Undescribed Compounds Research Articles

Discovery of ent-labdane derivatives from Andrographis paniculata and their anti-inflammatory activity

The plant Andrographis paniculata has a long history of cultivation in Southeast Asia, especially its extensive anti-inflammatory activity, and the famous natural antibiotic andrographolide comes from this plant. In China, A. paniculata, as the main crop, has become a major source of traditional Chinese medicine (TCM) for the clinical treatment of inflammation. To further explore the diverse diterpene lactones with better anti-inflammatory activity from A. paniculata, twenty-one ent-labdanes, including six undescribed compounds (andropanilides D-I), were isolated. Their structures with absolute configurations were thoroughly determined by comprehensive NMR spectroscopic data, HRESIMS analysis and quantum chemical calculations. All isolated compounds were evaluated for anti-inflammatory activities based on the Griess method. Meanwhile, after structure-activity relationships analysis, the anti-inflammatory activity of andropanilide D (1) (IC50 = 2.31 μM) was found to be better than that of the positive control drug (dexamethasone, IC50 = 6.52 μM) and andrographolide (IC50 = 5.89 μM). Further mechanisms of activity indicated that andropanilide D significantly reduced the secretion of TNF-α, IL-6 and IL-1β and downregulated the protein expression of COX-2 and iNOS in LPS-induced RAW264.7 macrophages in a concentration-dependent manner based on Western blot and ELISA experiments. In conclusion, andropanilide D possesses potential medicinal value for the treatment of inflammation and further expands the material basis of the anti-inflammatory effect of A. paniculata.

Brunonianines A-C, C20-diterpenoid alkaloids with cyano group from Delphinium brunonianum Royle

Cyano tends to have better biological activity, but it is rarely reported in natural products, especially in the C20-diterpene alkaloids. Herein, three unprecedented C20-diterpenoid alkaloids, brunonianines A-C (1-3), possessing rare cyano functional group as well as an atisine backbone constructed from a phenethyl substituent and a tetrahydropyran ring, along with four C19-alkaloids (4–7) and one amide alkaloids (8), were isolated from the whole plant of Delphinium brunonianum Royle. Compounds 1–3 are also the first atisine type diterpenoid alkaloids with cyano group obtained from nature. The structures of the previously undescribed compounds were elucidated by HR-ESI-MS, 1D/2D NMR spectroscopic data and electronic circular dichroism calculations and single-crystal X-ray diffraction. Reasonable speculations have also been made regarding the biogenic synthetic pathways of compounds 1–3. In addition, the inhibitory activity of all compounds was also tested against four tumor lines: A549, Caco-2, H460 and Skov-3, where compound 2 (IC50 2.20 ± 0.21 μM) showed better inhibitory activity against Skov-3 cells than the hydroxycamptothecin. Using flow cytometry, cell staining, migration and invasion analysis, and Western blot, compound 2 was found to arrest cells in the G2/M phase and was able to effectively inhibit cell motility to achieve potent anti-tumor effects. In addition, compound 2 can effectively induce apoptosis by activating the Bax/Bcl-2/Caspase-3 signaling pathway.

Angular dihydropyranocoumarins from the flowers of Peucedanum japonicum and their aldo-keto reductase inhibitory activities

Twenty-one angular dihydropyranocoumarins and a linear furanocoumarin, including four previously undescribed compounds (1–4), were isolated from the flowers of Peucedanum japonicum (Umbelliferae). The structures of 1–4, along with their absolute stereochemistry, were determined to be (3′S,4′S)-3′-O-propanoyl-4′-O-(3‴-methyl-2‴-butenoyl)khellactone (1), (3′S,4′S)-3′-O-propanoyl-4′-O-(2‴-methyl-2‴Z-butenoyl)khellactone (2), (3′S,4′S)-3′-O-propanoyl-4′-O-(2‴-methylbutanoyl)khellactone (3), and (3′S,4′S)-3′-O-(2″-methylpropanoyl)-4′-O-(3‴-methyl-2‴-butenoyl)khellactone (4) using one- and two-dimensional nuclear magnetic resonance, high-resolution electrospray ionization mass spectroscopy, and electronic circular dichroism spectroscopy. In addition, the absolute configuration of the three angular dihydropyranocoumarins (5–7) was determined for the first time in this study. Among the previously reported compounds isolated in this study, 8 and 9 were isolated for the first time from the genus Peucedanum, whereas 10 and 11 were previously unreported and had not been isolated from P. japonicum to date. Furthermore, all isolated compounds were evaluated for their aldo–keto reductase 1C1 inhibitory activities on A549 human non-small-cell lung cancer cells. Compounds 10 and 12 exhibited substantial AKR1C1 inhibitory activities with IC50 values of 35.8 ± 0.9 and 44.2 ± 1.5 μM, respectively.

Tsaokoflavanols A1–J1: Flavanol-fatty alcohol hybrids with HPL inhibitory activity from Amomum tsao-ko

Ten previously undescribed compounds were isolated from the fruits of Amomum tsao-ko (Zingiberaceae), including nine undescribed flavanol-fatty alcohol hybrids (1–6, 10−11, 13), and a flavanol-monoterpenoid hybrid (14), along with seven known flavanol hybrids (7−9, 12, 15−17). The structures of these compounds were determined using various analyses, such as HRESIMS, 1D/2D NMR, and ECD calculations. In terms of biological activity, compounds 1, 2, 5, and 6 exhibited inhibitions of human pancreatic lipase (HPL), with IC50 values ranging from 0.017 to 0.193 mM. Some of these values were found to be stronger than that of the positive control, orlistat (IC50, 0.067 mM). Molecular docking studies were also conducted to investigate the interactions between these compounds and HPL. The docking simulations revealed the importance of the orientation of the 3,4-dihydroxyphenyl in binding with HPL. Additionally, compound 9 demonstrated cytotoxicity against HepG2, with a CC50 value of 14.96 ± 0.62 μM as determined by the MTT assay. Flow cytometry analysis indicated that compound 9 induced apoptosis in HepG2 cells. Western blot results showed an up-regulation of apoptosis-related proteins, such as p53 protein, Bax and Caspase-3 proteins, while the expression of Bcl-2 protein was down-regulated.

Four uncommon cycloamphilectane-type diterpenoids with antibacterial activity from the South China Sea soft coral Sinularia brassica

The chemical investigation on the soft coral Sinularia brassica collected off Xuwen Country, Guangdong Province, China, has resulted in the isolation and characterization of three uncommon cycloamphilectane-type diterpenoids, namely sinucycloamtin A–C (1–3), along with two known analogues (5 and 6). In addition, compounds 2 and 3 were hydrolyzed and their hydrolytic derivative sinucycloamtin D (4) was obtained. The structures of these previously undescribed compounds were established on the basis of extensive spectroscopic analysis, X-ray diffraction analysis, chemical conversion, as well as the comparison with the literature reported data. Compounds 1–3 represented the first examples of benzene-containing cycloamphilectane-type diterpenoids isolated from soft coral of genus Sinularia. In the in vitro bioassays, all the isolated and derived diterpenoids exhibited significant antibacterial activities against the fish pathogenic bacteria Phoyobacterium damselae FP2244 and Streptococcus parauberis SPOF3K with MIC90 values ranging from 3.7 to 9.1 μM.

Three new compounds from the seeds of Sinapis alba L

Three undescribed compounds, 1-(4-hydroxyphenyl)-3-((4-hydroxyphenyl)thio) −2-propanone (I), 4′-hydroxybenzyl 4-(4′′- hydroxybenzyloxy) benzyl thioether (II) and 3-(4′-hydroxybenzyl)-6-hydroxy-quinazolinone (III) were isolated from the seeds of Sinapis alba L. The structures of all compounds were elucidated based on NMR and MS analysis, along with the comparison with published data. The potential targets of compounds I-III were identified by virtual screening. The potential inhibitory effects of these compounds on protein kinase C theta type were compared by molecular docking. The docking score of compound III was the highest.

Isoprenylated Flavonoids and 2-Arylbenzofurans from the Root Bark of Morus alba L. and Their Cytotoxic Activity against HGC27 Cancer Cells.

Three new compounds (1, 11, and 12), together with 32 known ones, were isolated from the root bark of Morus alba L. using various chromatographic methods. The structures of the undescribed compounds were elucidated based on 1D, 2D NMR, and HRESIMS dataanalysis, while the known ones were identified by comparison of their spectroscopic data with those reported in the literature. All the isolates were evaluated for their cytotoxic activities against human gastric cancer HGC27 cells by CCK-8 assay. Among them, compounds 5, 8, 10, and 30 exhibited cytotoxic activities on HGC27 cells with IC50 values of 33.76 ± 2.64 μM, 28.94 ± 0.72 μM, 6.08 ± 0.34 μM, and 10.24 ± 0.89 μM, respectively. Furthermore, compound 10 was confirmed to reduce proliferation ability, increase apoptosis rate, and inhibit cell migration pathway by annexin V/PI double staining experiment, transwell experiment, and Western blot analysis.

Diisoprenyl-cyclohexene-type meroterpenoids from a mangrove endophytic fungus Aspergillus sp. GXNU-Y65 and their anti-nonalcoholic steatohepatitis activity in AML12 cells

Nine previously undescribed diisoprenyl-cyclohexene-type meroterpenoids, aspergienynes A-I, together with five known analogues, were obtained from the mangrove endophytic fungal strain Aspergillus sp. GXNU-Y65. The diisoprenyl-cyclohexene-type meroterpenoids were elucidated based on multispectroscopic analysis, and the previously undescribed compounds’ absolute configurations were established via electronic circular dichroism calculations. Biological activity results indicated that aspergienyne C (compound 3) had strong anti-nonalcoholic steatohepatitis activity against AML12 cells treated with PA (Palmitic acid) + OA (Oleic acid). At the same concentration of 20 μM, 3 significantly reduced triglyceride (TG) content compared with fenofibrate (positive control) in PA + OA treated AML12 cells, and obviously increased phosphorylation of acetyl-CoA carboxylase.

N-containing phenolic compounds from Periplaneta americana with triple negative breast cancer inhibitory activity

Eight previously undescribed compounds comprising pyrrole-2-carboxaldehyde derivatives, namely periplanpyrroles A–D (1–4), spirooxindole derivatives perispirooxindoles A (5) and B (6), and the phenolic compounds periplanetols G (7) and H (8), along with eight known compounds were isolated from the 70% ethanol extract of the whole bodies of Periplaneta americana. Their structures including absolute configurations were unambiguously identified by comprehensive spectroscopic analyses and computational methods. In addition, all compounds were evaluated for their activities against triple negative breast cancer in vitro. The wound healing assay revealed that 7, 9, and 11 significantly inhibit the migration of BT549 and MDA-MB-231 cells. Further observations made in Western blotting experiments showed that 7 could dose-dependently decrease the protein level of vimentin and N-cadherin in MDA-MB-231 and BT549 cells.

Four Steroidal Saponins from the Trunks of Dracaena cambodiana with Inhibition of NO Production in LPS Activated RAW264.7 Cells.

Dracaena cambodiana Pierre ex Gagnep. is well known as a medicinal plant and widely distributed in Vietnam. Phytochemical investigation on the trunks of D. cambodiana lead to the isolation of four undescribed compounds (1-4) together with seven known ones (5-11). Their structures were determined to be pennogenin-24-yl-O-β-D-glucopyranoside (1), 17α-hydroxycambodianoside C (2), (25R)-27-hydroxypenogenin 3-O-α-L-rhamnopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranoside (3), (3β,25R)-17α,22α-dihydroxy-furost-5-en-3-yl-O-α-L-rhamnopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranoside (4), dracagenin A (5), 1-O-β-D-glucopyranosyl-2-hydroxy-4-allylbenzene (6), 1-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranosyl-2-hydroxy-allylbenzene (7), 2-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranosyl-1-hydroxy-allylbenzene (8), cinnamrutinoside A (9), icariside D1 (10), and seco-isolariciresinol 9-O-β-glucopyranoside (11) by extensive spectroscopic investigation, HR-ESI-MS, 1D and 2D NMR spectra. The anti-inflammatory activity of the isolated compounds was evaluated on macrophages. Compounds 1-6 significantly inhibited nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Among them, compound 1 showed the best inhibitory activity with an IC50 value of 8.90±0.56 μM.

Chemical constitutes from Tuber indicum with immunosuppressive activity uncovered by transcriptome analysis

Three previously undescribed compounds including a polyketide (1) and two lactams (2 and 3) were obtained from Tuber indicum. The structures of new findings were elucidated by HRESIMS, NMR as well as NMR and ECD calculations. Transcriptome analysis through RNA-seq revealed that compound 2 exhibits immunosuppressive activity. Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were employed as a model to explore the effect of these compounds in immunosuppressive activity. The results showed that 2 could reduce the generation of inflammatory mediators including nitric oxide (NO), reactive oxygen species (ROS), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). Western blotting analysis demonstrated that 2 could suppressed the PI3K pathway by decreasing the levels of p-PI3K and p-Akt, while increasing the levels of p-PTEN. The anti-inflammatory activity of 2 was further confirmed using a zebrafish in vivo model.

Structures and bioactivities of monomeric and dimeric carvotacetones from Sphaeranthus africanus

Four previously undescribed carvotacetones including one monomeric (1) and three dimeric (8, 9, 10) derivatives, together with six known compounds were isolated from the n-hexane extract of the aerial parts of Sphaeranthus africanus L. The structures of the previously undescribed compounds were elucidated as 3-angeloyloxy-5-isobutanoyloxy-7-hydroxycarvotacetone (1), 7,7′-oxybis{3-angeloyloxy-5-[(2R*,3R*)-2,3-dihydroxy-2-methylbutanoyloxy]carvotacetone} (8), (2″S*,3″R*)-7-{3-angeloyloxy-5-[(2R*,3R*)-2,3-dihydroxy-2-methylbuta-noyloxy]carvotaceton-7-yloxy}-3-angeloyloxy-5-(2,3-dihydroxy-2-methylbutanoyloxy)carvo-tacetone (9), and 7,7′-oxybis{3-angeloyloxy-5-[(2S*,3R*)-2,3-dihydroxy-2-methylbutanoyl-oxy]carvotacetone} (10). The three dimeric derivatives (8–10) showed potent anti-proliferative activity against human cancer cell lines (CCRF-CEM, MDA-MB-231, U-251, HCT-116) with IC50 values ranging from 0.2 to 2.0 μM. Caspases 3 and 7 were found to be activated by all compounds, indicating apoptosis induction activity. Monomers exhibited a specific inhibition of NO production in BV2 and RAW 264.7 cells with IC50 values ranging from 4.2 to 6.8 μM which were 2–3.5-fold lower than IC50 values causing cytotoxicity. In addition, the carvotacetones reduced NF-κB1 (p105) mRNA expression at concentrations of 10 and 2.5 μM. Altogether, the results indicate that carvotacetones may be interesting lead structures for the development of anti-cancer and anti-inflammatory drugs.

Structure and activity of new degraded products of limonoid from root bark of Dictamnus dasycarpus, and insights from broadened NMR spectra into self-aggregation of hydroxy acids

Five degraded products of limonoid, including two previously undescribed compounds (1, 3) and one pair of new natural products (4i, 4ii), were isolated from the root bark of Dictamnus dasycarpus Turcz. Their structures were elucidated by extensively spectroscopic methods (NMR, MS, ECD, etc), as well as quantum chemical calculations. The broadening NMR lines, along with the relaxation time and DOSY experiment revealed the self-aggregation of 1 in chloroform through H-bond between –COOH and –OH, which provided additional evidence to distinguish acid and ester/lactone in structure elucidation. Compounds 1–3 attenuated oleic acid-induced lipid accumulation in HepG2 cells significantly, with inhibition rates of 19.8%, 23.6%, and 13.5% at 10 μM, much stronger than fenofibrate, affording a novel scaffold for drug discovery against fatty liver disease.

Four pairs of neolignan enantiomers with distinctive isochroman moiety from the fruits of Crataegus pinnatifida and their protective activities against H2O2-induced SH-SY5Y cells

Four pairs of neolignan enantiomers (±)-1− (±)-4 with a distinctive isochroman moiety, including seven undescribed compounds, were isolated and identified from the fruits of Crataegus pinnatifida. Structural characterization of these compounds was established through comprehensive spectroscopic analyses, as well as quantum chemical calculations of ECD and NMR data. The preliminary bioassay displayed that compounds (+)-2 and (±)-3 exerted protective activities against H2O2-induced human neuroblastoma SH-SY5Y cells compared with the positive control. These bioactive compounds could be potential candidates for further pharmaceutical applications.

Three megastigmane glycosides from the stem of Mallotus barbatus

Three undescribed megastigmane glycosides, mallbarbalosides A-C (1–3) together with 3 known analogues (4–6) were isolated from the stem of Mallotus barbatus. Their structures were elucidated using extensive NMR spectroscopic methods (1D and 2D-NMR spectroscopy) and HRESIMS spectroscopic data analyses. The absolute configurations of the undescribed compounds were determined by the experimental circular dichroism spectroscopy. All the compounds were tested for their inhibitory effects on the production of NO in LPS-treated RAW 264.7 cells, and they showed no inhibitory effect to NO release.

Chemical structures and cell-death-inducing activities of metabolites produced by Penicillium maximae

Two previously undescribed compounds, maximeroterpenoid I (1) and maximazaphilone V (5), together with five known compounds (2–4, 6, and 7) were isolated from the airborne-derived fungus Penicillium maximae JKYM-AK2. The planar chemical structures and relative configurations of 1 and 5 were elucidated by high-resolution mass spectrometry and 1D and 2D NMR spectroscopy. The absolute configuration of 1 and 5 were established by comparing experimental and predicted electronic circular dichroism data. We isolated JBIR-113 (3), which has an interesting cyclic peptide structure, in relatively high yield (0.37 % from the EtOAc-soluble fraction); therefore, P. maximae JKYM-AK2 is a rich source of this unique peptide. The azaphilones [5, (+)-isochromophilone IX (6), and (+)-isochromophilone VI (7)] induce significant Adriamycin-treated HeLa-cell death.

Rare onocerane-type triterpenoid and γ-butyrolactone derivative isolated from Kermadecia sinuata

Genus Kermadecia (Proteaceae) showed interesting biological activities related to their macrocyclic derivatives (kermadecin). Nevertheless, chemistry of Kermadecia sinuata was not studied until now. Phytochemical investigation of the bark of K. sinuata led to the isolation of two previously undescribed compounds: 4-(hydroxymethyl)-3,5-diphenyldihydrofuran-2(3H)-one, kermafuranone (1) and (+)-(5S,8R,9R,10S,5’S,8’S,9’R,10’S)-onocerane-8,8’-diol (2), along with four known compounds: methyl haematommate (3), atranorine (4), β-sitosterol (5) and docosyl ferulate (6). The structures of these compounds were elucidated by HRESIMS and NMR spectroscopic data analysis, and the absolute configuration of compound 2 was determined by single-crystal X-ray diffraction analysis. This compound is the first non-symmetrical onocerane-8,8’-diol. Hypothesised biosynthesis pathway was suggested for kermafuranone (1).

Tocotrienol monomers and dimers from the roots of Litchi chinensis with tyrosinase inhibition activity

Four undescribed modified tocotrienols, including two monomers, litchinols A (1) and B (2), and two walsurol dimers, δ,δ-walsurol (3) and γ,δ-bi-O-walsurol (4), as well as seven known compounds (5–11) were isolated from the roots of Litchi chinensis. The structures of the undescribed compounds were elucidated based on analyses of spectroscopic data and ECD spectra. All tocotrienol derivatives (1–6) were evaluated for their tyrosinase inhibition activity. Only monomers 1–2 and 5–6 displayed potent inhibitory activity and greater than kojic acid. Kinetic analysis revealed that the representative compound 2 was uncompetitive inhibitor with the inhibition constant value of 5.70 μM.

Meroterpenoids with divers' rings systems from Phyllosticta capitalensis and their anti-inflammatory activity

Four undescribed sesquiterpene-shikimates (1–4), eight undescribed monoterpene-shikimates (5–12), together with two known ones were isolated and identified from the 95% ethanol extract of the plant endophytic fungus Phyllosticta capitalensis cultured in rice medium. Capitalensis A (1) was identified as the first sesquiterpene-shikimate-conjugated spirocyclic meroterpenoid degradation product, while capitalensis B (2) is a sesquiterpene-shikimate-conjugated spirocyclic meroterpenoid with a unique D-ring formed by a C-2–O–C-9′ connection. The structures of these previously undescribed compounds were elucidated by multiple techniques, including IR, HR-ESI-MS, and NMR analysis. Furthermore, their absolute configurations were established through the comprehensive approach that involved the calculations of ECD spectra, optical rotation values, and single-crystal X-ray analysis. Moreover, the anti-inflammatory activity of all isolated compounds was evaluated using a lipopolysaccharide (LPS)-induced inflammation model in BV2 microglial cells. Meanwhile, these compounds exhibited activity in inhibiting NO production. Four compounds, capitalensis C (3), capitalensis D (4), 15-hydroxyl tricycloalternarene 5b (13) and guignarenone A (14) showed strong inhibitory effects with IC50 values of 21.6 ± 1.33, 12.2 ± 1.08, 18.6 ± 1.27, and 15.8 ± 1.20 μM, respectively. In addition, the structure-activity relationship of the anti-inflammatory activity of the compounds was discussed.

Undescribed compounds from Clinopodium chinense (Benth.) O. Kuntze and their coagulation activity studies

Four rare compounds (1–4), including one 1,4-epoxy-benzoxepane derivative and one ringed prenylated naphthoquinoid skeleton, as well as one isopimarane-type diterpenoid and one megastigmane-type glycoside, along with three known megastigmane-type glycosides (5–7) were isolated from the ethanol extracts of C. chinense. Their structures were determined on the basis of 1D, 2D NMR, HR-ESI-MS and DP4+ analysis. Meanwhile, the in vitro evaluation indicated that compound 2 and 6 exhibited excellent procoagulant activities, which can significantly shorten prothrombin time (PT) and activated partial thromboplastin time (APTT), respectively.