterial, antifouling and antimalarial activity. In order to further study their bioactivities, we initially constructed a 14-membered RALs library, which contains 16 new derivatives. The anti-M. marinum activity was evaluated in vitro. Derivatives 12, 19, 20 and 22 exhibited promising activity with MIC₉₀ values of 80, 90, 80 and 80 μM, respectively. The preliminary structure–activity relationships showed that the presence of a chlorine atom at C-5 was a key factor to improve activity. Further studies showed that 12 markedly inhibited the survival of M. marinum and significantly reduced the dosage of positive drugs isoniazid and rifampicin when combined with them. These results suggest that 12 is a bioactive compound capable of enhancing the potency of existing positive drugs, and its effective properties make it a very useful leads for future drug development in combating TB resistance. Full article

Five new β-resorcylic acid derivatives, 14-hydroxyasperentin B (1), β-resoantarctines A-C (3, 5, 6) and 8-dehydro-β-resoantarctine A (4), together with known 14-hydroxyasperentin (5′-hydroxyasperentin) (2), were isolated from the ethyl acetate extract of the fungus Penicillium antarcticum KMM 4685 associated with the brown alga Sargassum miyabei. The structures of the compounds were elucidated by spectroscopic analyses and modified Mosher’s method, and the biogenetic pathways for compounds 3–6 were proposed. For the very first time, the relative configuration of the C-14 center of a known compound 2 was assigned via analyses of magnitudes of the vicinal coupling constants. The new metabolites 3–6 were biogenically related to resorcylic acid lactones (RALs); however, they did not possess lactonized macrolide elements in their structures. Compounds 3, 4 and 5 exhibited moderate cytotoxic activity in LNCaP, DU145 and 22Rv1 human prostate cancer cells. Moreover, these metabolites could inhibit the activity of p-glycoprotein at their noncytotoxic concentrations and consequently synergize with docetaxel in p-glycoprotein-overexpressing drug-resistant cancer cells. Full article

Meliaceae plants are found worldwide in tropical or subtropical climates. They are important ethnobotanically as sources of traditional medicine, with 575 species and 51 genera. Previous research found that microorganisms are plant pioneers to produce secondary metabolites with diverse compound structures and bioactivities. Several plants of the Meliaceae family contain secondary metabolites isolated from endophytic fungi. Furthermore, related articles from 2002 to 2022 were collected from SciFinder, Google Scholar, and PubMed. About 276 compounds were isolated from endophytic fungi such as terpenoids, polyketides, lactones, pyrones, quinone, anthraquinones, xanthones, coumarines, isocoumarines, resorcylic acid lactones, cytochalasins, aromatics, ester, quinols, alkaloids, nitro compound, fatty acids, and sugars with bioactivities such as antioxidant, antibacterial, antifungal, anti-influenza, neuroprotective activities, anti-HIV, cytotoxic, allelopathic, anti-inflammatory, antifeedant effects, and BSLT toxicity. Meanwhile, secondary metabolites isolated from endophytic fungi were reported as one of the sources of active compounds for medicinal chemistry. This comprehensive review summarizes the ethnobotanical uses and secondary metabolites derived from Meliaceae endophytic fungi. Full article

Phytoestrogens are literally estrogenic substances of plant origin. Although these substances are useful for plants in many aspects, their estrogenic properties are essentially relevant to their predators. As such, phytoestrogens can be considered to be substances potentially dedicated to plant–predator interaction. Therefore, it is not surprising to note that the word phytoestrogen comes from the early discovery of estrogenic effects in grazing animals and humans. Here, several compounds whose activities have been discovered at nutritional concentrations in animals and humans are examined. The substances analyzed belong to several chemical families, i.e., the flavanones, the coumestans, the resorcylic acid lactones, the isoflavones, and the enterolignans. Following their definition and the evocation of their role in plants, their metabolic transformations and bioavailabilities are discussed. A point is then made regarding their health effects, which can either be beneficial or adverse depending on the subject studied, the sex, the age, and the physiological status. Toxicological information is given based on official data. The effects are first presented in humans. Animal models are evoked when no data are available in humans. The effects are presented with a constant reference to doses and plausible exposure. Full article

Six new β-resorcylic acid derivatives (1–5 and 7) were isolated from a halophyte-associated fungus, Colletotrichum gloeosporioides JS0419, together with four previously reported β-resorcylic acid lactones (RALs). The relative and absolute stereochemistry of 1 was completely established by a combination of spectroscopic data and chemical reactions. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR data. Notably, compounds 1–3 had a β-resorcylic acid harboring a long unesterified aliphatic side chain, whereas the long aliphatic chains were esterified to form macrolactones in 4–9. Among the isolated compounds, monocillin I and radicicol showed potent antifungal activities against Cryptococcus neoformans, comparable to clinically available antifungal agents and radicicol showed weak antifungal activity against Candida albicans. These findings provide insight into the chemical diversity of fungal RAL-type compounds and their pharmacological potential. Full article

Cancer is one of the leading causes of death globally, accounting for an estimated 8 million deaths each year. As a result, there have been urgent unmet medical needs to discover novel oncology drugs. Natural and synthetic lactones have a broad spectrum of biological uses including anti-tumor, anti-helminthic, anti-microbial, and anti-inflammatory activities. Particularly, several natural and synthetic lactones have emerged as anti-cancer agents over the past decades. In this review, we address natural and synthetic lactones focusing on their anti-tumor activities and synthetic routes. Moreover, we aim to highlight our journey towards chemical modification and biological evaluation of a resorcylic acid lactone, L-783277 (4). We anticipate that utilization of the natural and synthetic lactones as novel scaffolds would benefit the process of oncology drug discovery campaigns based on natural products. Full article

Seven resorcylic acid lactones (RALs) including five new analog rhinoclactones, A–E (1, 2, 4–6), were isolated from an endophytic fungus Rhinocladiella similis in the plant Agriophyllum squarrosum collected from the Tengger Desert of the Ningxia Province, China. The structures of these new compounds were determined by HR-ESI-MS (High Resolution Electrospray Ionization Mass Spectrometry), NMR data, modified Mosher’s method, and X-ray diffraction experiments. All compounds isolated from this fungus possessed the 16-OMe/14-OH, not the common 16-OH/14-OH or 16-OH/14-OMe groups on the aromatic ring, which are rarely found in nature. Compound 7 displayed cytotoxic activities against HCT116 and HeLa cancer cell lines. The possible biosynthesis of 1–7 is suggested, and the potential ecological roles of these fungal secondary metabolites is discussed. Full article