Search

Three new lipopeptaibols, halovirs I-K (1-3), were isolated from the solid culture of the phytopathogenic fungus Paramyrothecium roridum NRRL 2183. Their planar structures, which consist of a hexapeptide backbone and acyl substitutions at the N- and C-termini, were elucidated by comprehensive analysis of the 1D and 2D NMR spectroscopic data along with the detailed interpretation of the MS/MS fragmentation pattern. Absolute configurations of the amino acid/1,2-amino alcohol residues were determined using the advanced Marfey's method. Bioinformatics analysis of the genome assembly of P. roridum NRRL 2183 revealed a gene cluster that is likely responsible for the biosynthesis of halovirs I-K. Analysis of the module and domain organization of the putative halovir synthetase PrHalA indicated that the assembly of 1-3 proceeds in an unconventional nonlinear fashion. 1 and 2 exhibited potent antibacterial activity against both antibiotic-sensitive and multidrug-resistant Gram-positive pathogens. These lipopeptaibols also displayed significant cytotoxicity toward human lung carcinoma A549, human breast carcinoma MCF-7, and human cervical carcinoma HeLa cells with IC 50 values ranging from 1.3 to 3.3 μM., (© 2022. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Three new actinopyrone derivatives, actinopyrones E-G ( 1 , 3 , and 4 ), together with three known analogues, PM050463 ( 2 ), actinopyrone D ( 5 ), and PM050511 ( 6 ), were isolated from Streptomyces sp. SCSIO ZS0520 derived from a deep-sea hydrothermal vent. Their structures, complete with absolute configurations, were elucidated using extensive spectroscopic analyses combined with Mosher's method, ECD calculations, and bioinformatics analyses. These findings corrected the absolute configurations of previously reported actinopyrone analogues 2 , 5 , and 6 at C-3, C-9, and C-10. Notably, compound 6 displayed notable cytotoxicity against six human cell lines with IC 50 values of 0.26-2.22 μM. A likely biosynthetic pathway and annotations of protein function are proposed on the basis of bioinformatics analyses. Genes coding for methyltransferase and glycosyltransferase tailoring chemistries needed to generate final structures were notably absent from the biosynthetic gene cluster. Taken together, these results enable further bioengineering of the actinopyrones and related congeners as potential antitumor agents.

Three new metabolites, including a cyclic tetrapeptide asperhiratide ( 1 ), an ecdysteroid derivative asperhiratine ( 2 ), and a sesquiterpene lactone asperhiratone ( 3 ), were isolated and identified from the soft coral-derived fungus Aspergillus hiratsukae SCSIO 5Bn 1 003, together with 10 known compounds. Their structures were elucidated via spectroscopic analysis, X-ray diffraction analysis, and electronic circular dichroism calculations. In addition, the absolute configuration of 1 was determined by Marfey's technique and an analysis of the acid hydrolysates using a chiral phase HPLC column. Among all the compounds, 6 and 8 showed medium cytotoxic activities against four tumor cell lines (SF-268, HepG-2, MCF-7, and A549), with IC 50 values ranging from 31.03 ± 3.04 to 50.25 ± 0.54 µM. Meanwhile, they strongly inhibited α-glucosidase activities, with IC 50 values of 35.73 ± 3.94 and 22.00 ± 2.45 µM, which were close to and even stronger than the positive control acarbose (IC 50 = 32.92 ± 1.03 µM). Compounds 6 - 8 showed significant antibacterial activities against Bacillus subtilis , with MIC values of 10.26 ± 0.76 µM, 17.00 ± 1.25 µM, and 5.30 ± 0.29 µM, respectively. Compounds 9 and 12 exhibited potent radical scavenging activities against DPPH, with IC 50 values of 12.23 ± 0.78 µM and 7.38 ± 1.16 µM. In addition, asperhiratide ( 1 ) was evaluated for anti-angiogenic activities in the in vivo zebrafish model, which showed a weak inhibitory effect on intersegmental vessel (ISV) formation.

Formicapyridine-type racemates, streptovertidines A ( 1 ) and B ( 2 ), a 7,24- seco -fasamycin, streptovertidione ( 3 ), and the fasamycin-type streptovertimycins I-T ( 4 - 15 ), together with 13 known fasamycin congeners ( 16 - 28 ), were isolated from soil-derived Streptomyces morookaense SC1169. Their structures were elucidated by extensive spectroscopic analysis and theoretical computations of ECD spectra. The fasamycin-type compounds 5 , 8 - 12 , 14 , and 15 exhibited activity against the drug-resistant bacteria MRSA and VRE (MIC: 1.25-10.0 μg/mL). All isolates, except 3 , 4 , 10 , and 24 , displayed cytotoxicity against at least one of the human carcinoma A549, HeLa, HepG2, and MCF-7 cells (IC 50 < 10.0 μM), of which some were also cytotoxic to the noncancerous Vero cells. Taken together, the activity data demonstrated that the fasamycin-type compounds were more selective to the tested bacteria over the mammalian cells. Structure-activity relationship analysis suggested that chlorination at C-2 in antibacterial fasamycin-type compounds improves the activity and selectivity to the bacteria. Theoretical simulations of reaction paths and chemical reactions for conversion of 3 to 1 were carried out and supported that the pyridine ring formation in formicapyridines proceeds nonenzymatically via 1,5-dicarbonyl condensation with ammonia.

Five new cytochalasans, diaporthichalasins D-H (1-5), along with five known cytochalasans (6-10) were isolated from solid cultures of the endophytic fungus Diaporthe sp. SC-J0138 isolated from the leaves of Cyclosorus parasiticus. Their structures were elucidated by analysis of spectroscopic data and theoretical calculations of electronic circular dichroism spectra. Compounds 1 and 5 showed noticeable cytotoxicity against human carcinoma A549, HeLa, and HepG2 cells. The structure-activity relationships in cytotoxicity were discussed for this group of compounds., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Two new γ-pyrones, xylaropyrones B (1) and C (2), together with three known compounds, xylaropyrone (3), annularin A (4) and annularin C (5), were isolated from solid cultures of the endophytic fungus Xylaria sp. SC1440. The structures of these compounds were determined mainly by analysis of their NMR spectroscopic data. The relative configurations of 1 and 2 were assigned on the basis of J-based configurational analysis, and the absolute configurations were established by experimental and TDDFT calculated ECD spectra. The isolated compounds were evaluated for cytotoxic and tyrosinase inhibitory activity.

Glycosylation is a prominent strategy to optimize the pharmacokinetic and pharmacodynamic properties of drug-like small-molecule scaffolds by modulating their solubility, stability, bioavailability, and bioactivity. Glycosyltransferases applicable for "sugarcoating" various small-molecule acceptors have been isolated and characterized from plants and bacteria, but remained cryptic from filamentous fungi until recently, despite the frequent use of some fungi for whole-cell biocatalytic glycosylations. Here, we use bioinformatic and genomic tools combined with heterologous expression to identify a glycosyltransferase-methyltransferase (GT-MT) gene pair that encodes a methylglucosylation functional module in the ascomycetous fungus Beauveria bassiana The GT is the founding member of a family nonorthologous to characterized fungal enzymes. Using combinatorial biosynthetic and biocatalytic platforms, we reveal that this GT is a promiscuous enzyme that efficiently modifies a broad range of drug-like substrates, including polyketides, anthraquinones, flavonoids, and naphthalenes. It yields both O - and N -glucosides with remarkable regio- and stereospecificity, a spectrum not demonstrated for other characterized fungal enzymes. These glucosides are faithfully processed by the dedicated MT to afford 4- O -methylglucosides. The resulting "unnatural products" show increased solubility, while representative polyketide methylglucosides also display increased stability against glycoside hydrolysis. Upon methylglucosidation, specific polyketides were found to attain cancer cell line-specific antiproliferative or matrix attachment inhibitory activities. These findings will guide genome mining for fungal GTs with novel substrate and product specificities, and empower the efficient combinatorial biosynthesis of a broad range of natural and unnatural glycosides in total biosynthetic or biocatalytic formats., Competing Interests: Conflict of interest statement: I.M. has a disclosed financial interest in TEVA Pharmaceuticals Hungary, which is unrelated to the subject of the research presented here. All other authors declare no competing financial interests.

Four dimeric acremines, bisacremines A-D (1-4), with a novel carbon skeleton and a new monomer, acremine T (5), were obtained from cultures of the soil-derived fungus Acremonium persicinum SC0105. Their structures were characterized by analysis of spectroscopic data, ECD/TDDFT computations, and X-ray diffraction. Compounds 1 and 2 exhibited weak cytotoxicity against HeLa cells, and 2 also showed modest activity against A549 and HepG2 cells.

Two new quinone sesquiterpenes named myrothecols G and H (1 and 2), a pair of C-1' diastereomers of 13-hydroxyl penicilliumin A, were isolated from the mycelia solid cultures of Myrothecium sp. SC0265. Their structures, including the absolute configurations, were established on the basis of the spectroscopic data combining with the theoretical conformational analysis. The cytotoxic activities of 1 and 2 were tested against a panel of human tumor cell lines.

Three new 4-hydroxy-2-pyridone alkaloids, arthpyrones A-C (1-3), were isolated from the sponge-derived fungus Arthrinium arundinis ZSDS1-F3. Their structures were elucidated on the basis of spectroscopic analysis, CD spectra, quantum chemical calculation, and X-ray single-crystal diffraction analysis. Compounds 1 and 2 possessed a 2-pyridone core featured with a decalin moiety linked via a carboxide bridge bearing a novel oxabicyclo[3.3.1]nonane ring system rarely discovered in nature. A possible biosynthetic pathway for them was proposed.

Six new quinone sesquiterpenes, myrothecols A-F (1-6), and hymenopsin B (7) were isolated from cultures of Myrothecium sp. SC0265 by bioassay-guided fractionation. Their structures were elucidated on the basis of 1D and 2D NMR and MS data. The absolute configurations of the new compounds were assigned by CD/TDDFT calculations, and that of and hymenopsin B was confirmed by X-ray diffraction analysis. Compounds 1-5 and hymenopsin demonstrated cytotoxic activity against human carcinoma A549, HeLa, and HepG2 cells. Compounds 1-5 also exhibited antibacterial activity against Staphylococcus aureus and Bacillus cereus.

A rearranged sterol with an unusual tetracycle core skeleton, penicillitone (1), and a new sterol, penicillisterol (2), were obtained from the culture of the fungus Penicillium purpurogenum SC0070. Their structures were characterized by spectroscopic analysis, DFT/TDDFT compuations, and X-ray diffraction. Compound 1 demonstrated potent inhibitory effects on tumor cell growth and key pro-inflammatory cytokine production in macrophages. A biogenetic pathway with oxidative cleavage and vinylogous aldol addition as key reactions is proposed for 1.

Twenty-two β-resorcylic acid lactones (RALs) were evaluated for cytotoxicity against human breast cancer cells to find their structure-activity relationship (SAR). Monocillin II, a trans-enone RAL without epoxy and conjugated dienone, was found to have higher activity in inhibiting tumor cell growth in both in vitro experiment and in vivo nude xenografted mice model than its analogue radicicol, an anticancer lead compound. We demonstrated for the first time that monocillin II could arrest breast cancer cell cycle in G1 phase, which might partially be the result of its inhibition effect on the phosphorylation of the Thr160 residue of cyclin dependent kinase 2 (CDK2), a key enzyme in cell-cycle regulation. Moreover, monocillin II exhibited inhibition of heat shock protein 90 (Hsp90) and depleted its target proteins, Raf-1 and A-Raf, which are involved in Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway. Remarkably, we found that monocillin II could inhibit activation of MAPKs including ERK, JNK and p38, which might be involved in the inactivation of CDK2. These results suggest that monocillin II has potential therapeutic benefits in breast cancer prevention and intervention., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Four novel prenylflavonols, macaranones A-D (1-4), were isolated from the leaves of Macaranga sampsonii. Their structures were elucidated on the basis of spectroscopic data. Macaranones C (3) and D (4) represent first two examples of flavonols having an unusual peltogynoid skeleton which is formed from a 2'-geranylflavonol by cyclization between 3-OH and C-1'' of the 2'-geranyl substituent of the flavonol. Compounds 1-4 were evaluated for the cytotoxicity against several human cancer cell lines.

Tetrahydrocurcumin (THC) is a major metabolite of curcumin and plays an important role in curcumin-induced biological effects. THC is a promising preventive and chemotherapeutic agent for cancer. A series of new pyrazole derivatives of THC have been synthesized as potent anticancer agents. Direct condensation of THC with various substituted hydrazines leads to new pyrazole derivatives of THC ( 1- 18). The prepared compounds have been evaluated via in vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay for their cell proliferation-inhibitory activity against human lung adenocarcinoma (A549), human cervical carcinoma (HeLa) and human breast carcinoma (MCF-7) cells. Most derivatives show significantly higher anticancer activity against all three tested cancer cell lines than the parent compound THC. Several compounds ( 7, 8, 12, 13 and 15) display promising anticancer activity against MCF-7 cell line with IC values ranging from 5.8 to 9.3 µM. The most active compound ( 8) is substituted with 4-bromophenyl group at the pyrazole ring and inhibits the growth of all three tested cancer cell lines with an IC values of (8.0 µM, A549), (9.8 µM, HeLa) and (5.8 µM, MCF-7). The obtained compounds can be a good starting point for the development of new lead molecules in the fight against cancer. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Abstract: The first stilbene possessing a γ-aminobutyric acid lactam function, artocarpene (1), and a new flavanone, 2-hydroxynaringenin 4′-O-β-d-glucopyranoside (2), were isolated from the stems of Artocarpus nitidus subsp. lingnanensis along with four known compounds, 2-hydroxynaringenin (3), oxyresveratrol (4), 3,4′,5-trihydroxy-3′-prenylstilbene (5) and norartocarpetin (6). Their structures were elucidated on the basis of spectroscopic data. Compounds 1 exhibited weak antioxidant activity and 2 displayed weak cytotoxicity against human lung cancer A549 cell line. [Copyright &y& Elsevier]

Abstract: Fruits of wampee [Clausena lansium (Lour.) Skeels] contain a significant amount of coumarins with many health benefits. The activity-guided separation of an ethyl acetate-soluble fraction on a polyamide column followed by silica gel column and high performance liquid chromatography (HPLC) preparation afforded a pure compound, which was identified to be 8-hydroxypsoralen based on the 1H, 13C NMR (nuclear magnetic resonance), and ESI-MS (electrospray ionisation mass spectrometric) analysis. This isolate exhibited good scavenging activities against DPPH radical and superoxide anion as well as significant reducing power. It also showed potent proliferation inhibitory activity against human hepatocellular liver carcinoma cell line (HepG2), human lung adenocarcinoma epithelial cell line (A549) and human cervical carcinoma cell line (HELA). This is the first report on the antioxidant and cytotoxic properties of C. lansium fruit extract. The food and pharmaceutical industry could be benefited by the usage of this extract containing this constituent. [Copyright &y& Elsevier]

Abstract: Longan fruit pericarp was extracted with 50% ethanol employing high pressure (500 MPa) and conventional extraction methods. Total phenolic contents of high pressure-assisted extract of longan (HPEL) and conventional extract of longan (CEL) were 20.8 and 14.6 mg gallic acid equivalents/g dry weight, respectively. Subsequently, the antioxidant activities of these extracts were analyzed employing various antioxidant model systems including 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, superoxide anion radical scavenging activity, total antioxidant capacity, and lipid peroxidation inhibitory activity. In addition, anticancer activity was also tested using HepG2, A549, and SGC 7901 cancer cell lines. HPEL showed excellent antioxidant and anticancer activities and were higher than CEL. Three phenolic compounds, namely gallic acid, corilagin, and ellagic acid, were identified and quantified by external standard methods. Compared with CEL, HPEL exhibited higher extraction effectiveness in terms of higher extraction yield, higher phenolic content, and higher antioxidant and anticancer activity with shorter extraction time. Industrial relevance: This study was focused to evaluate the antioxidant and anticancer activity of longan fruit pericarp by high-pressure treatment. The high-pressure treatment provided a better way of utilizing longan fruit pericarp as a readily accessible source of the natural anticancer and antioxidant in food and pharmaceutical industry. [Copyright &y& Elsevier]

Sarcandracoumarin (1), the first coumarin having a 1-phenylethyl substituent at the C-3 position, was isolated along with eleven known phenolic compounds from the water extract of Sarcandra glabra. Its structure was elucidated on the basis of spectroscopic data. Compound 1 exhibited moderate or weak cytotoxicity against several tumor cell lines. [Copyright &y& Elsevier]