Prenylated indole diketopiperazine alkaloids as phosphatase inhibitors from the marine-derived fungus Talaromyces purpureogenus.

Six previously undescribed prenylated indole diketopiperazine alkaloids, talaromyines A-F (1-6), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data including NMR, HR-ESI-MS, and electronic circular dichroism calculations, together with chemical analysis of hydrolysates. Compounds 1-5 represent the first example of spirocyclic indole diketopiperazines biosynthesized from the condensation of L-tryptophan and L-alanine. Compounds 2 and 4-5 showed selective inhibitory activities against phosphatases TCPTP and MEG2 with IC50 value of 17.9-29.7 µM, respectively. Compounds 4-5 exhibited mild cytotoxic activities against two human cancer cell lines H1975 and HepG-2.

New Antibacterial Peptaibiotics against Plant and Fish Pathogens from the Deep-Sea-Derived Fungus Simplicillium obclavatum EIODSF 020.

Bacterial diseases could severely harm agricultural production. To develop new antibacterial agents, the secondary metabolites of a deep-sea-derived fungus Simplicillium obclavatum EIODSF 020 with antibacterial activities against plant and fish pathogens were investigated by a bioassay-guided approach, which led to the isolation of 11 new peptaibiotics, simplicpeptaibs A-K (1-11). They contain 16-19 residues, including ß-alanine, tyrosine, or tyrosine O-sulfate, that were rarely present in peptaibiotics. Their structures were elucidated by spectroscopic analyses (NMR, HRMS, HRMS2, and ECD) and Marfey's method. The primary and secondary structures of novel sulfated peptaibiotic 9 were reconfirmed by single-crystal X-ray diffraction analysis. Genome sequencing of S. obclavatum EIODSF 020 allowed the detection of a gene cluster encoding two individual NRPSs (totally containing 19 modules) that was closely related to simplicpeptaib biosynthesis. Antibacterial investigations of 1-11 together with the previously isolated linear and cyclic peptides from this strain suggested the antibacterial property of this fungus was attributed to the peptaibiotics and cyclic lipopeptides. Among them, compounds 4, 6, 7, and 9 showed significant activity against the tobacco pathogen Ralstonia solanacearum or tilapia pathogens Streptococcus iniae and Streptococcus agalactiae. The antibacterial activity of 6 against R. solanacearum could be enhanced by the addition of 1% NaCl. The structure-bioactivity relationship of simplicpeptaibs was discussed.

Microascones, Decahydrofluorene-Class Alkaloids from the Marine-Derived Fungus Microascus sp. SCSIO 41821.

Eight new decahydrofluorene-class alkaloids, microascones A and B (1 and 2), 2,3-epoxyphomapyrrolidone C (3), 14,16-epiascomylactam B (4), 24-hydroxyphomapyrrolidone A (5), and microascones C-E (6-8), along with five known analogs (9-13) were isolated from the marine-derived fungus Microascus sp. SCSIO 41821. Compounds 1 and 2 have an unprecedented complex macrocyclic alkaloid skeleton with a 6/5/6/5/6/5/13 polycyclic system. Their structures and absolute configurations were determined by spectroscopic analysis, quantum chemical calculations of ECD spectra, and 13C NMR chemical shifts. Compounds 10-13 showed selective enzyme inhibitory activity against PTPSig, PTP1B, and CDC25B, and 4, 9, and 10 exhibited strong antibacterial activity against seven tested pathogens. Their structure-bioactivity relationship was discussed, and a plausible biosynthetic pathway for 1-8 was also proposed.

HPPO-Derived Meroterpenoids from the Marine-Derived Fungus Penicillium sp. SCSIO 41691.

Seven new 4-hydroxy-6-phenyl-2H-pyran-2-one (HPPO) derived meroterpenoids, 1-methyl-12a,12b-epoxyarisugacin M (1), 1-methyl-4a,12b-epoxyarisugacin M (2), 2,3-dihydroxy-3,4a-epoxy-12a-dehydroxyisoterreulactone A (3), 2-hydroxy-12a-dehydroxyisoterreulactone A (4), 3'-demethoxyterritrems B' (5), 4a-hydroxyarisugacin P (6), and 1-epi-arisugacin H (7), together with two known analogues (8 and 9), were isolated from the marine-derived fungal strain Penicillium sp. SCSIO 41691. Their structures were elucidated by spectroscopic methods, and the absolute configurations of compounds 1 and 3 were determined by single-crystal X-ray diffraction. Among them, 1 and 2 had a unique methyl migration in the basic meroterpenoid skeleton with a 12a,12b-epoxy or 4a,12b-epoxy group, and 3 was a highly oxygenated HPPO-derived meroterpenoid featuring a rare 6/5/6/6/6/6 hexacyclic system with a 3,4a-epoxy group. Biologically, 5 exhibited inhibitory activity against lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells with an IC50 value of 21 µM, more potent than the positive control indomethacin.

Lecanicilliums A-F, Thiodiketopiperazine-Class Alkaloids from a Mangrove Sediment-Derived Fungus Lecanicillium kalimantanense.

Six new thiodiketopiperazine-class alkaloids lecanicilliums A-F were isolated from the mangrove sediment-derived fungus Lecanicillium kalimantanense SCSIO41702, together with thirteen known analogues. Their structures were determined by spectroscopic analysis. The absolute configurations were determined by quantum chemical calculations. Electronic circular dichroism (ECD) spectra and the structure of Lecanicillium C were further confirmed by a single-crystal X-ray diffraction analysis. Lecanicillium A contained an unprecedented 6/5/6/5/7/6 cyclic system with a spirocyclic center at C-2'. Biologically, lecanicillium E, emethacin B, and versicolor A displayed significant cytotoxicity against human lung adenocarcinoma cell line H1975, with IC50 values of 7.2~16.9 µM, and lecanicillium E also showed antibacterial activity against four pathogens with MIC values of 10~40 µg/mL. Their structure-activity relationship is also discussed.

Two new linear peptides from the marine-derived fungus Penicillium sp. SCSIO 41512.

Two new linear peptides, penicamides A and B (1 and 2), together with four known analogous were isolated from the extracts of the marine-derived fungus Penicillium sp. SCSIO 41512. Their structures were elucidated by analysis of 1D/2D NMR data and HRESI-MS. Their absolute configurations were established by Marfey's methods and quantum chemical calculations.

Punicesterones A-G, polyhydroxylated mycoecdysteroids from the deep-sea-derived fungus Aspergillus puniceus SCSIO z021.

Seven undescribed polyhydroxylated mycoecdysteroids, punicesterones A-G, along with two known analogues, were isolated from the deep-sea-derived fungal strain Aspergillus puniceus SCSIO z021 (Trichocomaceae). Their structures with absolute configurations were elucidated by a combination of extensive NMR spectroscopic analysis, HRESIMS data, and single-crystal X-ray diffraction experiments. Punicesterone An unexpectedly possessed a nicotinoyl unit substituted at C-22 of a typical ecdysteroid skeleton. All of the isolated compounds were evaluated for their anti-inflammatory, lipid-lowering, and antibacterial activities. Punicesterones B and C showed the activity of reducing triglyceride in 3T3-L1 adipocytes in a dosage-dependent manner, and also exhibited antibacterial activity against five pathogens.

Pyrrospirones K-Q, Decahydrofluorene-Class Alkaloids from the Marine-Derived Fungus Penicillium sp. SCSIO 41512.

Seven new decahydrofluorene-class alkaloids, pyrrospirones K-Q (1-7), together with six known analogues (8-13) were isolated from the marine-derived fungal strain Penicillium sp. SCSIO 41512. Their structures were determined by extensive spectroscopic analysis, and their absolute configurations were established by single-crystal X-ray diffraction analysis and quantum chemical calculations of electronic circular dichroism spectra. Compounds 1 and 3 possess a novel decahydrofluorene-class alkaloid skeleton with a 6/5/6/8/5/6/13 and a 6/5/6/5/6/13 polycyclic system, respectively. Biologically, 13 displayed significant inhibitory activity against protein tyrosine phosphatases CD45, TCPTP, SHP1, and PTP1B with IC50 values of 8.1-17.8 µM, and 1, 2, 5, 8-10, 12, and 13 showed antibacterial activity against six pathogens. Their structure-activity relationship is also discussed.

Isoquinoline Alkaloids as Protein Tyrosine Phosphatase Inhibitors from a Deep-Sea-Derived Fungus Aspergillus puniceus.

Puniceusines A-N (1-14), 14 new isoquinoline alkaloids, were isolated from the extracts of a deep-sea-derived fungus, Aspergillus puniceus SCSIO z021. Their structures were elucidated by spectroscopic analyses. The absolute configuration of 9 was determined by ECD calculations, and the structures of 6 and 12 were further confirmed by a single-crystal X-ray diffraction analysis. Compounds 3-5 and 8-13 unprecedentedly contained an isoquinolinyl, a polysubstituted benzyl or a pyronyl at position C-7 of isoquinoline nucleus. Compounds 3 and 4 showed selective inhibitory activity against protein tyrosine phosphatase CD45 with IC50 values of 8.4 and 5.6 µM, respectively, 4 also had a moderate cytotoxicity towards human lung adenocarcinoma cell line H1975 with an IC50 value of 11.0 µM, and 14, which contained an active center, -C=N+, exhibited antibacterial activity. An analysis of the relationship between the structures, enzyme inhibitory activity and cytotoxicity of 1-14 revealed that the substituents at C-7 of the isoquinoline nucleus could greatly affect their bioactivity.

Fusidane-Type Antibiotics from the Marine-Derived Fungus Simplicillium sp. SCSIO 41513.

Simplifusidic acids A-K (1-11), 11 new fusidane-type nortriterpenoids, were isolated from the marine-derived fungus Simplicillium sp. SCSIO 41513. Compound 1 possessed an unprecedented fusidane triterpene skeleton with a 6/6/7/5/5 polycyclic system. Their structures were elucidated by spectroscopic methods, and their absolute configurations were further determined by quantum chemical calculations of ECD spectra, comparison of experimental ECD spectra, and single-crystal X-ray diffraction analysis. Compound 9 showed strong antibacterial activity toward Staphylococcus aureus with an MIC value of 0.078 µg/mL. Their structure-bioactivity relationship was also discussed.

Talaromynoids A-I, Highly Oxygenated Meroterpenoids from the Marine-Derived Fungus Talaromyces purpureogenus SCSIO 41517 and Their Lipid Accumulation Inhibitory Activities.

Nine new highly oxygenated 3,5-dimethylorsellinic acid-derived meroterpenoids, talaromynoids A-I (1-9), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated by HRMS, NMR, single-crystal X-ray diffraction analysis, and electronic circular dichroism calculations. Compounds 1 and 7-9 possessed unprecedented 5/7/6/5/6/6, 6/7/6/6/6/5, 6/7/6/5/6/5/4, and 7/6/5/6/5/4 polycyclic systems, respectively. Biologically, compound 5 showed selective inhibitory activity against phosphatase CDC25B with an IC50 value of 13 µM. Moreover, 7-9 and 12 exhibited the activity of reducing triglyceride in 3T3-L1 adipocytes in a dosage-dependent manner.

Antifungal peptides from the marine gorgonian-associated fungus Aspergillus sp. SCSIO41501.

Three undescribed cyclic lipopeptides maribasins C-E and four undescribed linear peptides aspergillipeptides H-K together with three known analogous maribasins A-B and marihysin A were isolated from the marine gorgonian-associated fungus Aspergillus sp. SCSIO 41501 (Trichocomaceae). Their structures were determined by spectroscopic analysis, and their absolute configurations were further confirmed by Marfey's methods. Maribasins C-E and maribasins A-B showed significant antifungal activity against five phytopathogenic fungal strains with MIC values of 3.12-50 µg/disc. Structure-bioactivity relationship exhibited that the ß-amino fatty acid chain could significantly affect the antifungal activity of this type of cyclic lipopeptides.

Talaromyoxaones A and B: Unusual Oxaphenalenone Spirolactones as Phosphatase Inhibitors from the Marine-Derived Fungus Talaromyces purpureogenus SCSIO 41517.

(+)- and (-)-talaromyoxaones A and B (1 and 2, respectively), two new oxaphenalenone derivatives with a hemiacetal frame and an unprecedented spirolactone frame of a 2'H,3H,4'H-spiro[isobenzofuran-1,3'-pyran]-3-one unit that show biosynthetic enantiodivergence, and two new oxaphenalenone analogues (±)-11-apopyrenulin (3) and (+)- or (-)-abeopyrenulin (4) were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculations of ECD spectra. Compounds 1 and 2 showed selective inhibitory activity against phosphatases SHP1, SHP2, and MEG2 with IC50 values of 1.3-3.4 µM, and the potential modes of action for 1 were investigated by a preliminary molecular docking study.

Mycotoxins as inhibitors of protein tyrosine phosphatases from the deep-sea-derived fungus Aspergillus puniceus SCSIO z021.

Nine new xanthone-type and anthraquinone-type mycotoxins including austocystins J-N (1-5), 7-chloro versicolorin A (6), 3'-hydroxy-8-O-methyl versicolorin B (7), 8-O-methyl versiconol (8) and 2',3'-dihydroxy versiconol (9), together with 17 known analogues (10-26) were isolated from an extract of the deep-sea-derived fungus Aspergillus puniceus SCSIO z021. Their structures were elucidated by detailed analysis of spectroscopic data, and their absolute configurations were further determined by quantum chemical calculations of ECD spectra or comparison of the experimental ECD spectra. Eleven hydrogenated austocystins were synthesized from 1-2, 10-15 and 17 by catalytic hydrogenation for bioactivities evaluation. Totally, 18 of the all 37 compounds showed strong toxicity against brine shrimps or Vero cell, and the toxicity of 8-O-methyldemethylsterigmatocystin (18) (LC50 = 0.020 µM) against brine shrimps was higher than those of three positive controls. In addition, 22 of the isolated compounds also exhibited significant inhibitory activity against seven different protein tyrosine phosphatases (PTPs), among them austocystin H (15) and methyl-averantin (24) were the most potent inhibitors with IC50 values of 0.20-3.0 µM. Their structure-bioactivity relationship was also discussed.

Eight new cyclopentenone and cyclohexenone derivatives from the marine-derived fungus Aspergillus sp. SCSIO 41501 by OSMAC strategy.

One strain many compounds (OSMAC) strategy was an effective method to activate the silent biosynthetic genes of microorganisms. Comparison with our previous investigations on the secondary metabolites of the marine-derived fungus Aspergillus sp. SCSIO 41501, in this study, three new cyclopentenone derivatives, aspergispones A-C (1-3), and five new cyclohexenone derivatives, aspergispones D-H (4-8), together with two known analogues, were further isolated from the fungal strain by altering culture medium compositions. The structures of new compounds were elucidated by extensive spectroscopic analysis. And the absolute configurations of 4 and 7 were further confirmed by single-crystal X-ray diffraction experiments.

New pyrone and cyclopentenone derivatives from marine-derived fungus Aspergillus sydowii SCSIO 00305.

Two new 2-pyrone derivatives sydowiones A-B (1, 2), one new cyclopentenone derivative sydowione C (3), and one new mycotoxin 6-methoxyl austocystin A (4) along with two known analogues paecilpyrone A (5) and austocystin A (6), were isolated from the marine-derived fungus Aspergillus sydowii SCSIO 00305. The structures of 1-4 were elucidated by extensive spectroscopic analysis. The absolute configuration of C-8 in 1 was established by Mosher method, and further confirmed by calculation of the electronic circular dichroism (ECD) spectra. The absolute configuration of C-11 in 3 was also determined by calculation of ECD spectra. The absolute configuration of 6 was determined by a single-crystal X-ray diffraction experiment for the first time. Compounds 1-4 showed moderate toxicity towards brine shrine naupalii with LC50 values of 19.5, 14.3, 8.3 and 2.9 µM, respectively. And 1 and 2 also showed antioxidant activity against 2,2-diphenyl-picrylhydrazyl (DPPH) radicals with IC50 values of 46.0 and 46.6 µM, respectively.[Formula: see text].

Penicimeroterpenoids A-C, Meroterpenoids with Rearrangement Skeletons from the Marine-Derived Fungus Penicillium sp. SCSIO 41512.

Three novel andrastin-type meroterpenoids, penicimeroterpenoids A-C (1-3), possessing two unprecedented skeletons consisting of fused 6/5/6/6/7 and 6/5/6/6/4 polycyclic systems, were obtained from the marine-derived fungus Penicillium sp. SCSIO 41512. Their structures were determined by spectroscopic methods, and the absolute configurations were further determined by single-crystal X-ray diffraction analysis for 1 and quantum chemical calculations of ECD spectra for 2 and 3, respectively. A plausible biosynthetic pathway for 1-3 was proposed.

A new iron(III) chelator of coprogen-type siderophore from the deep-sea-derived fungus Mycosphaerella sp. SCSIO z059.

Mycosphazine A (1), a new iron(III) chelator of coprogen-type siderophore, and mycosphamide A (2), a new cyclic amide benzoate, together with six known aryl amides (3-8), were isolated from the fermentation broth of the deep-sea-derived fungus Mycosphaerella sp. SCSIO z059. Alkaline hydrolysis of 1 afforded a new epimer of dimerum acid, mycosphazine B (1a), and a new bi-fusarinine-type siderophore, mycosphazine C (1b). The planar structures of the new compounds were elucidated by extensive spectroscopic data analysis. The absolute configurations of amino acid residues in 1a and 1b were determined by acid hydrolysis. And the absolute configuration of 2 was established by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Compound 1 is the first siderophore-Fe(III) chelator incorporating both L-ornithine and D-ornithine unites. Compounds 3-8 were reported as natural products for the first time, and the 1H and 13C NMR data of 6 and 8 were assigned for the first time. Compounds 1 and 1a could greatly promote the biofilm formation of bacterium Bacillus amyloliquefaciens with the rate of about 249% and 524% at concentration of 100 µg·mL-1, respectively.

Ansamycin derivatives from the marine-derived Streptomyces sp. SCSGAA 0027 and their cytotoxic and antiviral activities.

Fourteen ansamycin derivatives including seven new herbimycins G-L (1-6) and divergolide O (7), and seven known analogues were isolated from a culture broth of the marine-derived Streptomyces sp. SCSGAA 0027. Their complete structures were determined by detailed analysis of spectroscopic data and quantum chemical calculations. Compounds 1-5 and 7 featured an additional eight-membered O-heterocycle that has rarely been reported for ansamycins, and the Z,Z- and E,E-configurations for Δ2,Δ4 were reported for the first time in geldanamycin analogues. Compound 1 exhibited weak inhibition activity towards Hsp90α with an IC50 value of 96 µM, 2-5 showed mild cytotoxicity against four human cancer cell lines with IC50 values ranging from 13 µM to 86 µM, and 7 had moderate anti-HSV-1 activity with an IC50 value of 19 µM and very weak cytotoxicity towards Vero cell. The possible biosynthetic pathways for 1-5 were proposed. And their structure-bioactivity relationship was also discussed.

New alkaloids and isocoumarins from the marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501.

Two new ß-carboline alkaloids, aspergillspins A-B (1-2), three new quinolone alkaloids, aspergillspins C-E (3-5), and two new isocoumarins, aspergillspins F-G (6-7), together with four known alkaloids were isolated from the marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501. Their structures were identified by spectroscopic analysis, and the absolute configurations of several chiral carbons in 2 and 3 were further established by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Their cytotoxic and antibacterial activities were also evaluated.