Cytotoxic cycloartanes from the fruits of Caloncoba glauca

Two new cycloartane-type triterpenoids, glaucartanoic acids A (1) and B (2), together with five known compounds were isolated from the fruits of Caloncoba glauca. Their structures were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques, by chemical evidence and by comparison with literature data. The new compounds were evaluated for their in vitro cytotoxicity against five human cancer cell lines.     

Three new iridoid glycosides isolated from the traditional herb Siphonostegia chinensis with NF-κB inhibitory activity

Siphonoids A–C (1–3), among which siphonoids A-B (1–2) are rare (E)-p-coumaroyl iridoids, were isolated from Siphonostegia chinensis along with ten known iridoids (4–13) and four lignans (14–17). The structures of the compounds were established by 1D- and 2D-NMR spectroscopy and mass spectrometry. Most of the iridoids isolated from S. chinensis were found to possess (E)-p-coumaroyl iridoid subtype skeletons. Hence, this type of iridoid could be regarded as a chemotaxonomic marker of S. chinensis. The inhibition activities for the NF-κB pathway of iridoids (1–6) were detected. The present results showed that compounds 1–2 and 4–6 processed moderate activity towards the inhibition of NF-κB.     

Synthesis and in vitro antiviral activities of 3′-fluoro (or chloro) and 2′,3′-difluoro 2′,3′-dideoxynucleoside analogs against hepatitis B and C viruses

Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) lead to serious liver diseases worldwide. Co-infection with HBV and HCV is very common and is associated with increased risk of liver pathogenesis, liver cancer, and liver failure. Several 5-substituted 3′-fluoro (or chloro) (1–4, 6, 7, 17–19) and 2′,3′-difluoro 2′,3′-dideoxynucleosides (15 and 16) were synthesized and evaluated for in vitro antiviral activities against duck hepatitis B virus (DHBV), human hepatitis B virus, and hepatitis C virus. Of these compounds 4, 7, 17, and 19 demonstrated moderate anti-HBV activity, and 2, 4, 7, 8, and 19 were weak inhibitors of HCV. Although 5-iodo derivative (7) was most inhibitory against HCV, it exhibited a reduction in cellular RNA levels in Huh-7 cells. The 5-hydroxymethyl-3′-fluoro-2′,3′-dideoxyuridine (4) and 1-(3-chloro-2,3-dideoxy-β-d-erythro-pentofuranosyl)-5-fluorouracil (19) provided the most inhibition of both viruses without cytotoxicity.     

Tellimagrandin I,HCV invasion inhibitor from Rosae Rugosae Flos

By use of the model virus, expressing the HCV envelope proteins E1 and E2, bioassay guided separation of the MeOH extract from Rosa rugosa Thunb. disclosed tellimagrandin I (1) together with eugeniin (2) and casuarictin (3) as the potent HCV invasion inhibitors. Furthermore, structure–activity relationship analysis of some relative tannins including the synthesized analogs elucidated the partial structures crucial for potent activity of 1.     

Tanzawaic acid derivatives from a marine isolate of Penicillium sp. (SF-6013) with anti-inflammatory and PTP1B inhibitory activities

Chemical investigation of a marine-derived fungus Penicillium sp. SF-6013 resulted in the discovery of a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (1), together with four known analogues, tanzawaic acids A (2) and D (3), a salt form of tanzawaic acid E (4), and tanzawaic acid B (5). Their structures were mainly determined by analysis of NMR and MS data, along with chemical methods. Preliminary screening for anti-inflammatory effects in lipopolysaccharide (LPS)-activated microglial BV-2 cells showed that compounds 1, 2, and 5 inhibited the production of nitric oxide (NO) with IC₅₀ values of 37.8, 7.1, and 42.5 μM, respectively. Compound 2 also inhibited NO production in LPS-stimulated RAW264.7 murine macrophages with an IC₅₀ value of 27.0 μM. Moreover, these inhibitory effects correlated with the suppressive effect of compound 2 on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW264.7 and BV2 cells. In addition, compounds 2 and 5 significantly inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with the same IC₅₀ value (8.2 μM).     

Isopimarane diterpenes and flavan derivatives from the twigs of Caesalpinia furfuracea

The first phytochemical investigation of Caesalpinia furfuracea twigs led to the isolation and identification of four new compounds including two isopimarane diterpenes, caesalfurfuric acids A (1) and B (2), and two flavans, (2R)-caesalflavans A (5) and B (6), together with four known compounds, 4-epi-isopimaric acid (3), methyl (E)-3-(3,4-dihydroxyphenyl)acrylate (4), (E)-resveratrol (7) and oxyresveratrol (8). Their structures were elucidated by intensive spectroscopic analysis. Compound 1 was found to exhibit antibacterial activity against MRSA SK1 with an MIC value of 16 μg/mL.     

Xanthine oxidase inhibitory effects of the constituents of Chrysanthemum morifolium stems

The flowers of Chrysanthemum morifolium Ramat. (family: Asteraceae) are used in Traditional Chinese Medicine to treat fever, cold and swelling. However the aerial part is considered as agriculture waste and the chemical and pharmacological information is scanty. From the stems of this plant, four new compounds named as morineoliganosides A (1), B (2), C (3) and heterophyllol-1-O-β-d-glucopyranoside A (4) together with 27 known isolates (5–31), including flavonoids and caffeoylquinic acids were isolated. Their structures were elucidated by chemical and spectroscopic methods The inhibitory effects on xanthine oxidase of these compounds have been determined. This research provided a scientific development and utilization of C. morifolium stems.     

Discovery of pyrido[2,3-d]pyrimidine-based inhibitors of HCV NS5A

Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional ‘E’ ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series.     

α-Glucosidase inhibitory and nitric oxide production inhibitory activities of alkaloids isolated from a twig extract of Polyalthia cinnamomea

The first phytochemical investigation of Polyalthia cinnamomea led to the isolation and identification of two new oxoprotoberberine alkaloids, (−)-(13aS)-polyalthiacinnamines A and B, together with eleven known compounds. The structures of the new compounds were elucidated by extensive spectroscopic methods. The absolute configuration of miliusacunine E and consanguine B was established by X-ray diffraction analysis using Cu Kα radiation and ECD spectra, whereas the absolute configurations of polyalthiacinnamines A and B were established by comparison of their ECD spectra and specific rotations with those of miliusacunine E and consanguine B. Compounds 1–4, 6, and 8 exhibited α-glucosidase inhibitory activities (IC₅₀ values ranging from 11.3 to 57.9 µM) better than a positive control (acarbose, IC₅₀ 83.5 μM). Compound 2 also exhibited NO production inhibitory activity with an IC₅₀ value of 24.4 μM (indomethacin, a positive control, IC₅₀ = 32.2 μM).     

Design and evaluation of novel tetracyclic benzofurans as palm site allosteric inhibitors of HCV NS5B polymerase

Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.     

Polyacelylenic alcohols and alkaloid derivatives from a calcareous marine sponge,Leucetta chagosensis

A chemical investigation of the CH₂Cl₂ extract of the marine sponge Leucetta chagosensis afforded 8 secondary metabolites, namely, pellynol A (1), pellynol B (2), pellynol I (3), pellynol D (4), plakohypaphorine B (5), plakohypaphorine E (6), 4-bromo-1H-pyrrole-3-carboxamide (7), and 2-phenylacetamide (8). The structures of these secondary metabolites were elucidated via NMR spectroscopic analysis, MS experiment and compared with those reported in the literature. This is the first report of compounds 1–8 isolated from the marine sponge genus Leucetta and from the class Calcarea. This work contributes expands the knowledge of the chemical diversity of calcareous marine sponges, and the chemotaxonomic significance of the isolates is also discussed.     

Psorantin,a unique methylene linked dimer of vismin and kenganthranol E,two anthranoid derivatives from the fruits of Psorospermum aurantiacum (Hypericaceae)

Two prenylated anthranoids, psorantin and kenganthranol E, were isolated from the fruit of Psorospermum aurantiacum together with the known compounds ferruginin B, vismin, vismion D, haronginanthrone, kenganthranol B, kenganthraquinone, 1,7-dihydroxyxanthone, paradisiol, fridelin, fridelinol and betulinic acid. Their structures were determined on the basis of spectral data and by comparison with data reported in the literature as well as with authentic specimens for the known compounds. The structures of the new compounds were determined as bis-[3,8,9-trihydroxy-6-methyl-4,4-bis-(3,3-dimethylallyl)anthracenyl]methane (1) and 1,8,10-trihydroxy-6-methyl-4,5-bis-(3,3-dimethylallyl)-2,3-(2,2-dimethylpyrano)anthrone (2). Psorantin (1) is a dimer of vismin formed through a methylene linkage. The two new compounds when tested against the microbial strains Bacillus megaterium, Escherichia coli, Chlorella fusca and Microbotryum violaceum showed no activity.     

Three new phthalide glycosides from the rhizomes of Ligusticum chuanxiong

Three new phthalide glycosides, named chuanxiongoside A (1), chuanxiongoside B (2) and ligusticoside B (3) together with two known glycosides, celephthalide A (4) and icariside F₂ (5), were isolated from the rhizomes of Ligusticum chuanxiong. This is the first report of compounds 4⿿5 from the title plant. The structures of compounds 1⿿3 were identified using various spectroscopic methods.     

Cytosporones,coumarins, and an alkaloid from the endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove plant Rhizophora mucronata

Chemical examination of the endophytic fungus Pestalotiopsis sp., isolated from the leaves of the Chinese mangrove Rhizophora mucronata, yielded 11 new compounds including cytosporones J–N (1–3, 5–6), five new coumarins pestalasins A–E (8–12), and a new alkaloid named pestalotiopsoid A (14), along with the known compounds cytosporone C (4), dothiorelone B (7), and 3-hydroxymethyl-6,8-dimethoxycoumarin (13). The structures of the new compounds were unambiguously elucidated on the basis of extensive spectroscopic data analysis.     

Novel 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents

Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10 μM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile.     

Anti-HBV active constituents from Piper longum

In the screening search for Hepatitis B virus inhibitory agents from medicinal plants, the ethanol extract of Piper longum Linn. was found to possess superior anti-HBV activity in vitro. Bioassay-guided fractionation coupled with repeated purification resulted in the isolation of four new compounds, involving two new glycosides longumosides A (1) and B (2) and two new amide alkaloids erythro-1-[1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine (3), threo-1-[1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine (4), as well as two compounds 3β,4α-dihydroxy-2-piperidinone (5), 5,6-dihydro-2(1H)-pyridinone (6) from natural source for the first time. The structures of the four new compounds were determined by extensive analyses of the MS, IR, 1D and 2D NMR data. Besides, the compounds 2–6, together with the known compounds 7–11 obtained previously, were assayed for their anti-HBV activity by using Hep G 2.2.15 cell line in vitro. Results suggested the compound piperine (7) possessed remarkable inhibitory HBV activity, against the secretion of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) with the Selectivity Index (SI) values of 15.7 and 16.8, respectively.     

Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents

Previous investigations identified 2′-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin.     

Monoterpenoids and Triterpenoids from Pterocephalus hookeri with NF-κB inhibitory activity

In this study, we isolated two new monoterpenoids hookerinoids A and B (1 and 2; rare arranged nonglycosidic bis-iridoids) and hookerinoid C (3; a novel norursane-type triterpenoid) in addition to two known compounds, 11,12-epoxy-2,6-dihydroxy-24-norursa-1,4-dien-3-on-2-on-(28 → 13)-olide (4) and rivularicin (5), from Pterocephalus hookeri. The structures of 1–3 were established using one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution electrospray ionisation mass spectrometry. All compounds were isolated from this plant for the first time. Bis-iridoids isolated from P. hookeri possessed secoiridoid/iridoid subtype skeletons. Therefore, bis-iridoids can be considered chemotaxonomic markers of P. hookeri. The origins of the new compounds (1–3) were postulated and their inhibitory activities on a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway were assayed; 1 and 2 showed obvious activity in inhibiting NF-κB.     

Five new quassinoids and cytotoxic constituents from the roots of Eurycoma longifolia

Eurycoma longifolia has been widely used for various traditional medicinal purposes in South-East Asia. In this study, five new quassinoids, eurylactone E (1), eurylactone F (2), eurylactone G (3), eurycomalide D (4), and eurycomalide E (5), along with ten known quassinoids (6–15) were isolated from the roots of E. longifolia. Their structures were determined by extensive spectroscopic methods, including 1D and 2D NMR, and MS spectra data. Among the isolated compounds, 13β-methyl,21-dihydroeurycomanone (6) has been reported as a synthetic derivative. However, it was isolated from the natural product for the first time in this study. The cytotoxic activities of fifteen compounds were evaluated against human lung cancer cell line, A549 and human cervical cancer cell line, HeLa.     

Two new monoterpenes and one dicaffeic acid ester from Sibiraea angustata with hypolipidemic activities in HepG2 cells in Vitro

Two new monoterpenes, named sibiscolacton B (1) and sibiscolacton C (2), together with a sorbate obtained from the natural product 1, 6-sorbitol-O-dicaffeic acid ester (3), were isolated from an aqueous extract of the aerial portion of Sibiraea angustata. The compounds’ structures were elucidated on the basis of extensive spectroscopic analysis, as well as literature comparisons. A preliminary in vitro bioassay showed that all of the compounds exhibited hypolipidemic effects in HepG2 cells.