Resorcylic Acid Lactones Research Articles

Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups.

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.

Enzymatic Hydrolysis of Resorcylic Acid Lactones by an Aeromicrobium sp.

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.

Total Synthesis of (-)-Zearalenone and (-)-Zearalanone: A Macrocyclization Strategy by Ni/Zr/Cr-Mediated Reductive Ketone Coupling.

The total synthesis of the resorcylic acid lactones (-)-zearalenone and (-)-zearalanone is described. Our synthetic strategy relies on Ni-, Zr-, and Cr-mediated intramolecular reductive ketone coupling to create 14-membered macrolactones. Notably, the use of CrCl2 in addition to Ni/Zr-mediated reductive ketone coupling conditions was key for the success of the macrocyclization.

A new resorcylic acid lactone from the endophytic fungus Chaetosphaeronema sp.

A new 14-membered resorcylic acid lactone (RAL14), chaetolactone A (1), along with three known ones (2−4), was obtained from the fermentation of the soil-derived fungus Chaetosphaeronema sp. SSJZ001. Their structures were established based on extensive spectroscopic data analyses (UV, IR, HRESIMS, 1D, and 2D NMR),13C NMR chemical shifts calculations coupled with the DP4+ probability method, theoretical calculations of ECD spectra, as well as X-ray diffraction analysis. All compounds were evaluated for their cytotoxic effects against A549, HO-8910, and MCF-7 cell lines.

Nematicidal glycosylated resorcylic acid lactones from the fungus Pochonia chlamydosporia PC-170 and their key biosynthetic genes.

Chemical study of the nematicidal biocontrol fungus Pochonia chlamydosporia PC-170 led to discovery of six resorcylic acid lactones (RALs), including three nematicidal glycosylated RALs, monocillin VI glycoside (1), colletogloeolactone A (2) and monocillin II glycoside (3), and three antibacterial non-glycosylated RALs, monocillin VI (4), monocillin IV (5) and monocillin II (6). The planar structure of the new compound monocillin VI glycoside (1) was elucidated using HRESIMS and NMR data, and its monosaccharide configuration was further determined through sugar hydrolysis experiment and GC-MS analysis method. Furthermore, their two biosynthetic-related PKS genes, pchE and pchI, were identified through the gene knockout experiment. The glycosylated RALs 1-3 exhibited nematicidal activity against Meloidogyne incognita, with LC50 values of 94, 152 and 64 μg/mL, respectively, and thus had great potential in the development of new nematicidal natural products to control M. incognita in the future.

Study on the Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactone Derivatives.

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.

Ilyomycin L, a novel resorcylic acid lactone with furan nucleus from Ilyonectria sp. DWS906

A novel resorcylic acid lactone with furan nucleus, ilyomycin L (1), along with eleven known analogues (2–12) were isolated from the fermentation of the soil-derived fungus Ilyonectria sp. DWS906. Their chemical structures were identified by the comprehensive spectroscopic methods, including 1D/2D NMR and HRESI mass spectra. The absolute configuration of 1 were determined by quantum chemical calculations of the 13C NMR data and electronic circular dichroism (ECD) spectra. The cytotoxicity of all the isolates against the human colorectal cancer HCT116 cell line, as well as their potential protective effects on glutamate-induced injury in the retinal precursor R28 cell line were examined.

Simultaneous determination of chloramphenicol, stilbenes, and resorcylic acid lactones in pork using UPLC–MS/MS with a C18 cartridge and immunoaffinity microextraction in a packed syringe

Simultaneous determination of chloramphenicol, stilbenes, and resorcylic acid lactones in pork using UPLC–MS/MS with a C18 cartridge and immunoaffinity microextraction in a packed syringe

Chemoenzymatic asymmetric total synthesis of naturally occurring resorcylic acid lactones hamigeromycins F and G.

Asymmetric total synthesis of two naturally occurring resorcylic acid lactones (RALs), hamigeromycins F and G, was achieved for the first time. The synthetic strategy involved a late-stage intramolecular macrolactonization achieved with a transesterification reaction. Stereocenters (C10' and C6') in both the molecules were accessed via an enzymatic kinetic resolution reaction. The penta-substituted aromatic core present in hamigeromycins F and G was accessed using vanillin as a precursor. The crucial E-olefinic unsaturated bond at C1'-C2' was constructed with a stereoselective Julia-Kocienski olefination reaction.

Anti-Agrobacterium tumefactions sesquiterpene derivatives from the marine-derived fungus Trichoderma effusum.

Agrobacterium tumefaciens can harm various fruit trees, leading to significant economic losses in agricultural production. It is urgent to develop new pesticides to effectively treat this bacterial disease. In this study, four new sesquiterpene derivatives, trichoderenes A-D (1-4), along with six known compounds (5-10), were obtained from the marine-derived fungus Trichoderma effusum. The structures of 1-4 were elucidated by extensive spectroscopic analyses, and the calculated ECD, ORD, and NMR methods. Structurally, the hydrogen bond formed between the 1-OH group and the methoxy group enabled 1 to adopt a structure resembling that of resorcylic acid lactones, thereby producing the ECD cotton effect. Compound 3 represents the first example of C12 nor-sesquiterpene skeleton. Compounds 1-10 were tested for their antimicrobial activity against A. tumefactions. Among them, compounds 1-3 and 8-10 exhibited inhibitory activity against A. tumefactions with MIC values of 3.1, 12.5, 12.5, 6.2, 25.0, and 12.5 μg/mL, respectively.

Therapeutic efficacy of the resorcylic acid lactone LL-Z1640-2 for adult T-cell leukaemia/lymphoma.

Adult T-cell leukaemia/lymphoma (ATL) remains incurable. The NF-κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF-β-activated kinase 1 (TAK1), an IκB kinase-activating kinase, triggers the activation of NF-κB. The resorcylic acid lactone LL-Z1640-2 is a potent irreversible inhibitor of TAK1/extracellular signal-regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL-Z1640-2 against ATL. LL-Z1640-2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of IRF4 strongly induced ATL cell death while downregulating MYC. LL-Z1640-2 as well as the NF-κB inhibitor BAY11-7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF-κB-IRF4-MYC axis. The treatment with LL-Z1640-2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL-Z1640-2 against IL-2-responsive ATL cells in the presence of IL-2. Therefore, LL-Z1640-2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL-Z1640-2.

New Bioactive β-Resorcylic Acid Derivatives from the Alga-Derived Fungus Penicillium antarcticum KMM 4685.

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.

Report for 2021 on the results from the monitoring of veterinary medicinal product residues and other substances in live animals and animal products

The report summarises the monitoring data collected in 2021 on the presence of residues of veterinary medicinal products and other substances such as environmental contaminants in live animals and animal products in the European Union, Iceland, Norway and United Kingdom (Northern Ireland). A total of 621,205 samples were reported to the European Commission by the 27 EU Member States, Iceland, Norway and United Kingdom (Northern Ireland). They consisted of 351,637 targeted samples and 4,562 suspect samples reported under Council Directive 96/23/EC, and of 2,803 samples collected at import and 262,203 samples collected in the framework of programmes developed under the national legislation. The majority of countries fulfilled the minimum requirements for sampling frequency laid down in Council Directive 96/23/EC and in Commission Decision 97/747/EC. Overall, the percentage of non-compliant samples in 2021 (0.17%) was lower compared to the previous 12 years (0.19%-0.37%). Compared to the results from 2017, 2018, 2019 and 2020, in 2021 the frequency of non-compliant results was decreased for antithyroid agents, while for steroids and resorcylic acid lactones the frequency of non-compliant results was higher than in 2020, but lower compared to the previous years. For prohibited substances, compared to 2020 the frequency on non-compliance in 2021 was higher, although in line with that of 2017 and 2018. Decreases compared to all previous years were noted for other substances and environmental contaminants, chemical elements (including metals) and dyes. A sharp increase compared to all previous years was found for ‘other substances’.

Phytochemistry and Biological Activities of Endophytic Fungi from the Meliaceae Family.

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.

Phytoestrogens and Health Effects.

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.

Total Synthesis of Resorcylic Acid Lactone (−)‐Neocosmosin A Using Palladium‐Catalyzed α‐Arylation of Enones as the Key Step

AbstractThe total synthesis of the 14‐membered resorcylic acid lactone neocosmosin A is described. The key step in the synthesis is the palladium‐catalyzed α‐arylation of TES‐enol ethers of enones. The employment of the α‐arylation approach to this class of resorcylic acid lactones is a new approach, which has the scope of being generalized into a unified approach for the synthesis of this class of natural products.

Characterization of NRPS and PKS genes involved in the biosynthesis of SMs in Alternaria dauci including the phytotoxic polyketide aldaulactone

Alternaria dauci is a Dothideomycete fungus, causal agent of carrot leaf blight. As a member of the Alternaria genus, known to produce a lot of secondary metabolite toxins, A. dauci is also supposed to synthetize host specific and non-host specific toxins playing a crucial role in pathogenicity. This study provides the first reviewing of secondary metabolism genetic basis in the Alternaria genus by prediction of 55 different putative core genes. Interestingly, aldaulactone, a phytotoxic benzenediol lactone from A. dauci, was demonstrated as important in pathogenicity and in carrot partial resistance to this fungus. As nothing is known about aldaulactone biosynthesis, bioinformatic analyses on a publicly available A. dauci genome data set that were reassembled, thanks to a transcriptome data set described here, allowed to identify 19 putative secondary metabolism clusters. We exploited phylogeny to pinpoint cluster 8 as a candidate in aldaulactone biosynthesis. This cluster contains AdPKS7 and AdPKS8, homologs with genes encoding a reducing and a non-reducing polyketide synthase. Clusters containing such a pair of PKS genes have been identified in the biosynthesis of resorcylic acid lactones or dihydroxyphenylacetic acid lactones. AdPKS7 and AdPKS8 gene expression patterns correlated with aldaulactone production in different experimental conditions. The present results highly suggest that both genes are responsible for aldaulactone biosynthesis.

Ilyomycins A − K, radicicol-type resorcylic acid lactones as potential immunosuppressants from a soil-derived Ilyonectria sp.

Eleven previously undescribed radicicol-type resorcylic acid lactones (RALs), namely ilyomycins A − K (1–9, 10a and 10b), were isolated and identified from the fermented rice culture of a soil-derived fungus, Ilyonectria sp. (strain sb65). Their gross structures were determined by extensive spectroscopic data, and the absolute configurations were elucidated by single-crystal X-ray diffraction, the modified Mosher’s method, and Rh2(OCOCF3)4-induced electronic circular dichroism (ICD) experiment. Among them, 10a and 10b were a pair of inseparable regioisomers via intramolecular transacetylation. Compounds 3, 7, 8 and 10a/10b displayed immunosuppressive activities against T cell proliferation with IC50 values ranging from 1.2 to 21.7 μM, and against B cell proliferation with IC50 values ranging from 1.1 to 20.1 μM, which suggested that the α, β-unsaturated ketone from C-8 to C-10 was an important pharmacophore. Further study revealed that ilyomycin C (3) exerted anti-proliferative effect on T lymphocytes through Hsp90 inhibition.

Zearalenone toxicosis on reproduction as estrogen receptor selective modulator and alleviation of zearalenone biodegradative agent in pregnant sows

BackgroundZearalenone (ZEA) is a resorcylic acid lactone derivative derived from various Fusarium species that are widely found in food and feeds. The molecular structure of ZEA resembles that of the mammalian hormone 17β-oestradiol, thus zearalenone and its metabolites are known to compete with endogenous hormones for estrogen receptors binding sites and to activate transcription of oestrogen-responsive genes. However, the effect of long-term low-dose ZEA exposure on the reproductive response to Bacillus subtilis ANSB01G culture for first-parity gilts has not yet been investigated. This study was conducted to investigate the toxic effects of ZEA as an estrogen receptor selective modulator and the alleviating effects of Bacillus subtilis ANSB01G cultures as ZEA biodegraders in pregnant sows during their first parity.ResultsA total of 80 first-parity gilts (Yorkshire × Landrace) were randomly assigned to four dietary treatments during gestation: CO (positive control); MO (negative control, 246 μg ZEA/kg diet); COA (CO + B. subtilis ANSB01G culture with 2 × 109 CFU/kg diet); MOA (MO + B. subtilis ANSB01G culture with 2 × 109 CFU/kg diet). There were 20 replications per treatment with one gilt per replicate. Feeding low-dose ZEA naturally contaminated diets disordered most of reproductive hormones secretion and affected estrogen receptor-α and estrogen receptor-β concentrations in serum and specific organs and led to moderate histopathological changes of gilts, but did not cause significant detrimental effects on reproductive performance. The addition of Bacillus subtilis ANSB01G culture to the diet can effectively relieve the competence of ZEA to estrogen receptor and the disturbance of reproductive hormones secretion, and then ameliorate toxicosis of ZEA in gilts.ConclusionsCollectively, our study investigated the effects of feeding low-dose ZEA on reproduction in pregnant sows during their first parity. Feeding low-dose ZEA could modulate estrogen receptor-α and -β concentrations in specific organs, cause disturbance of reproductive hormones and vulva swelling, and damage organ histopathology and up-regulate apoptosis in sow models. Diet with Bacillus subtilis ANSB01G alleviated negative effects of the ZEA on gilts to some extent.

Resorcylic acid lactones from the ginseng pathogen Ilyonectria mors-panacis

Ilyonectria mors-panacis, previously Cylindrocarpon destructans, is the main plant pathogen responsible for the fungal disease ginseng root rot. This economically important disease, also called disappearing root rot, reduces crop yields by an average of 30% at harvest. While the disease is well studied from ecological and genomic perspectives, the role of I. mors-panacis secondary metabolites in the disease process is not well understood. Our previous metabolomics study showed Ilyonectria strains that cause ginseng root rot produce mixtures of putative resorcylic acid lactones, whereas avirulent strains did not, and collectively synthesize fewer metabolites. To confirm these metabolomics findings, we isolated and characterized the secondary metabolites from I. mors-panacis DAOMC 251601, a strain that causes ginseng root rot. From its EtOAc soluble culture filtrate extract, eight resorcylic acid lactones (1-8), including chlorinated and non-chlorinated congeners, were characterized by HRMS and spectroscopic approaches (NMR, OR, UV). The structure of one new metabolite, named radicicol E (1), was elucidated and additional spectroscopic data for the known compound nordinonediol (2) are reported. Further, radicicol (9) production was confirmed by comparison to a standard. The roles that resorcylic acid lactones and the siderophore N,N′,N” triacetylfusarine C have in promoting Ilyonectria ginseng root rot are also discussed.