Novel trichothecanes, paecilomycine A, B, and C, isolated from entomopathogenic fungus, Paecilomyces tenuipes

Paecilomycine A (1), B (2), and C (3) were isolated from cultivated fruiting bodies of Paecilomyces tenuipes (Isaria japonica), which is a popular entomopathogenic fungus used in folk medicine and health foods in China, Korea, and Japan. The structures of 1-3 were deduced from their spectroscopic data and their absolute configurations were elucidated by preparing their MPA esters. Compound 1 showed activity in the neurotrophic factor biosynthesis in glial cells.     

Cytotoxic dimeric sesquiterpenoids from Curcuma parviflora: isolation of three new parviflorenes and absolute stereochemistry of parviflorenes A, B, D, F, and G

Three novel dimeric sesquiterpenoids, named parviflorenes G-I (1-3), have been isolated from Curcuma parviflora (Zingiberaceae), and their structures were elucidated by means of spectroscopic studies. Absolute stereochemistry of parviflorene G (1) as well as previously isolated related compounds, parviflorenes A (4), B (5), D (6), and F (7), was revealed by CD spectral data and chemical means. Parviflorenes G (1) and I (3) were cytotoxic against HeLa cells, while parviflorenes A (4) and F (7) were cytotoxic against all tested tumor cell lines in the human cancer cell line panel assay.     

Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure–activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.     

Karatungiols A and B, two novel antimicrobial polyol compounds, from the symbiotic marine dinoflagellate Amphidinium sp.

Karatungiols A (1) and B (2), two novel antimicrobial polyol compounds, were isolated from the cultivated symbiotic marine dinoflagellate Amphidinium sp. Their structures were elucidated based on spectroscopic analysis and degradation reactions. Karatungiols A (1) and B (2) consisted of a C69-linear chain with a ketone moiety, 24 or 25 hydroxyl groups, and two tetrahydropyran rings. Karatungiol A (1) exhibited antifungal activity against Aspergillus niger at 12 μg/disc and antiprotozoan activity against Trichomonas foetus at 1 μg/ml.     

6′-Chloro-7- or 9-(2,3-dihydro-5H-4,1-benzoxathiepin-3-yl)-7H- or 9H-purines and their corresponding sulfones as a new family of cytotoxic drugs

A series of 1-(2,3-dihydro-5H-4,1-benzoxathiepin-3-yl)pyrimidine derivatives were synthesized and two of them (8 and 9) showed a modest antiproliferative activity against the MCF-7 breast cancer cell line. We then decided to change the pyrimidine base for the more lipophilic 6′-chloropurine, and the N-9′ purine (15) and N-7′ purine (17) were obtained. The sulfone N-7′-alkylated-6-chloropurine 18 was the most active derivative. Compound 17 was found to be slightly more active than its regioisomer 15, with an activity similar to that of 5-fluorouracil as a reference drug. Encouraged by these values, we tested these compounds against both the HT-29 human colon cancer cell line and the IEC-6 normal rat intestinal epithelial cell line, and 15 was found to be 12.7-fold more active against HT-29 than versus IEC-6.     

Novel cyclopropyl diketones and 14-membered macrolides from the soil fungus Hamigera avellanea BCC 17816

Two novel cyclopropyl diketones, hamavellone A (1) and B (2), and two new 14-membered nonaketide macrolactones, hamigeromycin A (3) and B (4), together with six known compounds, 89-250904-F1 (radicicol analogue A, 5), pseurotin A (6), emodin (7), ω-hydroxyemodin (8), and emodin bianthrones (9 and 10) were isolated from the soil fungus Hamigera avellanea BCC 17816. The structures of the new compounds were defined by analysis of NMR and MS data. The absolute stereochemistry of 3 was addressed by chemical correlation to 5. Hamavellone B (2) exhibited antimalarial activity with an IC₅₀ of 5.2 μg/mL, whereas it also showed comparable cytotoxicity.     

Synthesis of 4-aryl-6-indolylpyridine-3-carbonitriles and evaluation of their antiproliferative activity

A novel class of 6-indolypyridine-3-carbonitrile derivatives were synthesized and evaluated for antiproliferative activities to establish structure–activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, ethyl cyanoacetate, and ammonium acetate in the presence of piperidine as a catalyst, using a microwave irradiation method or a traditional thermal method. This was followed by chlorination for compounds 13a–e and subsequent nucleophilic substitution of the chlorine group by ethylenediamine at C₂ position of the pyridine ring. The antiproliferative activity of these new nicotinonitriles was evaluated against human ovarian adenocarcinoma (SK-OV-3), breast adenocarcinoma (MCF-7), and cervix adenocarcinoma (HeLa) cells. Among all compounds, 2-((2-aminoethyl)amino)-4-aryl-6-indolylnicotinonitriles series (15a, 15b, 15d, and 15e) exhibited higher antiproliferative activity on the three cancer cell lines with IC₅₀ values of 4.1–13.4 μM.     

Saccharonol B,a new cytotoxic methylated isocoumarin from Saccharomonospora azurea

From an antimicrobial gram-positive actinomycete strain of Saccharomonospora azurea (MTCC11714) isolated from high altitude soil of Kargil (J&K, India), a new isocoumarin saccharonol B (2) along with two known compounds viz. saccharonol A (1) and piericidin A₃ (3) was isolated and characterized. The structure of the new compound was established based on extensive 2D-NMR data. Saccharonol B (2) exhibited mild antimicrobial activity against a standard panel of microorganisms Staphylococcus aureus ATCC 29213, Candida albicans ATCC 90028, and Aspergillus fumigatus MTCC 1811 with MIC values in the range of 128–248 μg/mL. Saccharonol B (2) and piericidin A₃ (3) showed selective cytotoxic activity against human pancreatic carcinoma cell line (MIAPaCa-2) with IC₅₀ values of 9 and 8 μM, respectively. Mechanistic studies indicated that saccharonol B (2) arrests S-phase of the cell cycle and causes dose-dependent loss of mitochondrial potential in MIAPaCa-2 cells.     

Excavatoids A-D, new polyoxygenated briaranes from the octocoral Briareum excavatum

Three polyoxygenated briaranes, including two new compounds, excavatoids A (1) and B (2), and a known metabolite, briaexcavatin I (3), were isolated from the cultured octocoral Briareum excavatum. Moreover, the wild type B. excavatum, collected off southern Taiwan coast, yielded two new 5,6-epoxybriaranes, excavatoids C (4) and D (5). The structures of new compounds 1, 2, 4, and 5 were determined by spectroscopic methods and the structure of 1 was further confirmed by X-ray diffraction data analysis. The X-ray structure for briaexcavatin I (3) was also reported for the first time. Excavatoid A (1) is the first briarane which possesses six hydroxy groups and a 17-methoxy group. Excavatoid C (4) is the first 12,13-secobriarane which possesses a novel pentacyclic skeleton with an ?-lactone. Excavatoid D (5) displayed moderate inhibitory effects on superoxide anion generation and elastase release by human neutrophils.     

Dioxadispiroketal Compounds and a Potential Acyclic Precursor from Amomum aculeatum

Four new compounds having an unusual 1,7-dioxadispiro[5.1.5.2]-12-ene-11-one tricyclic ring system (1-4), their potential precursor, 5R-hydroxy-1-(4-hydroxyphenyl)-eicosan-3-one (5), and two known compounds, aculeatins A (6) and B (7), have been isolated from Amomum aculeatum. All compounds were characterized by spectroscopic methods and the configurations were established by 2D NOE correlations. Compounds 1-4, 6, and 7 showed cytotoxic activity against several human cancer cell lines.     

Briaexcavatins A and B, novel briaranes from the octocoral Briareum excavatum

Two novel briaranoidal derivatives, designated as briaexcavatins A (1) and B (2), along with two known metabolites, excavatolides B and C (3 and 4), were isolated from the octocoral Briareum excavatum. Both compounds 1 and 2 possess unprecedented 5,6-epoxy moiety in the 10-membered ring. Diterpenoid 1 possesses a novel pentacyclic skeleton with a ε-lactone. The structures of diterpenoids 1 and 2 were elucidated by interpretation of spectral data and the absolute stereochemistry was established by application of modified Mosher’s method on 3.     

Stereoselective synthesis of (6S) and (6R)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one and their cytotoxic activity against cancer cell lines

Stereoselective total synthesis of α,β-unsaturated lactone (1a), isolated from Ravensara crassifolia, has been achieved efficiently starting from chiral 2,3-O-isopropylidene-d-glyceraldehyde (3) followed by asymmetric allylation and ring-closing metathesis. The antiproliferative activities of compounds 1a, 1b and the unusual bicyclic compound 2 were evaluated against three-cancer cell lines, THP-1 and U-937 (leukemia) and A-375 (melanoma).     

Vernodalidimers A and B, novel orthoester elemanolide dimers from seeds of Vernonia anthelmintica

Two novel elemanolide dimers, vernodalidimers A (1) and B (2), possessing a rare tricyclic ortho ester moiety, were isolated from the seeds of Vernonia anthelmintica. Their structures were elucidated by 1D and 2D NMR data and CD spectra. Vernodalidimers A (1) and B (2) exhibited potent cell growth inhibitory activity against HL-60 cells (IC₅₀ 0.72 and 0.47 μM, respectively).     

Psoracorylifols A-E, five novel compounds with activity against Helicobacter pylori from seeds of Psoralea corylifolia

Five novel compounds, psoracorylifols A-E (1-5) with important activity against Helicobacter pylori have been isolated from a well-known traditional Chinese medicine (TCM), the seeds of Psoralea corylifolia. The structures of compounds 1-5, including their absolute configurations, were established on the basis of spectral methods and biogenetic reason. The structure of 1 was confirmed by a single-crystal X-ray diffraction. Psoracorylifols D and E (4 and 5) represent an unprecedented carbon skeleton. The biogenetic origin of psoracorylifols A-E (1-5) was also postulated.     

Pavidolides A-E, new cembranoids from the soft coral Sinularia pavida

Five new cembrane-based diterpenoids, namely pavidolides A-E (1-5) were isolated from the marine soft coral Sinularia pavida, together with sarcophytin and chatancin. The structures of new compounds were determined on the basis of extensive spectroscopic data analysis. Pavidolide B (2) possesses an unprecedented 6,5,7-tricarbocyclic nucleus, whereas pavidolide C (3) is characteristic of an unusual C-5 and C-9 conjuncted cembranoid. Pavidolides C and D showed moderate antifouling activity against the larval settlement of barnacle Balanus amphitrite, while pavidolides B and C exhibited inhibitory activity against the human leukemia cell line HL-60.     

Endoplasmic reticulum (ER) stress protecting compounds from the mushroom Mycoleptodonoides aitchisonii

Two novel compounds, 3-(hydroxymethyl)-4-methylfuran-2(5H)-one (1) and (3R,4S,1′R)-3-(1′-hydroxyethyl)-4-methyldihydrofuran-2(3H)-one (2), were isolated along with two known ones (3 and 4) from an edible mushroom Mycoleptodonoides aitchisonii. The structures of 1-4 were determined by the interpretation of spectroscopic data. Compounds 1-4 showed protective activity against endoplasmic reticulum (ER) stress-dependent cell death.     

Synthesis, characterization, and derivatization of some novel types of fluorinated mono- and bis-imidazolidineiminothiones with antitumor, antiviral, antibacterial, and antifungal activities

A series of thirty eight novel imidazolidineiminothiones (6a-g, 10a-h, 13a,b, 15a-d, and 16a), 5-thioxoimidazolidine-2,4-diones (7a-d, 11a-e, 14a,b, and 16b), and bis-imidazolidineiminothiones (17-20) with various fluorinated aromatic substituents at N-(1) and N-(3) were prepared in 75-85% yields. The imidazolidineiminothiones were synthesized from fluorinated N-arylcyanothioformanilides and substituted aromatic isocyanates, and by the reactions of fluorinated aromatic isocyanates with fluorinated and non-fluorinated aromatic N-arylcyanothioformanilides. Subsequent hydrolysis of selected products produced the corresponding 5-thioxoimidazolidine-2,4-diones. Preliminary screening of several compounds against Ehrlich ascites carcinoma (EAC) cells indicated that 6f and 16a were the most active (90% and 80% inhibition, respectively). Further evaluation for cytotoxicity against other tumor cell lines gave IC₅₀ values ranging from 0.67 to 3.83 μg/mL, where compounds 15a and 16a were markedly active against all cell lines. This highlights the synergistic effect of the suitably positioned fluorinated substituents on N-(1) and N-(3) of the imidazolidineiminothiones. Compounds 6a,e-g, 10a-c, 13b, 15a-d, and 17-20 were tested against microbial organisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Salmonella typhi, and Sarcina lutea), and fungal strains (Candida albicans, Aspergillus niger, and Aspergillus flavus). Whereas compound 6a exhibited the highest antibacterial activity against Gram positive and Gram negative bacteria, 13b displayed the strongest antifungal activity against all fungal strains, reaching as high as 30 mm. Finally, 15a,b,d were subjected to in vitro testing of antiviral activity against hepatitis A virus (HAV), human herpes simplex virus 1 (HSV1), and Coxsackie B4 (COxB4) viral strain, where 15b was the most effective, reducing virus plaque count of HSV1 and COxB4 by 50% and 60%, respectively.     

Isolation, structure elucidation and bioactivity of schischkiniin, a unique indole alkaloid from the seeds of Centaurea schischkinii

Reversed-phase HPLC analysis of the methanol extract of the seeds of Centaurea schischkinii afforded a novel indole alkaloid, named schischkiniin (1), together with four lignans, arctiin (2), matairesinoside (3), matairesinol (4), and arctigenin (5), and three flavonoids, astragalin (6), afzelin (7) and apigenin (8). While the structure of schiskiniin (1) was established unequivocally by UV, HRFABMS and a series of 1D and 2D NMR analyses, all known compounds were readily identified by comparison of their spectroscopic data with literature data. The free radical scavenging properties of these compounds were assessed using the DPPH assay, and their general toxicity and cytotoxicity were evaluated, respectively, by brine shrimp lethality and MTT cytotoxicity assays with CaCo-2 colon cancer cell lines. Arctigenin (5) exhibited promising in vitro anticancer activity (IC₅₀=7 μM) while with schischkiniin (1) the activity was of moderate level (IC₅₀=76 μM).     

Novel cyclopeptide and unique flavone from Desmos rostrata. Total synthesis of desmorostratone

Two new compounds, a cyclic peptide desmocyclopeptide (1) and a special flavone desmorostratone (2) were isolated from the stem bark of Desmos rostrata, along with two known compounds, desmosdumotins B (3) and C (4). Their structures were established on the basis of the spectral data, including mass spectrometry and 2D NMR. The total synthesis of desmorostratone (2) was performed in order to confirm its structure as well as that of desmosdumotin C (4), which was a tautomeric mixture in the solution. Finally, cytotoxity of these compounds were evaluated. Desmosdumotin C (4) displayed a moderate inhibition activity against KB cell line with an IC₅₀ of 19.2 μM, whereas the other products showed a weak inhibition against the same cell line target.     

Ecionines A and B, two new cytotoxic pyridoacridine alkaloids from the Australian marine sponge, Ecionemia geodides

Chemical investigations of the Australian marine sponge Ecionemia geodides resulted in the isolation of two new pyridoacridine alkaloids, ecionines A (1) and B (2), along with the previously isolated marine natural products, biemnadin (3) and meridine (4). Compounds 1 and 2 both contain an imine moiety, which is rare for the pyridoacridine structure class. The chemical structures of 1 and 2 were determined by extensive 1D and 2D NMR and MS data analyses. All compounds were tested against a panel of human bladder cancer cell lines, the increasingly metastatic TSU-Pr1 series (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2) and the superficial bladder cancer cell line 5637. Ecionine A (1) displayed cytotoxicity against all cell lines, with IC₅₀ values ranging from 3 to 7 μM. This is the first report of chemistry from the sponge genus Ecionemia.