Lycopodium alkaloids from Huperzia serrata

A new lycopodane-type Lycopodium alkaloid, 6α-hydroxy-5,15-oxide-lycopodane (1), and seven known alkaloids were isolated from the whole plants of Huperzia serrata. Their structures were elucidated by means of spectroscopic methods. 12-Deoxyhuperzine O (2) was reported as a naturally occurring alkaloid for the first time, and showed an antagonist effect on the N-methyl-d-aspartate receptor with an IC₅₀ value of 0.92 μM.     

Two new p-coumaroylated sesquiterpenoids from Pilea cavaleriei

A new p-coumaroylated santalane-type sesquiterpenoid, 8-p-coumaroyl-α-santalene (1), a new p-coumaroylated oplopanane-type sesquiterpenoid, 8-β-p-coumaroyl-oplopanone (2), and three known p-coumaroylated humulene-type sesquiterpenoids (3–5) were isolated from the ethanol extract of the whole herbs of Pilea cavaleriei. Their structures were elucidated based on the combination of 1D and 2D NMR and HRMS methods. Compound 2 was found to show anti-tuberculosis activity with MIC of 16 μg/ml.     

A new sesquiterpene ester from the fruits of Celastrus orbiculatus

From the fruits of Celastrus orbiculatus Thunb., a new dihydroagarofuran sesquiterpene ester named 6α,13β-diacetoxy-1β,8β,9β-tribenzoyloxy-β-dihydroagarofuran (1) has been isolated, along with three known compounds: 1β,6α,8β-triacetoxy-9α-benzoyloxy-β-agarofuran (2), 1β,6α-diacetoxy-9α-benzoyloxy-β-dihydroagarofuran (3) and β-sitostrol (4). The structure of 1 was elucidated on the basis of spectroscopic methods.     

Two new triterpenoids from the resin of Styrax tonkinensis

Two new triterpenoids, 3β,6β-dihydroxy-12-oxo-13Hα-olean-28,19β-olide (1) and 3-oxo-olean-11,13(18)-dien-28,19β-olide (2) were isolated from the resin of Styrax tonkinensis (Pier.) Craib. The structures of both triterpenoids were determined by physicochemical and spectroscopic methods. Compound 1 is the second triterpene found with cis-fused C/D ring from the resin, which is rarely observed in oleanane-type triterpenes.     

A new dihydroagarofuranoid sesquiterpene from the roots of Tripterygium hypoglaucum

A new sesquiterpene ester (1) has been isolated from the root bark of Tripterygium hypoglaucum. The structure was determined as 1α-acetoxy-6β,9β-dibenzoyloxy-4β-hydroxy-dihydroagarofuran by the extensive analysis of NMR data, and the absolute configurations were established as 1R, 4R, 6S, and 9R by application of the CD excitation chirality method. Compound 1 exhibited weak cytotoxicity against HeLa cells, with an IC₅₀ value of 30.2 μM.     

Two new C19-diterpenoid alkaloids from Aconitum straminiflorum

Two new C₁₉-diterpenoid alkaloids, straconitines A (1) and B (2), were isolated from the roots of Aconitum straminiflorum. Their structures were elucidated as 14-benzoylducloudine D (1) and 6-hydroxy-14-benzoylducloudine D (2) based on spectroscopic analysis, including IR, ESI-MS, HR-ESI-MS, 1D, and 2D NMR.     

Bioassay-guided isolation,identification of compounds from Origanum rotundifolium and investigation of their antiproliferative and antioxidant activities

Context: Origanum (Lamiaceae) has been used in food and pharmaceutical industries.

Objective: Isolation and identification of bioactive compounds from Origanum rotundifolium Boiss. and investigation of their antiproliferative and antioxidant activities.

Materials and methods: The aerial part of O. rotundifolium was dried and powdered (1.0?kg ±2.0?g) then extracted with hexane, ethyl acetate, methanol and water. Solvent (3?×?1?L) was used for each extraction for a week at room temperature. The aqueous extract was partitioned with ethyl acetate (3?×?1?L) to yield the water/EtOAc extract subjected to chromatography to isolate the active compounds. The structures of isolated compounds were elucidated by 1?D, 2?D NMR and LC-TOF/MS.

Results: Apigenin (1), ferulic acid (2), vitexin (3), caprolactam (4), rosmarinic acid (5), and globoidnan A (6) were isolated and identified. Globoidnan A (6), vitexin (3), and rosmarinic acid (5) revealed the excellent DPPH^? scavenging effect with IC₅₀ values of 22.4, 31.4, 47.2?μM, respectively. Vitexin (3) (IC₅₀ 3.6), globoidnan A (6) (IC₅₀ 4.6), apigenin (1) (IC₅₀ 8.9) and ferulic acid (2) exhibited more ABTS^?+ activity than standard Trolox (IC₅₀ 13.8?μg/mL). Vitexin (3) revealed the most antiproliferative activity against HeLa, HT29, C6 and Vero cells lines with IC₅₀ values of 35.6, 32.5, 41.6, 46.7 (μM), respectively.

Discussion and conclusion: Globoidnan A (6) has the most antioxidant effects on all assays. This has to do with the chemical structure of the compound bearing the acidic protons. Vitexin (3) could be a promising anticancer agent.     

Three new Lycopodium alkaloids from Lycopodium japonicum

Three new Lycopodium alkaloids (1–3), together with 15 known alkaloids, were isolated from club moss Lycopodium japonicum. Their structures were determined by extensive spectroscopic analysis, including 1D and 2D NMR spectra. Compound 1 has an unusual β-oriented methyl group substituted at C-15 and an α-hydroxy cyclopentenone moiety. All new alkaloids were evaluated for the inhibition of T-type calcium channel.     

Two new triterpenoid saponins from Ilex cornuta

Two new triterpenoid saponins (1 and 2) were isolated from the stems of Ilex cornuta, along with two known triterpenoids (3 and 4). The structures of compounds 1 and 2 were determined as ursane-12,19-diene-28-oic acid 3β-O-β-d-glucuronopyranoside-6-O-methyl ester (1), 3α,23α-dihydroxy-olean-9(11),12-diene-28-oic acid 28-O-β-d-glucopyranosyl ester (2), on the basis of hydrolysis and spectral evidence, including 1D and 2D NMR and high resolution electrospray ionization mass spectrometry (HR-ESI-MS) analyses. Protective effects of compounds 1–4 were tested against H₂O₂-induced H9c2 cardiomyocyte injury, and the data showed that all these compounds had no cell-protective effect.     

Two new compounds from Trifolium resupinatum var. microcephalum

An investigation of CH₂Cl₂ and EtOH extracts of Trifolium resupinatum L. var. microcephalum Zoh. has led to the isolation of two new compounds characterized as 4,15-dimethyl-2-(1,2-dihydroxyethyl)-hexadecene (1) and 1-undecene-1-O-β-2′,3′,4′,6′-tetraacetyl glucopyranoside (2a). Their structures were established by 1D and 2D NMR techniques, and mass spectroscopy.     

Three new dammarane-type triterpene saponins from the leaves of Panax ginseng C.A. Meyer

Three new dammarane-type triterpene ginsenosides, together with six known ginsenosides, were isolated from the leaves of Panax ginseng C.A. Meyer. The new saponins were named as ginsenoside Rh₁₁, ginsenoside Rh₁₂, and ginsenoside Rh₁₃. Their structures were elucidated as (20S)-3β,6α,12β,20-tetrahydroxydammara-25-ene-24-one 20-O-β-d-glucopyranoside (1), (20S)-3β,12β,20,24,25-pentahydroxydammarane 20-O-β-d-glucopyranoside (2), and (20S,23E)-3β,12β,20,25-tetrahydroxydammara-23-ene 20-O-β-d-glucopyranoside (3) on the basis of 1D and 2D NMR experiments and mass spectra. The known ginsenosides were identified as ginsenoside M_7cd, ginsenoside Rg₆, ginsenoside Rb₃, gypenoside XVII, gypenoside IX, and 20-(E)-ginsenoside F₄.     

Ingenine E,a new cytotoxic β-carboline alkaloid from the Indonesian sponge Acanthostrongylophora ingens

A new β-carboline alkaloid ingenine E (4), along with three known metabolites annomontine (1), acanthomine A (2), and 1,2,3,4-tetrahydronorharman-1-one (3) were isolated from the Indonesian marine sponge Acanthostrongylophora ingens. Their structure characterization was unequivocally carried out using one- and two-dimensional NMR spectroscopy, as well as high-resolution mass spectrometry. The cytotoxic activity of the isolated compounds was evaluated toward MCF7, A549, HCT116, PC12, and Hela cancer cell lines. Ingenine E (4) exhibited cytotoxic activity against MCF7, HCT116, and A549 cell lines with IC₅₀ values of 3.5, 0.67, and 2.15 μg/ml.     

Anti-inflammatory and anticancer effects of flavonol glycosides from Diplotaxis harra through GSK3β regulation in intestinal cells

Context and objective: Diplotaxis harra (Forssk.) Boiss. (Brassicaceae) is traditionally used as an antidiabetic, anti-inflammatory or anticancer agent. In these pathologies, the glycogen synthase kinase 3 β (GSK3β) is overactivated and represents an interesting therapeutic target. Several flavonoids can inhibit GSK3β and the purpose of this study was to search for the compounds in Diplotaxis harra which are able to modulate GSK3β.

Materials and methods: Methanol extracts from D. harra flowers were prepared and the bio-guided fractionation of their active compounds was performed using inflammatory [protease-activated receptor 2 (PAR₂)-stimulated IEC6 cells] and cancer (human Caco-2 cell line) intestinal cells. 50–100?μg/mL of fractions or compounds purified by HPLC were incubated with cells whose inhibited form of GSK3β (Pser9 GSK3β) and survival were analyzed by Western blot at 1?h and colorimetric assay at 24?h, respectively. LC-UV-MS profiles and MS-MS spectra were used for the characterization of extracts and flavonoids-enriched fractions, and the identification of pure flavonoids was achieved by MS and NMR analysis.

Results: The methanol extract from D. harra flowers and its flavonoid-enriched fraction inhibit GSK3β in PAR₂-stimulated IEC6 cells. GSK3β inhibition by the flavonoid-enriched D. harra fraction was dependent on PKC activation. The flavonoid-enriched D. harra fraction and its purified compound isorhamnetin-3,7-di-O-glucoside induced a 20% decrease of PAR₂-stimulated IEC6 and Caco-2 cell survival. Importantly, normal cells (non-stimulated IEC6 cells) were spared by these treatments.

Conclusion: This work indicates that flavonoids from D. harra display cytotoxic activity against inflammatory and cancer intestinal cells which could depend on GSK3β inhibition.     

A novel 3,4-dihydronaphthalen-1(2H)-one with spiro-butyrolactone and a new isocoumarin isolated from the endophytic fungus Phoma sp. YN02-P-3

A novel 3,4-dihydronaphthalen-1(2H)-one with spiro-butyrolactone phomol (1) and a new isocoumarin phomasatin (2), together with two known compounds (3–4) were isolated from the solid culture of the endophytic fungus Phoma sp. YN02-P-3. Their structures including the absolute configurations were characterized on the basis of extensive 1D, 2D NMR (HSQC, HMBC, NOESY), MS, and CD spectral data. Compound 1 showed selective cytotoxic activity against HL-60 cell line with the IC₅₀ value of 29.05 μM.     

Metabolism and clinical pharmacokinetics of 2-methyl-n-(2′-(pyrrolidinyl-1-ylsulfonyl)-n-[1,1′-biphenyl]-4-yl)propran-1-amine: insights into monoamine oxidase- and CYP-mediated disposition by integration of in vitro ADME tools

Abstract

1.?In early discovery stages, 2-methyl-N-(2′-(pyrrolidinyl-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)propan-1-amine (PBPA) demonstrated monoamine oxidase A (MAO-A) and cytochrome P450 (CYP)-mediated clearance. While human liver microsomes predicted low CL_b PBPA demonstrated a moderate CL_p/F in humans. The plasma pharmacokinetic (PK) of PBPA was characterized by unexpected high inter-individual variability. Hence, a retrospective analysis was undertaken to understand the disposition processes of PBPA, by applying in vitro mechanistic tools.

2.?The in vitro-to-in vivo of rat CL_b of PBPA was calculated as similar to that of human, suggesting rat to be a better predictor of a MAO-A/CYP substrate, but not dog or monkey; this is consistent with differences in expression of MAO-A in rat, dog, monkey and human. Fraction metabolized (f_m) of human MAO A (hMAO-A) (50%), CYP3A4 (8%), CYP3A5 (16%) and CYP2D6 (29%) was determined, in vitro.

3.?While the f_m of CYP3A5 was <50%, Michaelis–Menten kinetics demonstrated that it was a higher capacity pathway compared with MAO-A, 2D6 and 3A4. This was consistent with strong association of dose-normalized plasma C_max and area under the plasma concentration time curve (AUC_0-tlast) of PBPA with CYP3A5 genotype, but not with genotype of CYP2D6.

4.?This investigation demonstrates the value of integrating in vitro mechanistic tools to gain comprehensive understanding of disposition properties of drug candidates, in a discovery paradigm and prior to the investment in clinical trials.     

New cycloartanes and new iridoids from Dolichandrone spathacea collected in the mangrove forest of Soc Trang province,Vietnam

Abstract

Two new cycloartanes, named dolichandrone A (1) and dolichandrone B (2), as well as two new iridoids, named [6-O-[(E)-4-methoxycinnamoyl]-1β-hydroxy-dihydrocatalpolgenin (3) and 6-O-[(E)-4-methoxycinnamoyl]-1α-hydroxy-dihydrocatalpolgenin (4), together with four known iridoids (5–8), were isolated from the leaves and barks of Dolichandrone spathacea. Their structures were elucidated by means of extensive analysis of their HRESIMS, 1D and 2D NMR spectroscopic data. All of these compounds have been isolated for the first time from this plant. Compounds 1, 2, 5, and 7 were evaluated for their cytotoxic activity in vitro against four human cancer cell lines KB, Lu, HepG2, and MCF7. The results showed that only compound 2 exhibited a good cytotoxicity against KB cell line with IC₅₀ of 18.77 μM.     

A new triterpenoid from <Emphasis Type="Italic">Panax ginseng</Emphasis> exhibits cytotoxicity through p53 and the caspase signaling pathway in the HepG2 cell line

A new triterpenoid, 20(R),22(ξ),24(S)-dammar-25(26)-ene-3β,6α,12β,20,22,24-hexanol (1), and three known triterpenoids, β-D-glucopyranoside,(3β,12β)-12,20-dihydroxydammar-24-en-3-yl,6-acetate (2), 20(R)-ginsenoside Rg₃ (3), and 20(R)-ginsenoside Rh₂ (4), were isolated from the leaves of Panax ginseng. Their structures were determined by chemical analysis and spectral methods (IR, 1D and 2D NMR, HR-ESI-MS). Compounds 1–4 were exhibited various degrees of cytotoxicity in the human hepatoma cell line, HepG2. Compound 1 had the highest cytotoxic potency, with an IC₅₀ value of 20.1 μM, by stimulating p53-mediated cell cycle arrest at the G1 to S phase transition, leading to apoptosis via activation of the caspase signaling pathway.     

Two new asterriquinols from Aspergillus sp. CBS-P-2 with anti-inflammatory activity

Two new bisindolylbenzenoid alkaloids asterriquinol E (1) and asterriquinol F (2), together with four known compounds (3–6) were isolated from the fermentation products of the fungus Aspergillus sp. CBS-P-2. Their structures were established on the basis of extensive spectroscopic analysis, including HR-ESI-MS, UV, IR, 1D, and 2D NMR (HSQC, HMBC, and NOESY) methods. The stereochemical structure of 2 was confirmed via the CD data of the in situ formed [Rh₂(OCOCF₃)₄] complex method. All of the isolated compounds were tested for inhibitory activity against LPS (lipopolysaccharide)-induced nitric oxide production in microglia.     

Chemical constituents of the red alga Laurencia tristicha

Six new sesquiterpenes, 10-hydroxy-epiaplysin (1), 10-hydroxy-aplysin (2), 10-hydroxy-debromoepiaplysin (3), aplysin-9-ene (4), epiaplysinol (5) and debromoepiaplysinol (6), together with 13 known compounds (7–19), have been isolated from the red alga Laurencia tristicha. The structures of 1–6 were determined by spectroscopic methods including IR, EI-MS, HREI-MS, and 1D and 2D NMR techniques. All compounds were obtained from this species for the first time and were tested for cytotoxic activities against several human cancer cell lines including lung adenocarcinoma (A549), stomach cancer (BGC-823), hepatoma (Bel 7402), colon cancer (HCT-8) and HeLa cell lines. Compound 6 showed selective cytotoxicity against HeLa cell line with IC₅₀ 15.5 μM, cholest-5-en-3β,7α-diol (14) was toxic to all tested cell lines with IC₅₀ values of 16.8, 5.1, 0.5, 0.5, and 0.3 μM, respectively, and other compounds were inactive (IC₅₀>10 μg/ml).     

Prenylated C6–C3 compounds from the fruits of Illicium simonsii

Two new prenylated C₆–C₃ compounds, 4-epi-illicinone E-12-shikimate (1) and 3-hydroxyillifunone B (2), together with five known prenylated C₆–C₃ compounds (3–7), were isolated from the fruits of Illicium simonsii. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR, CD spectra, and ESI-MS analysis.