Triterpenoid saponins from Albizia boromoensis Aubrév. & Pellegr

As part of our search of new bioactive saponins from Cameroonian medicinal plants, phytochemical investigation of the roots of Albizia boromoensis led to the isolation of four new oleanane-type saponins, named boromoenosides A–D (1–4). Their structures were established by direct interpretation of their spectral data, mainly HRESIMS, 1D NMR (¹H, ¹³C NMR, and DEPT) and 2D NMR (COSY, NOESY, HSQC and HMBC), and by comparison with the literature data. All isolated saponins were assayed for their cytotoxicity against U-87 MG human glioblastoma cell lines and TG1 glioblastoma stem-like cells with no positive activity detected.     

Renal 25-hydroxyvitamin D-3 1 alpha-hydroxylase in guinea-pig: activity variations during development and pregnancy

The renal 25-hydroxyvitamin D-3-1 alpha-hydroxylase (1 alpha-hydroxylase) activity and circulating levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in pregnant guinea-pigs and their offspring. Serum levels of 1,25(OH)2D were significantly elevated in pregnant guinea-pigs but the renal enzyme activity was not different from non-pregnant animals. The fetal renal 1 alpha-hydroxylase activity was about 6-fold higher than the maternal level, whereas circulating 1,25(OH)2D was low. Treatment with pharmacological doses of 1,25(OH)2D3 increased circulating 1,25(OH)2D and depressed the renal 1 alpha-hydroxylases both in the mother and the fetus. In newborn guinea-pigs the enzyme activity was up to 10-times that seen in adults. It declined over the first 3 weeks, showing no difference between the sexes. In sexually mature animals the males had a significantly higher 1 alpha-hydroxylase activity than the female. However, this higher enzyme activity was not correlated to serum testosterone. Around the time the animals reached sexual maturity serum 1,25(OH)2D increased in both sexes. In the males this rise was correlated to an increase in serum testosterone. It is concluded that the maternal renal 1 alpha-hydroxylase activity is unchange in late pregnancy, compared to non-pregnant females. The data indicate that the fetus produces 1,25(OH)2D, and may contribute to the maternal circulating 1,25(OH)2D. The sex difference in 1 alpha-hydroxylase activity previously demonstrated is manifest at about the time of puberty.     

海南粗榧内生真菌S15的细胞毒活性产物

对海南粗榧(Cephalotaxus hainanensis Li)内生真菌S15次生代谢产物进行了研究。用多种柱色谱技术从S15的发酵液中分离得到2个化合物,根据波谱数据和理化性质将其鉴定为乙酰基细胞松弛素D(1)和细胞松弛素D(2),对其进行生物活性测试,发现2种细胞松弛素对肿瘤细胞SGC-7901有强细胞毒活性。     

Diterpenes from the brown algae Dictyota dichotoma and Dictyota linearis

Nineteen secondary metabolites of the brown alga Dictyota dichotoma (Huds.) Lam. and fifteen metabolites of the brown alga D. linearis (Ag.) Grev. were isolated and their chemical structures were elucidated on the basis of their NMR and mass spectral data. The diterpenes isopachydictyolal (1) from D. dichotoma and 4alpha-acetyldictyodial (2) from D. linearis are new natural products. The antiviral activity of metabolites isolated in adequate amounts was evaluated in laboratory assays against Herpes simplex virus I (HSV I) and Poliomyelitis Virus I, using Vero cells as hosts.     

Characterization of novel inhibitors of cyclin-dependent kinases.

In epithelial cells progression through the G1 phase of the cell cycle and preparing the cell for the S phase is regulated by cyclin D1-cdk4. Cells that express the retinoblastoma protein (pRb) are dependent on cyclin D1-cdk4 activity for their proliferation while cells that do not express pRb are not. Overexpression of cyclin D1 and/or cdk4, and loss of expression of p16 (the natural inhibitor of cyclin D1-cdk4 activity), have been implicated in several cancers. These data suggest that the aberrant activity of cyclin D1-cdk4 correlates with the tumor phenotype. Hence, blocking cyclin D1-cdk4 activity may prove to be an effective anticancer therapy for pRb(+) tumors. In this paper, we report the identification of four novel compounds that selectively inhibit cyclin D1-cdk4 activity to various degrees. We further demonstrate that two of these compounds also selectively inhibit the target, pRb(+) tumor cells. The implications of these discoveries and their utility as anticancer agents are discussed.     

New ceramides and isoflavone from the Egyptian Iris germanica L. rhizomes

Two new ceramides, irisamides A (1) and B (2), together with a new isoflavone, iridin S (3) have been isolated from the MeOH extract of the rhizomes of Iris germanica L. (Iridaceae). Their structures were established by UV, IR, HRESIMS, 1D and 2D NMR experiments, in addition to comparison with literature data. The isolated compounds were tested for their cytotoxic activity against different cancer cell lines.     

Renal 25-hydroxyvitamin D-3 1α-hydroxylase in guinea-pig: Activity variations during development and pregnancy

The renal 25-hydroxyvitamin D-3-1α-hydroxylase (1α-hydroxylase) activity and circulating levels of 1,25-dihydroxyvitamin D (1,25(OH)₂D) were measured in pregnant guinea-pigs and their offspring. Serum levels of 1,25(OH)₂D were significantly elevated in pregnant guinea-pigs but the renal enzyme activity was not different from non-pregnant animals. The fetal renal 1α-hydroxylase activity was about 6-fold higher than the maternal level, whereas circulating 1,25(OH)₂D was low. Treatment with pharmacological doses of 1,25(OH)₂D3 increased circulating 1,25(OH)₂D and depressed the renal 1α-hydroxylases both in the mother and the fetus. In newborn guinea-pigs the enzyme activity was up to 10-times that seen in adults. It declined over the first 3 weeks, showing no difference between the sexes. In sexually mature animals the males had a significantly higher 1α-hydroxylase activity than the female. However, this higher enzyme activity was not correlated to serum testosterone. Around the time the animals reached sexual maturity serum 1,25(OH)₂D increased in both sexes. In the males this rise was correlated to an increase in serum testosterone. It is concluded that the maternal renal 1α-hydroxylase activity is unchanged in late pregnancy, compared to non-pregnant females. The data indicate that the fetus produces 1,25(OH)₂D, and may contribute to the maternal circulating 1,25(OH)₂D. The sex difference in 1α-hydroxylase activity previously demonstrated is manifest at about the time of puberty.     

Lysine dendrimers as vectors for delivering genetic constructs to eukaryotic cells

Asymmetrical lysine dendrimers are promising as vectors for delivering gene expression constructs into mammalian cells. The condensing, protective, and transfection properties were studied for pentaspherical lysine dendrimer D5 and its analog D5C10, modified with capric acid residues at the outer sphere; in addition, the transfection activity was assayed for complexes DNA-dendrimer-endosomolytic peptide JTS-1. Fatty acid residues incorporated in lysine dendrimers proved to improve their ability to bind DNA, to protect DNA from nuclease degradation, and to ensure its transfer into the nucleus. Peptide JTS-1 introduced in DNA-dendrimer complexes significantly increased their transfection activity. The potentiating effect of JTS-1 was especially high with the DNA-D5C10 complex. An excess of JTS-1 changed the structure of the complexes and reduced their transfection activity. It was assumed that dendrimers D5 and D5C10 are promising vectors for delivering DNA to eukaryotic cells and provide a basis for constructing more refined nonvirus module carriers.     

Steroidal glycosides from the underground parts of Trillium erectum and their cytotoxic activity

Six steroidal glycosides, along with 14 known compounds, were isolated from the underground parts of Trillium erectum L. (Liliaceae). The structures of 1-6 were determined on the basis of extensive spectroscopic analysis, including two-dimensional (2D) NMR data, and a few chemical transformations. The isolated compounds were evaluated for their cytotoxic activity against HL-60 human promyelocytic leukemia cells.     

Cytotoxic Tetraprenylated Alkaloids from the South China Sea Gorgonian Euplexaura robusta

Nine achiral tetraprenylated alkaloids, including three new compounds, named malonganenones I–K ( 1 – 3 , resp.), together with six known analogs, 4 – 9 , were isolated from the gorgonian Euplexaura robusta collected from Weizhou Island of Guangxi Province, China. The structures of compounds 1 – 3 were elucidated by extensive spectral analyses, especially of their 1D‐ and 2D‐NMR data. Compounds 1, 4, 6 , and 7 showed moderate cytotoxicities against K562 and HeLa tumor cell lines with IC₅₀ values ranging from 0.35 to 10.82 μM . Compound 6 also showed moderate inhibitory activity against c‐Met kinase at a concentration of 10 μM .     

Lysine dendrimers as vectors for delivery of genetic constructs to eukaryotic cells

Asymmetrical lysine dendrimers are promising as vectors for delivering gene expression constructs into mammalian cells. The condensing, protective, and transfection properties were studied for pentaspherical lysine dendrimer D5 and its analog D5C10, modified with capric acid residues at the outer sphere; in addition, the transfection activity was assayed for complexes DNA-dendrimer-endosomolytic peptide JTS-1. Fatty acid residues incorporated in lysine dendrimers proved to improve their ability to bind DNA, to protect DNA from nuclease degradation, and to ensure its transfer into the nucleus. Peptide JTS-1 introduced in DNA-dendrimer complexes significantly increased their transfection activity. The potentiating effect of JTS-1 was especially high with the DNA-D5C10 complex. An excess of JTS-1 changed the structure of the complexes and reduced their transfection activity. It was assumed that dendrimers D5 and D5C10 are promising vectors for DNA delivery to eukaryotic cells and provide a basis for constructing more refined nonviral module carriers.     

Chemical synthesis,microbial transformation and biological evaluation of tetrahydroprotoberberines as dopamine D1/D2 receptor ligands

Dopamine D1/D2 receptors are important targets for drug discovery in the treatment of central nervous system diseases. To discover new and potential D1/D2 ligands, 17 derivatives of tetrahydroprotoberberine (THPB) with various substituents were prepared by chemical synthesis or microbial transformation using Streptomyces griseus ATCC 13273. Their functional activities on D1 and D2 receptors were determined by cAMP assay and calcium flux assay. Seven compounds showed high activity on D1/D2 receptor with low IC₅₀ values less than 1?µM. Especially, top compound 5 showed strong antagonistic activity on both D1 and D2 receptor with an IC₅₀ of 0.391 and 0.0757?µM, respectively. Five compounds displayed selective antagonistic activity on D1 and D2 receptor. The SAR studies revealed that (1) the hydroxyl group at C-9 position plays an important role in keeping a good activity and small or fewer substituents on ring D of THPBs may also stimulate their effects, (2) the absence of substituents at C-9 position tends to be more selective for D2 receptor, and (3) hydroxyl substitution at C-2 position and the substitution at C-9 position may facilitate the conversion of D1 receptor from antagonist to agonist. Molecular docking simulations found that Asp 103/Asp 114, Ser 107/Cys 118, and Trp 285/ Trp 386 of D1/ D2 receptors are the key residues, which have strong interactions with the active D1/D2 compounds and may influence their functional profiles.     

Sesquiterpenoid Compounds from Curcuma kwangsiensis

Two previously undescribed guaiane‐type sesquiterpenes ( 1 and 2 ), a pair of new salvialane‐type sesquiterpenes ( 3a and 3b ), together with 11 known compounds were isolated and purified from the rhizomes of Curcuma kwangsiensis. Their structures were elucidated by the extensive spectroscopic data (1D‐ and 2D‐NMR) analysis. All the isolated compounds were assessed for their anti‐neuroinflammatory activity by inhibiting the nitric oxide (NO) production in lipopolysaccharide (LPS)‐activated murine BV‐2 microglial cells in vitro assay, and the isolates 3 and 11 showed anti‐neuroinflammatory activity with IC₅₀ values of 1.85 and 20.05 μm , respectively.     

Prenylated indole alkaloids from the stem bark of Hexalobus monopetalus

Seven new prenylated indole alkaloids (1–7) together with two known compounds (8–9) were isolated from the stem bark of Hexalobus monopetalus. Their structures were established on the basis of comprehensive spectroscopic analysis, including HR-MS, 1D and 2D NMR and by comparison of their spectral data with those reported in literature. The new compounds were tested for antimicrobial activity against selected pathogenic bacteria and fungi but showed no activity. The marked presence of prenylated indole alkaloids in Hexalobus and closely related genera makes them useful chemotaxonomic markers.     

Aspergetherins A-D,New Chlorinated Biphenyls with anti-MRSA Activity from the Marine Sponge Symbiotic Fungus Aspergillus terreus 164018

Aspergetherins A-D ( 1 – 4 ), four new chlorinated biphenyls, were isolated from the rice fermentation of a marine sponge symbiotic fungus Aspergillus terreus 164018, along with seven known biphenyl derivatives ( 5 – 11 ). The structures of four new compounds were determined by a comprehensive analysis of the spectroscopic data, including HR-ESI-MS and 2D NMR data. All 11 isolates were evaluated for their anti-bacterial activity against two strains of methicillin-resistant Staphylococcus aureus (MRSA). Among them, compounds 1 , 3 , 8 and 10 showed anti-MRSA activity with MIC values of 1.0–128 μg/mL. Preliminary structure-activity relationship analysis unveiled that both chlorinated substitution and esterification of 2-carboxylic acid could impact the antibacterial activity of biphenyls.     

CYP2D6.10 present in human liver microsomes shows low catalytic activity and thermal stability

Comparing bufuralol 1'-hydroxylase activity among liver microsomes prepared from individuals whose CYP2D6 genotypes had been determined, we found that the activity tended to decrease depending on the number of the CYP2D6*10 allele. Pre-incubation of liver microsomes from individuals homozygous for the CYP2D6*10 allele resulted in a decrease in the enzyme activity more rapidly than those from individuals homozygous for the CYP2D6*1, suggesting that not only the catalytic activity but also the thermal stability of the enzyme appeared to be affected by the genetic polymorphism. To confirm this hypothesis, the kinetic parameters of CYP2D6.1 and CYP2D6.10 were compared for bufuralol 1'-hydroxylation and dextromethorphan O-demethylation using microsomes prepared from yeast transformed with plasmids carrying CYP2D6 cDNAs (*1A and *10B). Kinetic studies of these CYP2D6 forms indicated clear differences in the metabolic activities between the wild (CYP2D6.1) and the mutant enzymes (CYP2D6.10). Bufuralol 1(')-hydroxylase activity in microsomes of yeast expressing CYP2D6.10 was rapidly decreased by heat treatment, supporting the idea that the thermal stability of the enzyme was reduced by amino acid replacement from Pro (CYP2D6.1) to Ser (CYP2D6.10). These data strongly suggest that the thermal instability together with the reduced intrinsic clearance of CYP2D6.10 is one of the causes responsible for the known fact that Orientals show lower metabolic activities than Caucasians for drugs metabolized mainly by CYP2D6, because of a high frequency of CYP2D6*10 in Orientals.     

Isolation, structure elucidation, antioxidative and immunomodulatory properties of two novel dihydrocoumarins from Aloe vera

Two new dihydrocoumarin derivatives, compounds 1 and 2, were isolated from Aloe vera. Their structures were determined by X-ray crystallographic diffraction analysis and extensive 1D, 2D NMR spectroscopic data. Both of them evidently showed antioxidant activity against superoxide and hydroxyl radicals. Only 1 obviously exhibited immunomodulatory activity in relation to increasing the phagocytic activity and stimulating the production of superoxide anions in the oxygen respiratory burst of rat peritoneal macrophages.     

Four New Flavonoid C-Glycosides Isolated from Achyranthes aspera and Their Nitric Oxide Production Inhibitory Activities

A chemical study of the methanol extract of the aerial parts of Achyranthes aspera led to the isolation of four new flavonoid C-glycosides ( 1 – 4 ) along with eight known analogs ( 5 – 12 ). Their structures were elucidated by a combination of spectroscopic data analysis, HR-ESI-MS, 1D and 2D NMR spectra. All the isolates were evaluated their NO production inhibitory activity in LPS-activated RAW264.7 cells. Compounds 2 , 4 , and 8 – 11 showed significant inhibition with IC₅₀ values ranging from 25.06 to 45.25 μM, compared to that of the positive control compound, L-NMMA, IC₅₀ value of 32.24 μM, whereas the remaining compounds were weak inhibitory activity with IC₅₀ values over 100 μM. This is the first report of 7 from Amaranthaceae family, and 11 from the genus Achyranthes.     

Virginols A–C,three new withanolides from Physalis virginiana

Virginols A–C are three new withanolides containing an epoxylactol at the side chain. They were isolated from the aerial parts of Physalis virginiana Miller. Structures of these compounds were determined by analyses of their spectroscopic data, including 1D and 2D NMR. The structure of virginol A was confirmed by X-ray diffraction analysis. The anti-inflammatory activity of virginols was evaluated in the TPA-induced ear mouse edema model.