Citrinin Derivatives Research Articles

Dicitrinols A-C: Citrinin Derivatives from Hydrothermal Vent-Associated Fungus Penicillium citrinum TW132-59.

Three new unusual citrinin derivatives with a unique 6/5/7/5 core, dicitrinols A-C (1-3, respectively), were isolated via the fermentation of hydrothermal vent-associated fungus Penicillium citrinum TW132-59. Their structures were unambiguously determined by nuclear magnetic resonance, mass spectrometry, and electronic circular dichroism calculations. Dicitrinols A-C represent a novel cage carbon skeleton with a decahydro-5,9,4-(epipropane[1,1,3]triyl)cycloocta[b]furan ring system. Dicitrinols A-C showed moderate antifungal activity against Candida albicans, Cryptococcus neoformans, and Fusarium oxysporum and antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii with minimum inhibitory concentrations ranging from 4 to 16 μg/mL.

Theoretical study of atomic electronegativity effects on the excited‐state behavior of fluorescent compounds of citrinin

AbstractThe present work focuses on the light‐induced behavior of citrinin derivatives in relation to atomic electronegativity. A detailed theoretical study on the photophysical properties and excited‐state behavior of fluorescent compounds of citrinin (Cit‐O, Cit‐S, and Cit‐Se, with different atomic electronegativity) has been conducted, and the effect of electronegativity on the proton transfer in this system has been explained. First, the relevant hydrogen bond parameters and infrared vibrational spectra of the optimized geometrical configurations have been insightfully investigated. It is elucidated that the hydrogen bond is strengthened after photoexcitation, and it provides a driving force for excited‐state intramolecular proton transfer (ESIPT). In addition, the frontier molecular orbitals were analyzed, and the intramolecular charge transfer process in all Cit systems, the phenomenon of charge redistribution, facilitates the ESIPT reaction. By constructing potential energy surfaces for different transfer paths, the atomic electronegativity impact on the ESIPT dynamical behavior of the Cit system was determined. This work clarifies the mechanism of the intramolecular proton transfer process in the excited state of citrinin molecules and complements the theoretical study of the atomic electronegativity‐regulated citrinin system, which provides a corresponding theoretical basis for the design and synthesis of new luminescence‐adjustable citrinin systems.

Novel Metabolites from the Marine-Derived Fungus Peniophora sp. SCSIO41203 Show Promising In Vitro Antitumor Activity as Methuosis Inducers in PC-3 Cells.

Two new cytochalasin derivatives, peniotrinins A (1) and B (2), three new citrinin derivatives, peniotrinins C-E (4, 5, 7), and one new tetramic acid derivative, peniotrinin F (12), along with nine structurally related known compounds, were isolated from the solid culture of Peniophora sp. SCSIO41203. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis, quantum chemical calculations, and the calculated ECD. Interestingly, 1 is the first example of a rare 6/5/5/5/6/13 hexacyclic cytochalasin. We screened the above compounds for their anti-prostate cancer activity and found that compound 3 had a significant anti-prostate cancer cell proliferation effect, while compounds 1 and 2 showed weak activity at 10 μM. We then confirmed that compound 3 exerts its anti-prostate cancer effect by inducing methuosis through transmission electron microscopy and cellular immunostaining, which suggested that compound 3 might be first reported as a potential anti-prostate methuosis inducer.

Five previously undescribed citrinin derivatives from the endophytic fungus Penicillium citrinum GZWMJZ-836

Penicillium citrinum GZWMJZ-836 is an endophytic fungus from Drynaria roosii Nakaike. Five previously undescribed citrinin derivatives (1–5) and six intermediates related to their biosynthesis (6–11) were obtained from the extract of this strain's solid fermentation using multiple column chromatography separations, including high-performance liquid chromatography. The structures of these compounds were determined through comprehensive spectroscopic analyses, primarily using NMR and HRESIMS data. The stereochemistry was mainly confirmed by ECD calculations, and the configurations of C-7′ in compounds 4 and 5 were determined using 13C NMR calculations. Compounds 4–5 and 8 showed antibacterial activity against five strains, with minimum inhibitory concentration values ranging from 7.8 to 125 μM. Compounds 4 and 7 exhibited inhibitions against three plant pathogenic fungi, with IC50 values ranging from 66.6 to 152.1 μM. Additionally, a putative biosynthetic pathway for compounds 1–5 derived from citrinin was proposed.

The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome.

Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 106 BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1mg/kg) and 5-FU (30mg/kg) for 4weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.

Novel citrinin derivatives from fungus Penicillium sp. TW131-64 and their antimicrobial activities.

Six new citrinin derivatives (1, 2, 4, 10, 11, and 16), along with fourteen known analogues, were acquired from Penicillium sp. TW131-64, a marine-derived fungus strain. The chemical structures of new compounds were identified through adopting various spectroscopic methods in combination with X-ray diffraction technology and comparison of the experimental electronic circular dichroism (ECD) with calculated ones. Among them, compounds 1-4 were nitrogen-containing citrinin derivatives existing in enantiomers which were resolved by chiral chromatography. A putative biosynthetic pathway for compounds 1-4 was proposed. Additionally, the antimicrobial activities of these compounds were detected by the broth microdilution assays. Citrinin derivatives 1, 2, 4 and their corresponding enantiomers (1a, 2a, 4a, 1b, 2b, and 4b) exhibited potent antimicrobial activities towards Helicobacter pylori standard strains and multidrug-resistant strains (MIC values ranging from 0.25 to 8μg/mL), which were comparable or even better than metronidazole. Moreover, compounds 1a and 1b also showed remarkable broad antimicrobial effects towards Staphylococcus aureus, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, vancomycin-resistant Enterococcus faecium (VRE), and Candida albicans. In summary, our studies demonstrated that citrinin enantiomers 1a-4a and 1b-4b, especially 1a and 1b, can be lead compounds in the research and development (R & D) of novel antimicrobial drugs. KEY POINTS: • 3 novel nitrogen-containing citrinin derivatives (1, 2, 4) were isolated. • citrinin derivatives 1-4 in enantiomers were resolved by chiral chromatography. • citrinin derivatives 1a and 1b showed broad and significant antimicrobial effects.

Peniciriols A and B, two new citrinin derivatives from an endophytic fungus Penicillum citrinum TJNZ-27

Two undescribed citrinin derivatives, named peniciriols A-B (1–2), together with six known compounds were isolated from endophytic fungus Penicillum citrinum TJNZ-27. The structures of two new compounds were well established by the detail interpretation of NMR and HRESIMS data as well as ECD measurement powered by molecular calculation. Among them, compound 1 shared an unprecedented dimerized citrinin skeleton with the formation of an intriguing 9H-xanthene ring system, whereas compound 2 possess a highly substituted phenylacetic acid skeleton, which was rarely-occurring in natural secondary metabolites. Moreover, these novel compounds were tested for cytotoxic and antibacterial activities, whereas these novel compounds did not exhibit any noticeable cytotoxic or antibacterial activities.

Action of the fungal compound citrinin, a bioherbicide candidate, on photosystem II.

Bioherbicides are becoming more attractive as safe weed control tools towards sustainable agriculture. Natural products constitute an important source chemicals and chemical leads for discovery and development of novel pesticide target sites. Citrinin is a bioactive compound produced by fungi of the genera Penicillium and Aspergillus. However, its physiological-biochemical mechanism as a phytotoxin remains unclear. Citrinin causes visible leaf lesions on Ageratina adenophora similar to those produced by the commercial herbicide bromoxynil. Phytotoxicity bioassay tests using 24 plant species confirmed that citrinin has a broad activity spectrum and therefore has potential as a bioherbicide. Based on chlorophyll fluorescence studies, citrinin mainly blocks PSII electron flow beyond plastoquinone QA at the acceptor side, resulting in the inactivation of PSII reaction centers. Furthermore, molecular modeling of citrinin docking to the A. adenophora D1 protein suggests that it binds to the plastoquinone QB site by a hydrogen bond between the O1 hydroxy oxygen atom of citrinin and the histidine 215 of the D1 protein, the same way as classical phenolic PSII herbicides do. Finally, 32 new citrinin derivatives were designed and sorted according to free energies on the basis of the molecular model of an interaction between the citrinin molecule and the D1 protein. Five of the modeled compounds had much higher ligand binding affinity within the D1 protein compared with lead compound citrinin. Citrinin is a novel natural PSII inhibitor that has the potential to be developed into a bioherbicide or utilized as a lead compound for discovery of new derivatives with high herbicidal potency. © 2023 Society of Chemical Industry.

GKK1032B from endophytic Penicillium citrinum induces the apoptosis of human osteosarcoma MG63 cells through caspase pathway activation.

Chemical investigation of the culture extract of an endophytic Penicillium citrinum from Dendrobium officinale, afforded nine citrinin derivatives (1-9) and one peptide-polyketide hybrid GKK1032B (10). The structures of these compounds were determined by spectroscopic methods. The absolute configurations of 1 and 2 were determined for the first time by calculation of electronic circular dichroism (ECD) data. Among them, GKK1032B (10) showed significant cytotoxicity against human osteosarcoma cell line MG63 with an IC50 value of 3.49 μmol·L-1, and a primary mechanistic study revealed that it induced the apoptosis of MG63 cellsvia caspase pathway activation.

Xanthene and citrinin derivatives from the endophytic fungus Penicillium sp. T2-11

A new xanthene derivative penicnthene (1), a new citrinin derivative penicitrinone H (2), along with three known analogues were isolated from rice solid culture media of the endophytic fungus Penicillium sp. T2-11 through the application of one strain many compounds (OSMAC) strategy. Their structures and stereochemistry were determined by comprehensive spectroscopic analyses and electronic circular dichroism (ECD) analysis aided by TDDFT-ECD calculations. Penicnthene (1) represented the first xanthene featuring a 3-hydroxy-2-butyl chain functionality. Compounds 1–3 were assessed for their DPPH radical scavenging, antimicrobial, acetylcholinesterase inhibitory, and cytotoxic activities. Both 1 and 2 exhibited radical scavenging activities against DPPH with potency comparable to the positive control trolox. Compound 1 showed remarkable antibacterial activity against Bacillius subtilis with MIC value of 4.0 μg/mL. 2 also displayed potent activity against Staphylococcus aureus. A putative biosynthetic pathway for compounds 1–6 were proposed.

Penitol A and Penicitols E-I: Citrinin Derivatives from Penicillium citrinum and the Structure Revision of Previously Proposed Analogues.

Penitol A (1), a new citrinin derivative with a rare tricyclic spiro skeleton, was isolated from a coral-derived strain of the fungus Penicillium citrinum. In addition, penicitols E-I (2-6), five new citrinin analogues, were coisolated. Their structures were determined by an analysis of 1D/2D NMR and HRESIMS data, statistical DP4+ analyses based on DFT-GIAO NMR calculations, quantum chemistry ECD calculations, and a single-crystal X-ray diffraction study. The structures of penicitol A (7) and two related synthetic intermediates were revised. Biological evaluation results revealed that penitol A (1) exhibited cytotoxic activity against K562 tumor cells, with an IC50 value of 8.8 μM. A proposed route of formation of compounds 1-7 was reported.

A New Citrinin Derivative from the Indonesian Marine Sponge-Associated Fungus Penicillium citrinum.

Sponge-associated fungi are attractive targets for the isolation of bioactive natural products with different pharmaceutical purposes. In this investigation, 20 fungi were isolated from 10 different sponge specimens. One isolate, the fungus Penicillium citrinum strain WK-P9, showed activity against Bacillus subtilis JH642 when cultivated in malt extract medium. One new and three known citrinin derivatives were isolated from the extract of this fungus. The structures were elucidated by 1D and 2D NMR spectroscopy, as well as LC-HRMS. Their antibacterial activity against a set of common human pathogenic bacteria and fungi was tested. Compound 2 showed moderate activity against Mycobacterium smegmatis ATCC607 with a minimum inhibitory concentration (MIC) of 32 µg/mL. Compound 4 exhibited moderate growth inhibition against Bacillus subtilis JH642, B. megaterium DSM32, and M. smegmatis ATCC607 with MICs of 16, 16, and 32 µg/mL, respectively. Furthermore, weak activities of 64 µg/mL against B. subtilis DSM10 and S. aureus ATCC25923 were observed for compound 4.

New citrinin derivatives from the deep-sea-derived fungus Cladosporium sp. SCSIO z015

During the course of our search for novel bioactive compounds from marine fungi, four new citrinin derivatives, cladosporins A–D (1–4) were isolated from a culture broth of the deep-sea-derived fungus Cladosporium sp. SCSIO z015. Their complete structural assignments were elucidated by the extensive spectroscopic investigation. The absolute configurations of 1–3 were established by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Compounds 1–4 showed weak toxicity towards brine shrine naupalii with LC50 values of 72.0, 81.7, 49.9 and 81.4 μM, respectively. And 4 also showed significant antioxidant activity against ɑ,α-diphenyl-picrylhydrazyl (DPPH) radicals with an IC50 value of 16.4 μM.

Total Syntheses of Stoloniferol B and Penicitol A, and Structural Revision of Fusaraisochromanone.

The first total synthesis of stoloniferol B and penicitol A has been achieved. Stoloniferol B, which is the common structure of citrinin derivatives, has been constructed by a sequential elaboration that includes a stereoselective vinylogous Mukaiyama aldol reaction, a thermal esterification with methyl acetoacetate, an intramolecular Michael reaction, and a vinylogous Dieckmann cyclization. The enantiomer of the proposed structure of fusaraisochromanone and ( S)-7-hydroxy-3-(( R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3 H)-one (the enantiomer of a natural stoloniferol derivative) also have been synthesized. The synthesis revised the structure of fusaraisochromanone to ( S)-7-hydroxy-3-(( R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3 H)-one.

Pencitrin and pencitrinol, two new citrinin derivatives from an endophytic fungus Penicillium citrinum salicorn 46

Two new citrinin derivatives, pencitrin (1) and pencitrinol (2), and a known compound citrinin (3), together with its two known dimers, penicitrinone A (4), penicitrinone E (5), were isolated from an endophytic fungus P. citrinum 46 derived from Salicornia herbacea Torr. by adding CuCl2 into fermentation medium. The structures of these compounds were elucidated by detailed spectroscopic analysis, and the absolute configurations of 1, 4, and 5 were determined by comparison of quantum chemical time-dependent density functional theory (TDDFT) calculated and electronic circular dichroism (ECD) spectra. Compound 1 exhibited potent cytotoxic activities towards A549 human lung cancer cells and HepG2 human liver cancer cells with IC50 values of 23.73±3.61 and 35.73±2.15μM, respectively, whereas compound 5 showed moderate cytotoxic activities towards A549 and HepG2 cancer cells with IC50 values of 40.47±4.52 and 53.57±3.24μM, respectively. The results from the current research highlighted the effectiveness and usefulness of the pipeline to discover novel bioactive fungal secondary metabolites by modification of the culture media.

Screening of Anti-Biofilm Compounds from Marine-Derived Fungi and the Effects of Secalonic Acid D on Staphylococcus aureus Biofilm.

Biofilm formation of Staphylococcus aureus is one of its mechanisms of drug resistance. Antibiofilm screening of 106 compounds from marine-derived fungi displayed that 12 compounds inhibited S. aureus biofilm formation by >50% at the concentration of 100 μg/ml, and only secalonic acid D (SAD) and B inhibited by >90% at 6.25 μg/ml without inhibiting cell growth after 24-h incubation. Meanwhile, it was found that the double bond between C-1 and C-10 of citrinin derivatives and the C-C connection position of two chromone monomers may be important for their anti-biofilm activities. Moreover, SAD slightly facilitated biofilm eradication and influenced its architecture. Furthermore, SAD slowed the cell growth rate in the preceding 18-h incubation and differentially regulated transcriptional expression of several genes, such as agr, isaA, icaA, and icaD, associated with biofilm formation in planktonic and biofilm cells, which may be the reason for the anti-biofilm activity of SAD. Finally, SAD acted synergistically against S. aureus growth and biofilm formation with other antibiotics. These findings indicated that various natural products from marine-derived fungi, such as SAD, could be used as a potential biofilm inhibitor against S. aureus.

Citrinin Derivatives and Unusual C25 Steroids from a Sponge-Derived Penicillium sp. Fungus

Citrinin Derivatives and Unusual C25 Steroids from a Sponge-Derived Penicillium sp. Fungus

Polyketides from a Marine-Derived Fungus Xylariaceae sp.

Eighteen polyketides (1–18) including six citrinin derivatives, two phenol derivatives, one cyclopentenone, two naphthol derivatives, and seven tetralone derivatives were isolated from the culture broth of a marine-derived fungal strain Xylariaceae sp. SCSGAF0086. Five of these compounds (1, 2, 8, 9, and 10) were new, and their structures were determined by spectroscopic methods. Compounds 4, 6, 7, and 17 showed enzyme-inhibitory activities towards several tested enzymes, and 6 and 7 showed strong antifouling activity against Bugula neritina larvae settlement. This is the first time that the antifouling and enzyme-inhibitory activities of these compounds has been reported.

Four New Citrinin Derivatives from a Marine-Derived Penicillium sp. Fungal Strain

Four new citrinin derivatives, including two citrinin dimers and two citrinin monomer derivatives, were isolated and identified from a marine-derived fungal strain Penicillium sp. ML226 along with six known related compounds. Their structures were elucidated by spectroscopic and chemical methods. The new compounds showed modest cytotoxic activity against HepG-2 cell line and weak antimicrobial activity against Staphylococcus aureus.

ChemInform Abstract: Penicitrinols F—I, New Citrinin Derivatives from the Marine‐Derived Fungus Penicillium citrinum.

AbstractPenicitrinols I(Ia), H(Ib), G(II), and F(III), are isolated from the title plant along with four known analogues.