Ianthesine E, a new bromotyrosine-derived metabolite from the Great Barrier Reef sponge Pseudoceratina sp

The new compound ianthesine E (1) was isolated from the Great Barrier Reef marine sponge Pseudoceratina sp. along with the known metabolites 11-hydroxyaerothionin (2), aerothionin (3) and 11,19-dideoxyfistularin 3 (4). Structures were determined on the basis of their spectroscopic data. The compounds were tested for inhibition of [(3)H] DPCPX binding to adenosine A(1) receptors in a whole cell binding assay. At 100 microM, aerothionin was the most potent, inhibiting 67% of binding, followed by ianthesine E and 11-hydroxyaerothionin which inhibited 61% of binding, and 11,19-dideoxyfistularin which initiated 51% of binding Ianthesine E (EC(50) 60 microM), aerothionin (EC(50) 42 microM) and 11,19-dideoxyfistularin-3 (EC(50) 2.6 microM) exhibited moderate cytotoxicity against the HeLa cell line.     

Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy

(1) Background and Aim: All-trans retinoic acid (ATRA) induces differentiation and inhibits growth of many cancer cells. However, resistance develops rapidly prompting the urgent need for new synthetic and potent derivatives. EC19 and EC23 are two synthetic retinoids with potent stem cell neuro-differentiation activity. Here, these compounds were screened for their in vitro antiproliferative and cytotoxic activity using an array of different cancer cell lines. (2) Methods: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, AV/PI (annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI)), cell cycle analysis, immunocytochemistry, gene expression analysis, Western blotting, measurement of glutamate and total antioxidant concentrations were recruited. (3) Results: HepG2, Caco-2, and MCF-7 were the most sensitive cell lines; HepG2 (ATRA; 36.2, EC19; 42.2 and EC23; 0.74 µM), Caco-2 (ATRA; 58.0, EC19; 10.8 and EC23; 14.7 µM) and MCF-7 (ATRA; 99.0, EC19; 9.4 and EC23; 5.56 µM). Caco-2 cells were selected for further biochemical investigations. Isobologram analysis revealed the combined synergistic effects with 5-fluorouracil with substantial reduction in IC₅₀. All retinoids induced apoptosis but EC19 had higher potency, with significant cell cycle arrest at subG₀-G₁, -S and G₂/M phases, than ATRA and EC23. Moreover, EC19 reduced cellular metastasis in a transwell invasion assay due to overexpression of E-cadherin, retinoic acid-induced 2 (RAI2) and Werner (WRN) genes. (4) Conclusion: The present study suggests that EC-synthetic retinoids, particularly EC19, can be effective, alone or in combinations, for potential anticancer activity to colorectal cancer. Further in vivo studies are recommended to pave the way for clinical applications.     

N-monocarbamoyl derivatives of symmetrical diamines with antiviral activity

Some new N-monocarbamoyl symmetrical diamines have been prepared by the addition of symmetrical amines to isocyanates or isothiocyanates. 2,6-Diaminopyridine (1), (1R,2R)-1,2-diaminocyclohexane [(1R,2R)-2], meso-1,2-diaminocyclohexane (meso-2), or (1R,2R)-1,2-diphenylethylenediamine (3) were used as the starting symmetrical diamine frameworks. All of the newly synthesized compounds were subjected to an evaluation of antiviral activity with herpes simplex virus (HSV)-1. N-Monocarbamoyl 2,6-diaminopyridines (5a, b) showed significant antiviral activity (EC(50)=17.0, 6.2 microg/ml) comparable to that of N-monododecanoyl 2,6-diaminopyridine (A2). As a result, compound 5a showed a better selectivity index (CC(50)/EC(50) = ca. 10.0) than that of A2.     

Design and Synthesis of 1-Benzyl-3-(a-hydroxy-(un)substituted benzylidene)pyrrolidine-2,4-diones as Potential Herbicides

The inhibitors of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) are an new kind of herbicides.[1]Generally, in structure, potent herbicides of this kind must possess: (1) a tricarbonyl methane structure and one of the three carbonyl groups must be a subustituted benzoyl group; (2) the compound must be able to enolise so that the enolate is capable of inhibiting HPPD enzyme by competitive combination with Fe2+, the reaction center of HPPD enzyme.[2]Recently, we noticed that the 3-acyltetramic acids form an expanding group of antibiotics and pigments from micro-organisms,[3] they display a range of biological activities[4] and all of this kind compounds possess all of the characters mentioned above. Tests of their antimicrobial activities indicated that the structure of the acyl substituent at the 3-position was important to many typical antibiotics.[4～6] These characters stimulated us to study this kind of compounds so as to discover new herbicides. In this report, we synthesized a series of compounds 3 and tested their herbicidal activities to investigate their structure-activity relationships.     

Pregnane‐Type Steroidal Alkaloids of Sarcococca saligna: a New Class of Cholinesterase Inhibitors

Phytochemical investigation of Sarcococca saligna by extensive bioassay‐guided fractionation resulted in the isolation of the pregnane‐type steroidal alkaloids 1 – 15 , i.e. of the five new compounds 1 – 5 and the ten known alkaloids 6 – 15 . The structures of the new alkaloids salignenamide C ( 1 ), salignenamide D ( 2 ), 2β‐hydroxyepipachysamine D ( 3 ), salignenamide E ( 4 ), and salignenamide F ( 5 ) were elucidated with the help of modern spectroscopic techniques, while the known alkaloids axillarine C ( 6 ), axillarine F ( 7 ), sarcorine ( 8 ), N³‐demethylsaracodine ( 9 ), saligcinnamide ( 10 ), salignenamide A ( 11 ), vaganine A ( 12 ), axillaridine A ( 13 ), sarsalignone ( 14 ), and sarsalignenone ( 15 ) were identified by comparing their spectral data with those reported earlier. Inhibition of electric‐eel acetylcholinesterase (EC 3.1.1.7) and horse‐serum butyrylcholinesterase (EC 3.1.1.8) by alkaloids 1 – 15 were investigated. These new cholinesterase inhibitors may act as potential leads in the discovery of clinically useful inhibitors for nervous‐system disorders, particularly by reducing memory deficiency in Alzheimer's disease patients by potentiating and effecting the cholinergic transmission process. These compounds were found to inhibit both enzymes in a concentration‐dependent fashion with the IC₅₀ values ranging from 5.21–227.92 μM against acetylcholinesterase and 2.18–38.36 μM against butyrylcholinesterase.     

Electrochemical Detection of Retinoids Using Normal Phase HPLC

Abstract

Non-aqueous electrochemical (EC) detection of 13-cis-retinoic acid, all-trans retinoic, acitretin and vitamin A palmitate in non-aqueous solvents are reported.

Non-aqueous (EC) detection allows for normal-phase chromato-graphy of these compounds prior to detection. The normal phase system used a mobile phase of HEX/THF/AcOH for the separation of all four compounds. The stationary phase was either silica or PVA-sil. The lipophilic salts, t-butylammoniumtetrafluoroborate or t-butyl-ammoniumhexafluorophosphate necessary for EC detection were added post-column.

The limit of detection (LOD) for EC detection of these compounds is approximately 1 ng on column compared with an LOD by UV absorption of 2 ng on column.

The linear detection for these compounds with the EC detector was about two orders of magnitude.     

Three new compounds from Kadsura longipedunculata

Two new tetrahydrofuran lignans, kadlongirins A and B (1, 2), a new cadinane-type sesquiterpenoid, 2,7-dihydroxy-11,12-dehydrocalamenene (3), together with seven known lignans, grandisin, fragransin B1, vladirol F, kadsuralignan C, otobaphenol, isoanwulignan, and 4-[4-(3,4-dimethoxyphenyl)-2,3-dimethylbutyl]-2-methoxy-phenol, were isolated from the leaves and stems of Kadsura longipedunculata. The structures of these new compounds were elucidated by spectroscopic methods. Compound 2 exhibited weak anti-human immunodeficiency virus-1 activity with an EC50 value of 16.0 microg/ml, and therapeutic index (TI) value of 6.7.     

A novel antioxidant isobenzofuranone derivative from fungus Cephalosporium sp.AL031

Bioassay-guided fractionation of metabolites from the fungus Cephalosporium sp.AL031 isolated from Sinarundinaria nitida led to the discovery of a new isobenzofuranone derivative, 4,6-dihydroxy-5-methoxy-7-methylphthalide (1), together with three known compounds: 4,5,6-trihydroxy-7-methyl-1,3-dihydroisobenzofuran (2), 4,6-dihydroxy-5-methoxy-7-methyl-1,3-dihydroisobenzofuran (3) and 4,5,6-trihydroxy-7-methylphthalide (4). The structure of the new compound 1 was determined based on MS, 1D and 2D NMR spectral data. Compounds 1-4 showed potent antioxidant activity with EC?? values of 10, 7, 22 and 5 μM by 1,1-diphenyl-2-picryhydrazyl (DPPH) radical-scavenging assay.     

Synthesis of new <Emphasis Type="Italic">N</Emphasis>-(pyridin-3-ylmethyl)-2-aminothiazoline derivatives possessing anticholinesterase and antiradical activity as potential multifunctional agents for the treatment of neurodegenerative diseases

New N-(pyridin-3-ylmethyl)-2-aminothiazolines containing various substituents at the 5 position of the thiazoline ring and the 4-tert-butylbenzyl, 4-isopropylbenzyl, or 4-fluorobenzyl moiety at the nitrogen atom of the amino group were synthesized. The inhibitory activity of the synthesized compounds against human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), equine serum butyrylcholinesterase (BChE, EC 3.1.1.8), and porcine liver carboxylesterase (CaE, EC 3.1.1.1) was evaluated and their antioxidant properties were studied by ABTS assay. N-(Pyridin-3-ylmethyl)-2-aminothiazolines proveded to be very weak AChE inhibitors, while their inhibitory activity against BChE and CaE was structure-dependent. 2-Aminothiazolines containing the 4-tert-butylbenzyl moiety are more efficient BChE inhibitors compared to the derivatives containing the 4-isopropylbenzyl or 4-fluorobenzyl substituent. An analysis of the dependence of the esterase profile of N-(pyridin-3-ylmethyl)-2-aminothiazolines on the structure of the substituent at the 5 position of the thiazoline ring of these compounds demonstrated that the derivatives containing the iodomethyl substituent possess the highest anti-BChE activity, the compounds with R² = H and R³ = CH₂I have the optimal esterase profile. Regardless of the structure of the substituents in the benzyl moiety, all N-(pyridin-3-ylmethyl)-2-aminothiazolines containing the iodomethyl substituent at the 5 position of the thiazoline ring exhibited high radical scavenging activity comparable with that of the standard antioxidant Trolox. N-(Pyridin-3-ylmethyl)-2-aminothiazolines were shown to be a new promising class of compounds for the design of multifunctional agents for the treatment of neurodegenerative diseases.     

Design, synthesis and biological evaluation of hydroxamic acid derivatives as potential high density lipoprotein (HDL) receptor CLA-1 up-regulating agents

Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) were reported in our recent publication as novel human high density lipoprotein (HDL) receptor CD36 and Lysosomal integral membrane protein-II Analogous-1 (CLA-1) up-regulators. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of CLA-1 up-regulators, we synthesized a series of hydroxamic acid derivatives and evaluated their CLA-1 up-regulating activities in HepG2 cells. Some compounds exhibited over 10-fold up-regulation of CLA-1 expression in HepG2 cells at 10 μg/mL concentration. The compound 1g showed the best potency, with a lower EC(50) than TSA (EC(50) = 0.32 μM versus 1.2 μM). These compounds provide early new CLA-1 up-regulators with potential for treating atherosclerosis.     

Phenolics with antiviral activity from Millettia erythrocalyx and Artocarpus lakoocha

From the leaves of Millettia erythrocalyx, a new flavone named 3',5'-dimethoxy-[2",3": 7,8]-furanoflavone and three known compounds were isolated. Assays for anti-herpes simplex virus activity (HSV-1 and HSV-2) were performed on 24 phenolic compounds obtained from M. erythrocalyx and Artocarpus lakoocha. It was found that the flavones ovalifolin, pongol methyl ether and millettocalyxin A, and the stilbene oxyresveratrol possessed moderate activity against both types of HSV. In addition, oxyresveratrol was evaluated for potential anti-HIV activity against a wild-type human immunodeficiency virus type 1 (HIV-1/LAI) isolate and was found to be a modest inhibitor of HIV (EC50 28.2 microM), showing no toxicity in PBM, CEM and Vero cells at 100 microM. The heartwood of A. lakoocha, which contains a large amount of oxyresveratrol, could be considered as a source of starting material for the development of new natural product-based anti-HSV and anti-HIV agents.     

Separation of eight selected flavan-3-ols on cellulose thin-layer chromatographic plates

The potential of microcristaline cellulose as sorbent in the separation of eight compounds: (+)-catechin (C), (-)-epicatechin (EC), (-)-gallocatechin (GC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECg), (-)-epigallocatechin gallate (EGCg), procyanidin B1 and procyanidin B2 was studied. Cellulose HPTLC plates prewashed in water (not necessary, when water was used as developing solvent) and dried with a hair dryer, bandwise application and development in horizontal developing chamber (sandwich configuration) gave the best results. Detection was performed using vanillin-H3PO4 reagent. Four new developing solvent systems were proposed: water, 1-propanol-water (20:80, v/v), 1-propanol-water-acetic acid (4:2:1, v/v) and 1-propanol-water-acetic acid (20:80:1, v/v), and at least two of them were needed for the differentiation between all eight compounds. Surprisingly, water enabled the separation of epimers C from EC and GC from EGC, as well as the dimers procianidin B1 and B2. Additionally, C, EGC, B1 and B2 were separated from all the other compounds. The best choice for developing solvent is given for each of the studied compounds. The best separation of the five main catechins (EC, GC, EGC, ECg, EGCg) present in green tea extract was achieved using 1-propanol-water-acetic acid (20:80:1, v/v). The chromatograms of oak bark extract developed in solvents with higher water content (1-propanol-water (1:4, v/v) and 1-propanol-water-acetic acid (20:80:1, v/v)) showed less bands than chromatograms developed in solvents with higher organic modifier content (e.g. 1-propanol-water-acetic acid (4:2:1, v/v)). It was proved that such behavior was due to the presence of procyanidins beside the main component catechin.     

5-乙氧羰基甲硫基-1,2,4-三唑席夫碱的合成及杀菌活性

以3-甲基-4-氨基-5-乙氧羰基甲硫基-1,2,4-三唑为原料,与取代芳醛合成9种3-甲基-4-(X-取代基苯亚甲基氨基)-5-乙氧羰基甲硫基-1,2,4-三唑席夫碱化合物a～i。 产物结构经1H NMR、IR和MS等技术手段确证。 其中化合物3-甲基-4-(4-羟基苯亚甲基氨基)-5-乙氧羰基甲硫基-1,2,4-三唑h进一步经X射线单晶衍射得到其晶体结构（CCDC：910927）：C14H16N4O3S,Mr=320.37,Orthorhombic,P2(1)2(1)2(1)/n,a=0.9220(10) nm,b=1.5823(17) nm,c=2.1667(2) nm,V=3.161(6) nm3,Z=8,F(000)=1344。 化合物对4种植物病原菌的初步生物活性测试结果(EC95值)表明,化合物d、e、f对供试菌种西瓜枯萎病和小麦赤霉病的抑菌活性优于对照原药三唑酮。     

Structure-activity relationships for abiotic thiol reactivity and aquatic toxicity of halo-substituted carbonyl compounds

Using abiotic thiol reactivity (EC50) and Tetrahymena pyriformis toxicity (IGC50) data for a group of halo-substituted ketones, esters and amides (i.e. SN2 electrophiles) and related compounds a series of structure-activity relationships are illustrated. Only the alpha-halo-carbonyl-containing compounds are observed to be thiol reactive with the order I > Br > Cl > F. Further comparisons disclose alpha-halo-carbonyl compounds to be more reactive than non-alpha-halo-carbonyl compounds; in addition, the reactivity is reduced when the number of C atoms between the carbonyl and halogen is greater than one. Comparing reactivity among alpha-halo-carbonyl-containing compounds with different beta-alkyl groups shows the greater the size of the beta-alkyl group the lesser the reactivity. A comparison of reactivity data for 2-bromoacetyl-containing compounds of differing dimensions reveals little difference in reactivity. Regression analysis demonstrates a linear relationship between toxicity and thiol reactivity: log (IGC(50)(-1)) = 0.848 log (EC(50)(-1)) + 1.40; n=19, s=0.250, r2=0.926, r2(pred)=0.905, F=199, Pr > F=0.0001.     

Antioxidant activity and cytotoxicity study of the flavonol glycosides from Bauhinia galpinii

The antioxidant activity of the crude extract and solvent fractions obtained from the leaves of Bauhinia galpinii was evaluated in terms of capacity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals. The crude extract and the more polar solvent fractions (ethyl acetate and butanol) showed considerable antioxidant activity. The antioxidant potential of the extracts, expressed as EC50, ranged between 28.85 +/- 1.28 microg mL(-1)and 118.16 +/- 6.41 microg mL(-1). L-Ascorbic acid was used as a standard (EC50 = 19.79 +/- 0.14 microM). Bioassay guided fractionation of the two active solvent fractions led to the isolation of three flavonoid glycosides, identified as: quercetin-3-O-galactopyranoside (1), myricetin-3-O-galactopyranoside (2), and 2'-O-rhamnosylvitexin (3). These compounds are reported for the first time from this species. The structures of the compounds were determined on the basis of spectral studies (1H NMR, 13C NMR and MS). Their antioxidant potential was evaluated using a DPPH spectrophotometric assay. Compound 2 had higher and 3 had lower antioxidant activity than L-ascorbic acid. No cytotoxic effects were displayed by compounds 1 and 3, but compound 2 was cytotoxic to Vero cells (LC50 = 74.68 microg mL(-1)) and bovine dermis cells (LC50 = 30.69 microg mL(-1)).     

藤三七中一个新黄烷醇和抗HIV活性成分

利用各种色谱(硅胶和凝胶)方法, 从藤三七[Boussingaultia gracilis Miers var. pseudobaselloides Bailey]的70%(体积分数)的乙醇提取物中分离得到2个黄烷醇类化合物(1, 2)和4个黄酮类化合物(3~6). 采用UV, IR, MS 和1D, 2D NMR方法, 分别鉴定出如下化合物: 7-羟基-5-甲氧基-8-甲基-6-甲酰基-3,4-黄烷二醇, 命名为藤三七醇A(1); 4,7-二羟基-5-甲氧基-8-甲基-6-甲酰基黄烷(2); 7-O-methylunonal(3); 5,7-二羟基-6, 8-二甲基-2-苯基-4H-1-苯并吡喃-4-酮(4); Desmosflavone(5)和Demethoxymatteucinol(6). 其中化合物1是一个新的黄烷二醇化合物, 化合物2~6为首次从该植物中分离得到. 抗HIV-1活性筛选结果表明: 化合物1, 2, 5, 6对HIV-1诱导合胞体的形成具有一定的抑制作用, 其半数有效浓度(EC50)分别为45.09, 48.73, 55.47 和 82.75 μmol/L, 治疗指数(TI)分别为1.41, 1.20, 7.15 和>8.51.     

Synthesis and biological activities of conformationally restricted cyclopentenyl-glutamate analogues.

An efficient method for preparing conformationally restricted cyclopentenyl-glutamate analogues in a regioselective and diastereoselective manner has been developed using a formal [3 + 2] cycloaddition reaction of dehydroamino acids. Methods for preparing optically active versions of these compounds have also been devised. Of these compounds, (S)-2 is an agonist at the mGlu5 (EC(50) 18 microM) and mGlu2 (EC(50) 45 microM) receptors.     

The effects of substituting groups in cyclic carbonates for stable SEI formation on graphite anode of lithium batteries

Monofluoropropylene carbonate (MFPC) and trifluoropropylene carbonate (TFPC) with a monofluoromethyl (or trifluoromethyl) replacing the methyl group in propylene carbonate (PC) as well as EC-CH₂CH₂Si(CH₃)₂OSi(CH₃)₃ (Si-A) and EC-CH₂CH₂Si(CH₃)₃ (Si-B) have been synthesized. The charge–discharge studies in a Li/MCMB (mesocarbon microbeads) cell using electrolyte containing these compounds show that the solid electrolyte interphase (SEI) formation capability of MFPC/DMC (dimethyl carbonate) and TFPC/DMC are about the same as ethylene carbonate (EC)/DMC, and TFPC/PC/DMC is better than that of EC/PC/DMC, while MFPC/PC/DMC is poorer than the EC/PC/DMC. The superior SEI formation capability of TFPC could be attributed to the strong electron withdrawing group of CF₃, which promote the “ring-opening” reaction. In contrast, the electron donating group CH₃ in the PC structure may demote the “ring opening” and cause the poor SEI formation. The results of MFPC with weaker electron withdrawing group give further support of this hypothesis. The bi-solvent electrolytes of Si-A/DMC and Si-B/DMC have comparable SEI formation capability as EC/DMC and TFPC/DMC, regardless of their bulky chains. This indicates that if proper chain structures are used, good SEI formation capability could be obtained for cyclic carbonate with bulky chains. These new solvents provide valuable information in studying the SEI formation mechanism and designing new electrolytes.     

Prolyl endopeptidase inhibitors from the underground part of Rhodiola sachalinensis

The methanolic extract of the underground part of Rhodiola sachalinensis was found to show inhibitory activity on prolyl endopeptidase (PEP, EC. 3.4.21.26), an enzyme that plays a role in the metabolism of proline-containing neuropeptidase which is recognized to be involved in learning and memory. From the MeOH extract, five new monoterpenoids named sachalinols A (24), B (25) and C (26) and sachalinosides A (23) and B (27) were isolated, together with twenty-two known compounds, gallic acid (1), trans-p-hydroxycinnamic acid (2), p-tyrosol (3), salidroside (4), 6n-O-galloylsalidroside (5), benzyl beta-D-glucopyranoside (6), 2-phenylethyl beta-D-glucopyranoside (7), trans-cinnamyl beta-D-glucopyranoside (8), rosarin (9), rhodiocyanoside A (10), lotaustralin (11), octyl beta-D-glucopyranoside (12), 1,2,3,6-tetra-O-galloyl-beta-D-glucose (13), 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (14), kaempferol (15), kaempferol 3-O-beta-D-xylofuranosyl(1-->2)-beta-D-glucopyranoside (16), kaempferol 3-O-beta-D-glucopyranosyl(1-->2)-beta-D-glucopyranoside (17), rhodionin (18), rhodiosin (19), (-)-epigallocatechin (20), 3-O-galloylepigallocatechin-(4-->8)-epigallocatechin 3-O-gallate (21) and rosiridin (22). Among these, nineteen compounds other than 3, 4 and 9 have been isolated for the first time from R. sachalinensis, and six (6, 8, 13, 16, 17, 20) are isolated from Rhodiola plants for the first time. Among them, six compounds (13, 14, 18, 19, 21, 22) showed noncompetitive inhibition against Flavobacterium PEP, with an IC50 of 0.025, 0.17, 22, 41, 0.44 and 84 microM, respectively.