Two new sesquiterpenes and six norsesquiterpenes from the solid culture of the edible mushroom Flammulina velutipes

One new sesquiterpene with a novel carbon skeleton, flammulinol A (1), one new isolactarane sesquiterpene and six isolactarane-related norsesquiterpenes, flammulinolides A–G (2–8), as well as sterpuric acid, were isolated from the solid culture of Flammulina velutipes. The structures of the new compounds were elucidated by spectroscopic methods. The absolute configuration of C-3 in 1 was determined via the circular dichroism data analysis based on the octane rule of cyclopentenone, whereas the absolute configurations of compounds 2, and 5–8 were assigned using the circular dichroism data of the [Rh₂(OCOCF₃)₄] complex. Compounds 2, 3, and 7 showed strong cytotoxicity against KB cell line with the IC₅₀ of 3.9, 3.6, and 4.7 μM, respectively. Compound 4 showed strong cytotoxicity against Hela cell line with the IC₅₀ of 3.0 μM. The plausible biosynthetic pathway for 2–9 in F. velutipes was discussed.     

Kadpolysperins A–N,lanostane triterpene acids possessing rich structure types from Kadsura polysperma

Fourteen new lanostane triterpene acids (1–14), and five known analogues (15–19) were isolated from the stems of Kadsura polysperma. Compound 1, with a rearranged tetracyclic skeleton, is an important biogenic precursor of longipedlactone skeleton. Compounds 2–6 are members of 18(13→12)-abeo-lanostane triterpene acids. The structures of new compounds were elucidated by spectroscopic evidence. Selected compounds were evaluated for their in vitro cytotoxicity against human tumor HL-60, SMMC-7721, A-549, MCF-7, and SW-480 cell lines.     

New sesquiterpenes from the red alga Laurencia microcladia

Three new aromatic sesquiterpenes (1, 2, and 4), one new dimeric sesquiterpene of the cyclolaurane-type (3), one sesquiterpene alcohol of bisabolene type (8) along with three previously reported metabolites (5-7), were isolated from the organic extracts of Laurencia microcladia, collected from the Chios island in the North Aegean Sea. The structures of the new natural products, as well as their relative stereochemistries, were established by means of spectral data analyses, including 2D experiments. The cytotoxicity of the isolated metabolites was evaluated against five human tumor cell lines.     

Cytotoxic and anti-inflammatory diterpenoids from the Dongsha Atoll soft coral Sinularia flexibilis

Seven new diterpenoids, namely, flexibilisolides C–G (1–5), flexibilisin C (6), and a novel 11,12-secoflexibillin (7), along with seven known compounds, 8–14, were isolated from the Dongsha Atoll soft coral Sinularia flexibilis. The structures of the new metabolites were elucidated by extensive spectroscopic analysis and comparison of the NMR data with those of known analogues. Compounds 1, 8, and 11 were shown to exhibit moderate cytotoxic activity against HeLa and B16 cancer cell lines, and compound 10 was found to exhibit more potent cytotoxic activity against SK-Hep1 and B16 cancer cell lines. Moreover, compounds 1, 2, 8, 9, and 11–14 could significantly inhibit the accumulation of the pro-inflammatory iNOS protein and 1, 8, 11, and 14 could reduce the accumulation of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells.     

Alokicenones A-H,eight tetrahydroanthracenes from the mangrove-derived Streptomyces sp. HN-A101

Alokicenones A-H (1–8), eight new tetrahydroanthracenes and one known okicenone (9) were identified from the secondary metabolites of mangrove-derived Streptomyces sp. HN-A101. Their structures were elucidated by HRESIMS and NMR spectroscopic data. The absolute configurations of them were determined by the calculated and experimental ECD curves. Compounds 1–2 and 9 showed moderate cytotoxicity against HCT116 and SW620 cancer cell lines with IC₅₀ values from 0.63 to 7.73?μM. In addition, compounds 1–3 and 7–9 also exhibited inhibitory activities against ROCK2 or BRD4.     

Nortriterpene constituents from Schisandra sphenanthera

Nine new highly oxygenated nortriterpenoids, pre-schisanartanins E–J (1–6) and sphenadilactones D–F (7–9), together with 17 known ones (10–26), have been isolated from the acetone extract of the roots and stems of Schisandra sphenanthera. The structures of the new metabolites were characterized on the basis of extensive spectroscopic analyses including 1D and 2D NMR experiments. These compounds were all evaluated for their cytotoxicity against HL-60, SMMC-7721, A549, MCF-7, and SW480 tumor cell lines.     

Synthesis and biological evaluation of indole-2-carbohydrazides and thiazolidinyl-indole-2-carboxamides as potent tubulin polymerization inhibitors

A new series of N’-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI₅₀ values < 0.4 μM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.     

New cytotoxic sesquiterpenes from the red algae Laurencia obtusa and Laurencia microcladia

Three new sesquiterpenes (1-3), along with five known (5-9), were isolated from the organic extract of the red alga Laurencia obtusa, collected from the coastal rocks of Serifos in the Aegean Sea. A new dimeric sesquiterpene of the cyclolaurane-type (4) along with four previously reported (7, 10-12) metabolites, were isolated from the extract of Laurencia microcladia, collected at Chios island in the North Aegean Sea. The structures and the relative stereochemistry of the compounds are proposed on the basis of their spectral data. The cytotoxicity of the isolated metabolites was evaluated against several cell lines including human tumor cell lines.     

Guignardins A–F,spirodioxynaphthalenes from the endophytic fungus Guignardia sp. KcF8 as a new class of PTP1B and SIRT1 inhibitors

Six new guignardins A–F (1–6) were isolated from the cultures of endophytic fungus Guignardia sp. KcF8 derived of a mangrove plant Kandelia candel, along with three known analogues, palmarumycins C₁ (7), BG1 (8), and JC1 (9). Compounds 2, 3, 7, and 8 showed antimicrobial activities. Compounds 5–7 exhibited significant cytotoxicities against 10 human tumor cell lines. Compound 3 also displayed significant inhibitory activity against human protein tyrosine phosphatase 1B and histone deacetylase silent information regulator T1enzymes, two key targets for the treatment of diabetes. This is the first report on the anti-PTP1B and anti-SIRT1 activities of spirodioxynaphthalenes.     

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.     

Bis-spiro-azaphilones and azaphilones from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05

Four new dimeric spiro-azaplilones, cochliodones A-D (1-4), two new azaphliones, chaetoviridines E and F (5 and 6), a new epi-chaetoviridin A (7), together with five known compounds, chaetoviridin A (8), ergosterol (9), chaetochalasin A (10), 24(R)-5α,8α-epidioxyergosta-6-22-diene-3β-ol (11), and ergosterol-β-d-glucoside (12) were isolated from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05. Structures and stereochemistry of the atropisomers 1-3 were determined by single-crystal X-ray diffraction analysis. Compounds 5, 10, and 11 exhibited antimalarial activity against Plasmodium falciparum, while 3, 5, 6, 10, and 11 showed antimycobacterial activity against Mycobacterium tuberculosis. In addition, 5 and 6 also showed cytotoxicity against the KB, BC1, and NCI-H187 cell lines.     

Three new inositol derivatives from Chisocheton paniculatus

Three new inositol derivatives (1–3) were isolated from the leaves of Chisocheton paniculatus collected in Vietnam, along with four known compounds, including a limonoid (4), two triterpenoids (5–6), and a tocopherol (7). The structures of the new compounds were elucidated by 1D- and 2D-NMR and HRESIMS analyses. Compound 4 showed the highest cytotoxicities against the human lung cancer A549 and cervical cancer HeLa cell lines, with IC₅₀ values of 7.3 and 8.8 µM, respectively, among the isolated compounds. Compounds 5 and 7 displayed moderate to weak cytotoxicities against the A549, HeLa, and human stomach cancer GSU cell lines, with IC₅₀ values ranging from 17.7 to 68.0 µM.     

Halichonic acid,a new rearranged bisabolene-type sesquiterpene from a marine sponge Halichondria sp.

A new compound, halichonic acid (1), was isolated from a marine sponge Halichondria sp., together with (6R,7S)-7-amino-7,8-dihydro-α-bisabolene (2). The structure of 1 was elucidated by spectroscopic analysis and ECD spectrum calculation to be a rearranged bisabolene-type sesquiterpene having a 3-azabicyclo[3.3.1]nonene moiety. Compound 2 was cytotoxic against HeLa cells with an IC₅₀ value of 50?μM, whereas 1 did not show cytotoxicity even at 50?μM. It is possible that 1 is biosynthesized from farnesyl pyrophosphate and glycine, with rearrangement.     

Sesquiterpenoid with new skeleton from Chloranthus henryi

Dayejijiol (1), a novel sesquiterpene with a new carbon skeleton, and a novel labdane-type diterpenoid (13S)-13-hydroxy-19-methoxy-5αH-8(17), 14-labdadien (3), together with three known compounds chloranthalactone A (4), shizukanolide (5), shizukolidol (6) were isolated from Chloranthus henryi Hemsl. Their structures were established by a combination of 1D and 2D NMR spectroscopic techniques. Compounds 1 and 5 exhibited anti-tumor activities against Hela and K562 human tumor cell lines.     

Meloslines A and B,two novel indole alkaloids from Alstonia scholaris

An unprecedented indole alkaloid melosline A (1), with 6/5/6/6 tetracyclic ring skeleton, together with a new alkaloid melosline B (2) and one known compound (3) were isolated from the leaves and twigs of Alstonia scholaris. The new structures were elucidated by comprehensive spectroscopic analysis. The absolute configuration of compound 1 was confirmed by comparison of experimental data with calculated electronic circular dichroism (ECD). Compound 1 exhibited moderate cytotoxicity against MCF-7 cancer cell lines.     

Bioactive meroterpenoids and alkaloids from the fungus Eurotium chevalieri

Five new meroterpenoids, chevalones A-D (1-4), aszonapyrone B (8), and a new sequiterpene alkaloid, eurochevalierine (5), together with four known compounds, sequiterpene (6), terpenoid pyrrolobenzoxazine named CJ-12662 (7), meroterpenoid, aszonapyrone A (9), and ergosterol were isolated from the fungus Eurotium chevalieri. The structures were established on the basis of spectroscopic evidence. The configurations of 1 and 5 were determined by X-ray analysis. The biosynthetic pathway of 1-3, 8, and 9 were proposed. Chemical transformation of aszonapyrone A (9) was also studied. Compounds 4, 5, and 7 exhibited antimalarial activity against Plasmodium falciparum, while 3, 5, and 7 showed antimycobacterial activity against Mycobacterium tuberculosis. In addition, compounds 2-7 showed cytotoxicity against cancer cell lines.     

Novel quinolinone alkaloids bearing a lignoid moiety and related constituents in the leaves of Melicope denhamii

Six novel quinolinone alkaloids bearing a phenylpropanoid or a coumarin moiety, named melicodenines C–H (1–6), two new cinnamyl alcohol derivatives, named melicodins A (7) and B (8), and a new coumarinolignan, named melicodin C (9), were isolated from the leaves of Melicope denhamii (Seem.) T. G. Hartley. Their structures were established by spectroscopic analyses including extensive 2D-NMR experiments. Compounds 1–5 and 9 possess a cyclobutane ring and are hypothetically produced by a [2+2] cycloaddition, whereas compound 6 is presumed to form through a Diels–Alder cycloaddition followed by the elimination of an acetone molecule. Ten quinolinone alkaloids (1–6, 10–13) and a coumarinolignan (9) were tested for anti-proliferative activity against DLD-1 human colon cancer cells. Melicodenine G (5) showed the most potent inhibitory activity, causing the induction of apoptosis with an IC₅₀ value of 9.4±0.3 μM.     

Iodo–sesquiterpene hydroquinone and brominated indole alkaloids from the Thai sponge Smenospongia sp.

6′-Iodoaureol, an iodo–sesquiterpene hydroquinone, 6′-aureoxyaureol, a bissesquiterpene hydroquinone, and four brominated indole alkaloids 3–6 were isolated from the Thai sponge Smenospongia sp. Additionally, four known sesquiterpene hydroquinones 12–15, ten known brominated indole alkaloids 7–11, 17–18, and 20–22, ergosterol, and furospinosulin-1 were also isolated. Compound 1 is the first reported iodo–sesquiterpene hydroquinone and compounds 7–11 were isolated for the first time from natural sources. The structures were characterized by spectroscopic analyses as well as comparison with literature data. Several of these metabolites were evaluated for cytotoxic activity against seven tumor cell lines.     

Antifouling and cytotoxic constituents from the South China Sea sponge Acanthella cavernosa

A bioassay-guided chemical investigation of the South China Sea sponge Acanthella cavernosa resulted in the isolation of eight new diterpenoids, kalihinols M–T (1–8), together with seven known analogues (9–15). These compounds featured a trans-decalin ring bearing a tetrahydrofuran or a tetrahydropyran ring at C-7. Compounds 1 and 2, with a formamide functionality beared at C-4, extended the structure breadth of this diterpenoid family. The absolute stereostructures of 1–14 were determined by a combination of 2D NMR and CD spectroscopic analysis and single crystal X-ray diffraction. Compounds 1 and 2 were confirmed to have the configurations of 4S, 5S, whereas 3–14 were determined as 4R, 5R. Compounds 3–14 displayed significant antifouling activity against the barnacle Balanus amphitrite larvae, and the cytotoxic activities of 3–14 were evaluated against the H1299, A549, PC3, CT-26, and HCT-116 cancer cell lines.     

Chemical-epigenetic method to enhance the chemodiversity of the marine algicolous fungus, Aspergillus terreus OUCMDZ-2739

Four new meroterpenoids identified as (R)-4-((2,2-dimethylchroman-6-yl)methyl)-3-(4-hydroxyphenyl)-5-methoxyfuran-2(5H)-one (1), 1-(2,2-dimethylchroman-6-yl)-3-(4-hydroxyphenyl)propan-2-one (2), (R,E)-3-(2,2-dimethylchroman-6-yl)-4-hydroxy-5-((2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl)methylene)furan-2(5H)-one (3), methyl (R)-2-(2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl) acetate (4), along with nine known compounds (5–13) were isolated from a chemical-epigenetic culture of Aspergillus terreus OUCMDZ-2739 with 10 μM trichostatin A (TSA). Under the same condition without TSA, A. terreus OUCMDZ-2739 produced different compounds (14–20), supporting that the chemical-epigenetic modification of fungi could enrich the chemodiversity of the fungal products. The cytotoxicity was observed for compound 8 against K562 cell, 9 against MCF-7 and K562 cells and 12 against MCF-7 cell with IC₅₀ values of 9.5, 10.1, 13.0 and 8.5 μM, respectively. Compounds 3, 8 and 17 exhibited stronger α-glucosidase inhibition than 1-deoxynojirimycin and acarbose (positive controls) with IC₅₀ values of 24.8, 1.2, 61.6, 191.7 and 555.1 μM, respectively. The enzyme kinetics study further indicated that compound 8 was an anticompetitive inhibitor with K_i value of 1.42 μM.