Tyrosine derivatives isolated from Streptomyces sp. IFM 10937 in a screening program for TRAIL-resistance-overcoming activity

Exploration of actinomycetes for isolation of natural products for abrogating TRAIL resistance led to the isolation of two new tyrosine derivatives (1 and 2) along with novobiocin (3). The structures of 1 and 2 were determined by spectroscopic methods, while the absolute configuration was determined by analyzing CD spectra and by a modified Marfey's method. Compounds 1 (150 μM) and 3 (37.5 and 75 μM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma cells.     

Eudesmane-Type Sesquiterpenoid and Guaianolides from Kandelia candel in a Screening Program for Compounds to Overcome TRAIL Resistance

In a screening program for natural products that can overcome TRAIL resistance, a new eudesmane-type sesquiterpenoid (1), three new guaianolides, mehirugins A-C (2-4), and two known guaianolides (5 and 6) were isolated from a MeOH extract of Kandelia candel leaves. Compounds 1 and 3-6 in combination with TRAIL showed cytotoxic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma cells.     

Cytotoxic and antimalarial azaphilones from Chaetomium longirostre

Four new azaphilones named longirostrerones A-D (1-4) and three known sterols, ergosteryl palmitate, ergosterol, and ergosterol peroxide, have been isolated from ethyl acetate extract of the fungus Chaetomium longirostre. These structures were determined by 1D and 2D NMR, IR, UV, MS, and CD spectroscopy. Compounds 1-4 exhibited strong cytotoxicity against KB cancer cell lines (IC(50) 0.23-6.38 μM), while only 1 showed potent cytotoxicity against MCF7 and NCI-H187 cell lines (IC50 0.24 and 3.08 μM, respectively). In addition, 1-3 showed antimalarial activity against Plasmodium falciparum (IC50 0.62-3.73 μM).     

Camphoratins A-J, potent cytotoxic and anti-inflammatory triterpenoids from the fruiting body of Taiwanofungus camphoratus

Ten new triterpenoids, camphoratins A-J (1-10), along with 12 known compounds were isolated from the fruiting body of Taiwanofungus camphoratus. Their structures were established by spectroscopic analysis and chemical methods. Compound 10 is the first example of a naturally occurring ergosteroid with an unusual cis-C/D ring junction. Compounds 2-6 and 11 showed moderate to potent cytotoxicity, with EC(50) values ranging from 0.3 to 3 μM against KB and KB-VIN human cancer cell lines. Compounds 6, 10, 11, 14-16, 18, and 21 exhibited anti-inflammatory NO-production inhibition activity with IC(50) values of less than 5 μM, and were more potent than the nonspecific NOS inhibitor N(ω)-nitro-L-arginine methyl ester.     

Phenanthrene derivatives from Cymbidium Great Flower Marie Laurencin and their biological activities

A new phenanthrendione, ephemeranthoquinone B (1), two phenanthrenes, marylaurencinols A (2) and B (3), and a phenanthrene glucoside, marylaurencinoside A (4), were isolated from the roots of Cymbidium Great Flower Marie Laurencin, along with six known phenanthrenes, 5-10. The structures of these compounds were established by a combination of extensive NMR spectroscopy and/or X-ray crystallographic analysis and chemical degradation. The compounds were tested for antibacterial activities against Bacillus subtilis and Klebsiella pneumoniae and for cytotoxic activity against the human promyelocytic leukemia (HL-60) cell line. Compounds 1, 3, and 6 showed antibacterial activities with minimum inhibitory concentration (MIC) values in the range of 4.88 to 65.10 μM. Notably, ephemeranthoquinone B (1) had a strong antibacterial effect on B. subtilis. Furthermore, 1 exhibited moderate cytotoxic activity (IC(50) 2.8 μM) against HL-60 cells. Compounds 4-9 also showed weak cytotoxic activity against the HL-60 cell line with IC(50) values of 19.3-52.4 μM.     

Caffeic acid esters and lignans from Piper sanguineispicum

Three new caffeic acid esters (1-3), four new lignans (4-7), and the known compounds (7'S)-parabenzlactone (8), dihydrocubebin (9), and justiflorinol (10) have been isolated from leaves of Piper sanguineispicum. Their structures were determined by spectroscopic methods, including 1D and 2D NMR, HRCIMS, CD experiments, and chemical methods. Compounds 1-10 were assessed for their antileishmanial potential against axenic amastigote forms of Leishmania amazonensis. Caffeic acid esters 1 and 3 exhibited the best antileishmanial activity (IC(50) 2.0 and 1.8 μM, respectively) with moderate cytotoxicity on murine macrophages.     

Synergistic TRAIL sensitizers from Barleria alluaudii and Diospyros maritima

Barleria alluaudii and Diospyros maritima were both investigated as part of an ongoing search for synergistic TRAIL (tumor necrosis factor-α-related apoptosis-inducing ligand) sensitizers. As a result of this study, two naphthoquinone epoxides, 2,3-epoxy-2,3-dihydrolapachol (1) and 2,3-epoxy-2,3-dihydro-8-hydroxylapachol (2), both not previously isolated from natural sources, and the known 2-methylanthraquinone (3) were identified from B. alluaudii. Time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra were utilized to establish the absolute configuration of 1 and 2. Additionally, five known naphthoquinone derivatives, maritinone (4), elliptinone (5), plumbagin (6), (+)-cis-isoshinanolone (7), and ethylidene-6,6'-biplumbagin (8), were isolated from D. maritima. Compounds 1, 2, and 4-6 showed varying levels of synergy with TRAIL. Maritinone (4) and elliptinone (5) showed the highest synergistic effect, with more than a 3-fold increase in activity observed with TRAIL than with compound alone.     

Cytotoxic triterpenoid saponins from Lysimachia clethroides

Seven oleanane-type triterpenoid saponins, named clethroidosides A-G (1-7), an ursane-type triterpenoid saponin, clethroidoside H (8), and six known saponins were isolated from the aerial parts of Lysimachia clethroides. The structures of the saponins were elucidated on the basis of physical data analysis (1D and 2D NMR, HR-ESIMS) and chemical evidence. The cytotoxic activities of compounds 1-14 were evaluated against five human tumor cell lines (HT-29, HePG2, BGC-823, A549, and A375). Compounds 3, 4, 6, and 11-13 exhibited moderate cytotoxic activity, with IC50 values of 0.75-2.62 μM, while compound 5 showed selective cytotoxic activity.     

Bioactive hydroanthraquinones and anthraquinone dimers from a soft coral-derived Alternaria sp. fungus

Five new hydroanthraquinone derivatives, tetrahydroaltersolanols C-F (1-4) and dihydroaltersolanol A (5), and five new alterporriol-type anthranoid dimers, alterporriols N-R (12-16), along with seven known analogues (6-11 and 17), were isolated from the culture broth and the mycelia of Alternaria sp. ZJ-2008003, a fungus obtained from a Sarcophyton sp. soft coral collected from the South China Sea. Their structures and the relative configurations were elucidated using comprehensive spectroscopic methods including 1D and 2D NOE spectra as well as single-crystal X-ray crystallography. Compound 13 represents the first isolated alterporriol dimer with a C-4-C-4' linkage, and the absolute configuration of 4 was determined using the modified Mosher's method. Compounds 1 and 15 exhibited antiviral activity against the porcine reproductive and respiratory syndrome virus (PRRSV), with IC?? values of 65 and 39 μM, respectively. Compound 14 showed cytotoxic activity against PC-3 and HCT-116 cell lines, with IC?? values of 6.4 and 8.6 μM, respectively.     

Radical scavenging and antioxidant activities of isocoumarins and a phthalide from the endophytic fungus Colletotrichum sp

Five known isocoumarins, monocerin (1), derivative 2, and fusarentin derivatives 3-5, and a new phthalide (6) were isolated from the endophytic fungus Colletotrichum sp. 2 selectively exhibited cytotoxic activity toward the HepG2 cell line. Compounds 2 and 4 scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals (IC(50) values of 23.4 and 16.4 μM, respectively) and inhibited superoxide anion radical formation (IC(50) values of 52.6 and 4.3 μM, respectively). The C-7 hydroxyl group in 2 and 4 might be important for radical scavenging activities. Isocoumarins 1-3 and phthalide 6 showed potent antioxidant activity.     

Cyclic depsipeptides, grassypeptolides D and E and Ibu-epidemethoxylyngbyastatin 3, from a Red Sea Leptolyngbya cyanobacterium

Two new grassypeptolides and a lyngbyastatin analogue, together with the known dolastatin 12, have been isolated from field collections and laboratory cultures of the marine cyanobacterium Leptolyngbya sp. collected from the SS Thistlegorm shipwreck in the Red Sea. The overall stereostructures of grassypeptolides D (1) and E (2) and Ibu-epidemethoxylyngbyastatin 3 (3) were determined by a combination of 1D and 2D NMR experiments, MS analysis, Marfey's methodology, and HPLC-MS. Compounds 1 and 2 contain 2-methyl-3-aminobutyric acid and 2-aminobutyric acid, while biosynthetically distinct 3 contains 3-amino-2-methylhexanoic acid and the β-keto amino acid 4-amino-2,2-dimethyl-3-oxopentanoic acid (Ibu). Grassypeptolides D (1) and E (2) showed significant cytotoxicity to HeLa (IC?? = 335 and 192 nM, respectively) and mouse neuro-2a blastoma cells (IC?? = 599 and 407 nM, respectively), in contrast to Ibu-epidemethoxylyngbyastatin 3 (neuro-2a cells, IC?? > 10 μM) and dolastatin 12 (neuro-2a cells, IC?? > 1 μM).     

JBIR-94 and JBIR-125, antioxidative phenolic compounds from Streptomyces sp. R56-07

Two phenolic compounds, JBIR-94 (1) and JBIR-125 (2), were isolated from the fermentation broth of strain R56-07, which was identified by phylogenetic methods as a novel species of Streptomyces. The structures of 1 and 2 were assigned on the basis of 1D and 2D NMR spectroscopy and MS analyses. Compounds 1 and 2 exhibited 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity with an IC(50) value of 11.4 and 35.1 μM, respectively. These compounds are the first examples of hydroxycinnamic acid amides containing putrescine or spermidine produced by actinomycetes.     

Alkaloids from the root of Isatis indigotica

Seventeen new alkaloids (1-17) and 14 known analogues have been isolated from an aqueous extract of the root of Isatis indigotica. The structures and absolute configurations of these compounds were determined by extensive spectroscopic data analysis, including 2D NMR, single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation, and electronic circular dichroism spectra calculations based on the quantum-mechanical time-dependent density functional theory. Compounds 1, 2, and 3 are the first examples of natural products with unique linkages between a molecule of 2-(4-methoxy-1H-indol-3-yl)acetonitrile and 2-(1H-indol-3-yl)acetonitrile, 2-(4-methoxy-1H-indol-3-yl)acetonitrile, and 4-hydroxyphenylethane, respectively. Compounds (-)-4 and (+)-4 represent the first natural products with the pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline skeleton. Some structural assignments for the new alkaloids suggest that the assignments made for certain previously reported alkaloids require revision. Compounds 1-3 and arvelexin (18) show antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2), with IC(50) values of 3.70-12.35 μM, and 17 inhibits Coxsackie virus B3 replication with an IC(50) of 6.87 μM.     

Structure and cytotoxicity of diterpenoids from Isodon eriocalyx

A new ent-atisanoid, eriocatisin A (1), six new ent-abietanoids, eriocasins B-E (2-4, 7), 3-acetyleriocasin C (5), and 3β-acetoxyeriocasin D (6), and seven new ent-kauranoids, maoesins A-F (8, 10-14) and 3α-acetoxy-maoesin A (9), together with 21 known compounds, were isolated from the aerial parts of Isodon eriocalyx. The structures of 1-14 were determined by spectroscopic data interpretation. All compounds isolated were evaluated for their in vitro growth inhibitory activity against the HT-29, BEL-7402, and SK-OV-3 human cancer cell lines. Compounds 17, 18, and 20 showed inhibitory effects for all three tumor cell lines used, with IC(50) values in the range 2.1-7.3 μM.     

Bioactive neolignans and lignans from the bark of Machilus robusta

Sixteen new neolignans and lignans (1-16), together with 12 known analogues, have been isolated from an ethanol extract of the bark of Machilus robusta. Compounds 1 and 2 showed activity against HIV-1 replication in vitro, with IC(50) values of 2.52 and 2.01 μM, respectively. At 10 μM, 6, 8, and 9 reduced dl-galactosamine-induced hepatocyte (WB-F344 cells) damage, and 9 could additionally attenuate rotenone-induced PC12 cell damage. The known compounds (-)-pinoresinol (17) and (+)-lyoniresinol (18) were active against serum deprivation induced PC12 cell damage.     

Spirocyclic nortriterpenoids with NGF-potentiating activity from the fruits of Leonurus heterophyllus

Four new spirocyclic nortriterpenoids, leonurusoleanolide A (1), leonurusoleanolide B (2), leonurusoleanolide C (3), and leonurusoleanolide D (4), were isolated from the MeOH extract of the fruits of Leonurus heterophyllus. Compounds 1 and 2, and compounds 3 and 4, were found to exist as equilibrium mixtures of trans and cis isomers. Mixtures of 1 and 2, and 3 and 4, significantly enhanced the neurite outgrowth of nerve growth factor-treated PC12 cells at concentrations ranging from 1 to 30 μM. Compound 8 was also found to have a neurite outgrowth-promoting effect at concentrations of 1 and 10 μM. The structure-activity relationship of these compounds is discussed.     

2-Arylbenzofuran, flavonoid, and tyrosinase inhibitory constituents of Morus yunnanensis

Two novel 2-arylbenzofuran dimers, morusyunnansins A and B (1 and 2), two new biflavonoids, morusyunnansins C and D (3 and 4), two new flavans, morusyunnansins E and F (5 and 6), and four known flavans (7-10) were isolated from the leaves of Morus yunnanensis. Compounds 5-8 showed potent inhibitory effects on mushroom tyrosinase with IC(50) values ranging from 0.12 ± 0.02 to 1.43 ± 0.43 μM.     

Cyclic heptapeptides, cordyheptapeptides C-E, from the marine-derived fungus Acremonium persicinum SCSIO 115 and their cytotoxic activities

Three new cycloheptapeptides, cordyheptapeptides C-E (1-3), were isolated from the fermentation extract of the marine-derived fungus Acremonium persicinum SCSIO 115. Their planar structures were elucidated on the basis of extensive MS, as well as 1D and 2D (COSY, HMQC, and HMBC) NMR spectroscopic data analyses. The absolute configurations of the amino acid residues were determined by single-crystal X-ray diffraction, Marfey's method, and chiral-phase HPLC analysis. Compounds 1 and 3 displayed cytotoxicity against SF-268, MCF-7, and NCI-H460 tumor cell lines with IC(50) values ranging from 2.5 to 12.1 μM.     

Bioactive diterpenes and other constituents of Croton steenkampianus

A new indanone derivative (1) and two new diterpenoids (2 and 3), together with three known flavonoids, have been isolated from an ethanol extract of the leaves of Croton steenkampianus. The structure of 2 was solved by single-crystal X-ray diffraction analysis, whereas those of 1 and 3 were established mainly by 1D and 2D NMR spectroscopic methods. The isolated compounds were tested for their antiplasmodial activity and cytotoxicity. Antiplasmodial assays against chloroquine-susceptible strains (D10 and D6) and the chloroquine-resistant strains (Dd2 and W2) of Plasmodium falciparum showed that compound 2 gave moderate activities at 9.1-15.8 μM, while none of the compounds were cytotoxic against Vero cells.     

Lindenane disesquiterpenoids with anti-HIV-1 activity from Chloranthus japonicus

Five new lindenane disesquiterpenoids, chlorajaponilides A-E (1-5), together with 11 known analogues were isolated from whole plants of Chloranthus japonicus. The structure and absolute configuration of 1 was confirmed by X-ray crystallography. Compounds 1 and 2 represent the first examples of lindenane disesquiterpenoids with a C-5 hydroxy group and a C-4-C-15 double bond. Compounds 8, 9, 11, and 12 showed anti-HIV-1 replication activities in both wild-type HIV-1 and two NNRTIs-resistant strains. Shizukaol B (8) exhibited the best activity against HIV(wt), HIV(RT-K103N), and HIV(RT-K103N) with EC?? values of 0.22, 0.47, and 0.50 μM, respectively. Compounds 8, 9, 11, and 12 had significant cytotoxicities against C8166 cells with CC?? values of 0.020, 0.089, 0.047, and 0.022, respectively, and exhibited inhibitory activities against HIV-1 with EC?? values of 0.0014, 0.016, 0.0043, and 0.0033 μM, respectively.