Alkaloids from the endophytic fungus Penicillium brefeldianum and their cytotoxic activities

One new indoloditerpene,6,7-dehydropaxilline(1),one new indole-diketopiperazine,spirotryprostatin F(2),and one new 13-membered macrolide,N-demethylmelearoride A(3),as well as 8 known alkaloids(4-11),were isolated from the solid cultures of the endophytic fungus,Penicillium brefeidianum.The structures and absolute configurations of compounds 1-3 were elucidated by comprehensive spectroscopic analysis and the circular dichroism(CD) exciton chirality method.All the metablites were evaluated for their cytotoxic activites against three human tumor cell lines.Compound 2 exhibited cytotoxicities against HepG2 and MDA-MB-231 cells with IC_(50) values of 14.1 μmol/L and 35.5μmol/L,respectively.Compound 3 showed moderate activity against HepG2 cells with IC_(50) values of 36.6 μmol/L.     

New ent-kaurane diterpenes with chiral epoxyangelate moieties from Wedelia prostrata

Four new ent-kaurane diterpenes with chiral epoxyangelate moieties, (2′R,3′R)-3 a- (2′,3′-epoxyangeloyloxy)-kaur-16-en-19-oic acid (1), (2′S,3′S)-3 a- (2′,3′-epoxyangeloyloxy)-kaur-16-en-19-oic acid (2), (2′S,3′R)-3 a- (2',3'-epoxyangeloyloxy)-kaur-16-en-19-oic acid (3) and (2′R,3′S)-3α- (2′,3'-epoxyangeloyloxy)-kaur-16-en-19-oic acid (4), along with eight known diterpenes (5-12), were isolated from Wedelia prostrata. The absolute configurations of the new structures were determined by X-ray crystallography,ECD calculations and chemical methods. All compounds were evaluated for their cytotoxicity activities on human HepG-2 cells,with IC_(50) values of 11.72 ±0.22 μmol/L to 54.75±1.12 μmol/L.     

New cyclopiane diterpenes with anti-inflammatory activity from the sea sediment-derived fungus Penicillium sp. TJ403-2

Three new rare cyclopiane diterpenes(1-3),together with thirteen known compounds(4-16),were isolated and identified from a sea sediment-derived fungus Penicillium sp.TJ403-2.The planar and relative structures of compounds 1-3 were elucidated by HRESIMS,one-and two-dimensional NMR analyses,and their absolute configurations were further established by X-ray crystallography experiment.Compounds 1-3 were evaluated for the anti-inflammatory activity against LPS-induced NO production,and compound 1 showed notable inhibitory potency with an IC50 value of2.19±0.25μmol/L,which was three fold lower than the positive control indomethacin(IC50=8.76±0.92μmol/L).Further Western blot and immunofluorescence experiments demonstrated its mechanism of action to be that 1 inhibited the NF-κB-activated pathway,highlighting it as a promising starting point for the development of new anti-inflammatory agents.     

Periconones B-E,new meroterpenoids from endophytic fungus Periconia sp.

Periconones B-E(1-4),four new polyketide-terpenoid hybrid molecules were isolated from the endophytic fungus Periconia sp.F-31.Their structures and absolute configurations were established by extensive spectroscopic data analysis and electronic circular dichroism(ECD).Compound 4 exhibited in vitro cytotoxic activity against the human MCF-7 tumor cell line with an IC_(50) value of 4.2 μmol/L,and compound 1 displayed anti-HIV activity with an IC_(50) value of 18.0 μmol/L.     

Phenolic constituents from the roots of Alangium chinense

Three new phenolics(1–3) and twenty-eight known compounds(4–31) were isolated from an ethanolic extract of roots of Alangium chinense. Compound 11 exhibited antiviral activity against Coxsackie virus B3 with IC50 values of 16.89 mmol/L. Compounds 1, 10–17, 19–21, and 23 showed strong antioxidant activity against Fe~(2+)-cysteine-induced rat liver microsomal lipid peroxidation, with IC_(50) values of 0.14–8.18 mmol/L.     

Four new diterpenoid alkaloids with antitumor effect from Aconitum nagarum var. heterotrichum

Four new diterpenoid alkaloids,nagaconitines A-D(1-4),were isolated from the roots of Aconitum nagarum var.heterotrichum.Their structures were elucidated as 8-(4'-hydroxylbutyryl) aconitine(1),15-oxo-13-deoxyludaconitine(2),15-hydroxyldelphisine(3),and 14-hydroxyl-2- acetoxyspiradine C(4)based on extensive UV,IR,MS,1D NMR and 2D NMR analyses.Compounds 3-4 showed inhibition of cancer cell line SK-OV-3 with 31%(IC_(50) 43.78 μmol/L) and 24%(IC_(50) 32.14 μmol/L),respectively.     

Synthesis and Activity Evaluation of Novel Prenylated Flavonoids as Antiproliferative Agents

Twenty prenylated flavonoids 1-20 were synthesized by glycoside hydrolysis, dehydrogenation, selective O-methylation, O-prenylation and Claisen rearrangement reaction, from abundant and inexpensive natural flavonoids naringin, hespiredin, quercetin and myricetin. Among them, 1-7, 10-15 and 17-20 are novel compounds, the natural product 3,3',4',7-tetramethoxy-8-prenyl-5-hydroxy flavonoid(16) was synthesized in a high yield. Their antiprolirative activities were evaluated in vitro on a panel of three human cancer cell lines(HeLa, HCC1954 and SK-OV-3). The results show that most of the target compounds displayed moderate to potent antiprolirative activities against the three cancer cells with half maximal inhibitory concentration(IC₅₀) values from 0.49 μmol/L to 95.07 μmol/L. Among them, 3',4',7-trimethoxyl-5-hydroxyl-8-prenyl flavonoid(12) exhibited the strongest antiprolirative activity against the three cancer cells mentioned above with IC₅₀ values of 0.91-7.08 μmol/L. 3',7-Dimethoxy-5-O-prenyl flavone(6) and 3',4',7-trimethoxy-5-O-prenyl flavone(10) showed selective antiproliferative activity against HCC1954 cells with IC₅₀ value of 0.49 and 5.32 μmol/L, respectively.     

Synthesis and cytotoxic activity of novel 2, 6-disubstituted-4-mor- pholinothieno[3, 2-d]pyrimidines as potent anti-tumor agents

正A series of 2,6-disubstituted-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and their cytotoxic activity against H460,HT-29,MDA-MB-231,U87MG and H1975 cancer cell lines were evaluated in vitro.Most of the target compounds exhibited moderate to excellent activity to the tested cell lines.The most promising compound 23(0.84μmol/L,0.23μmol/L, 2.52μmol/L,1.80μmol/L) was 1.0,2.9,29.3 and 4.3 times more active than GDC-0941(0.87μmol/L,0.66μmol/L,73.8μmol/L, 7.77μmol/L) against H460,HT-29,MDA-MB-231 and U87MG cell lines,respectively.     

Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

An efficient synthesis of novel 3-(piperidin-4-yl)isoxazolo[4, 5-d]pyrimidine scaffold has been designed and deveopled. A series of 5-phenylurea derivatives was synthesized using this method. Their cytotoxic activities against breast cancer cell line BT-474 were evaluated by CCK-8 assay. Most of them showed potent anti-proliferative activities, of which compound 20 and 21 exhibited IC₅₀s of 1.565 μmol/L and 1.311 μmol/L, respectively. Furthermore, compound 20 and 21 also showed potent inhibitory activities against PI3Kδ with IC₅₀s of 0.286 μmol/L and 0.452 μmol/L, respectively. These results indicate that these 3-(piperidin-4-yl)isoxazolo[4, 5-d] pyrimidine derivatives are novel antitumor agents through the inhibition of PI3Kδ.     

New cytotoxic apigenin derivatives from Selaginella doederleinii

75%aqueous ethanol extract from the whole herbs of Selaginella doederleinii was isolated,and two new apigenin derivatives,doederflavones A(1) and B(2),together with ten known compounds(3-12) were characterized.Their structures were assigned by extensive spectroscopic methods including 1D/2D NMR and HR-ESIMS.Compounds 1-6 bear an aryl substituent at the C-8 or C-6 positions in ring A of apigenin skeleton.Compounds 1 and 2 were evaluated for their in vitro cytotoxicity against four human cancer cell lines A549,MCF-7,SMMC-7721,and LoVo,both of which exhibited significant cytotoxicity against A549 with IC_(50) values of 0.82 μmol/L and 1.32 μmol/L,respectively.     

Synthesis and pharmacological properties of naturally occurring prenylated and pyranochalcones as potent anti-inflammatory agents

An efficient approach has been developed for the synthesis of naturally occurring prenylated chalcones viz. kanzonol C(1), stipulin(2), crotaorixin(3), medicagenin(4), licoagrochalcone A(5) and abyssinone D(6) along with the pyranochalcones paratocarpin C(7), anthyllisone(8) and 3-O-methylabyssinone A(9).The key step of the synthesis is a Claisen–Schmidt condensation. Subsequently, their anti-inflammatory effects were investigated in lipopolysaccharides(LPSs)-induced RAW-264.7 macrophages. Of the synthesized chalcones, compounds 5(IC_(50)= 10.41 μmol/L), 6(IC_(50)= 9.65 μmol/L) and 8(IC_(50)= 15.34 μmol/L) show remarkable activity with no cytotoxicity. Compound 9(IC_(50)= 4.5 μmol/L)exhibits maximum(83.6%) nitric oxide(NO) inhibition, but shows slight cytotoxicity. The results reveal that the chalcones bearing the prenyl group at 3- and/or 5-position on ring A(acetophenone moiety), i.e.,1–4 and 7 show weak, or no inhibition activity, whereas chalcones having the prenyl group only on ring B(aldehyde part), i.e., 5, 6 and 8 show significant activity on the production of inflammatory mediated NO with no cytotoxicity.     

Detection of dopamine using self-assembled diazoresin/single-walled carbon nanotube modified electrodes

Ultrathin films of diazoresin(DR)/single-walled carbon nanotube(SWNT) were fabricated on thioglycollic acid(TGA) decorated gold(Au) electrodes by the self-assembly method combined with the photocrosslinlcing technique.The electrochemical behavior of dopamine(DA) at the DR/SWNT modified electrodes was studied using the cyclic voltammetry(CV) and differential pulse voltammetry(DPV) methods.Under the optimal conditions,a linear CV response to DA concentration from 1 μmol/L to 40 μmol/L was observed,and the detection limit of DA was 2.1 ×10~(-3) μmol/L via the DPV method in the presence of 10 μmol/L of uric acid(UA) or 2.5 × 10~(-3) μmol/L via the DPV method in the presence of10 μmol/L of ascorbic acid(AA).Moreover,the modified electrodes exhibited good reproducibility and sensitivity,demonstrating its feasibility for analytical purposes.     

Development of bis-thiobarbiturates as successful urease inhibitors and their molecular modeling studies

Bis-thiobarbiturate derivatives 1–15 have been synthesized, characterized by1 HNMR and EI-MS and screened for urease inhibition. All compounds showed various degree of urease inhibitory activity with IC_(50) values ranging 7.45 0.12 74.24 0.81 mmol/L while the standard thiourea behaved normally(IC_(50) = 21.10 0.12). Compounds 1(IC_(50) = 7.45 0.12 μmol/L), 9(IC_(50) = 18.17 1.03 μmol/L) and 13(IC_(50) = 8.61 0.45 μmol/L) showed excellent urease inhibitory activity in the series. Molecular modeling studies were performed to understand the binding site with the bimetallic nickel center of the enzyme.Structure-activity relationship has also been established for these compounds. This study identified bisthiobarbiturate as a novel class of urease inhibitors.     

A New Tetrasubstituted Imidazole Based Difunctional Probe for UV-spectrophotometric and Fluorometric Detecting of Fe3+ Ion in Aqueous Solution

Two new compounds,4-(2-bromophenxl-4,5-diphenyl-imidazol-1-yl)ani 1 ine(probe 1)and 4-[2,4,5-tris(4-bromopheny1)-1H-imidazol-1-y1]aniline(probe 2),were synthesized via a soft and high-efficiency one-pot microwave-assisted method under solvent-free conditions.Their sensing to different metal ions was detected by UV spectrophotometry and fluorescence spectrometry.Probe 2 revealed highly selective and sensitive UV and fluorescence response to Fe^3+ion.Upon the addition of Fe^3+ion,probe 2 showed obvious color change of the solution,conspicuous absorbance enhancement and relatively quick fluorescence quenching.The detection limit for Fe^3+ion was respectively calculated to be 0.72μmol/L(fluorescent detection)and 0.48μmol/L(UV-spectnim detection).Also,probe 2 was bound by Fe^3+ion to tonn a 1:1 complex.Moreover,preliminary application of probe 2 tor detecting Fe^3+ion in aqueous solution was attempted,and satisfying results were obtained.     

Design,Synthesis and Antitumor Activity of Novel Indolin-2-one Derivatives Containing 4-Thiazolidinone Moiety

A series of novel indolin-2-one derivatives containing 4-thiazolidinone moiety(7a―7r) were synthesized and evaluated for their in vitro antitumour activities against MDA-MB-231(human breast cancer), H460(human lung cancer) and HT-29(human colon cancer) cell lines by standard 3-(4,5-dimethylthiazae-2-yl)-2,5-diphenyltetrazo- lium bromide(MTT) assay. Representative compounds(7d, 7k, 7m, 7p) with higher cytotoxicity were further examined against one normal cell line(WI-38, human fetal lung fibroblasts). The preliminary investigation shows that most of the compounds display moderate to excellent potency and high selectivity against different human cancer cell lines. In particular, the most potent compound 7m shows promising cytotoxicity against MDA-MB-231, H460 and HT-29 cell lines with IC₅₀ values of 0.78, 0.056 and 0.018 μmol/L, respectively. The potency is much higher than that of Sunitinib(IC₅₀=3.46 μmol/L against MDA-MB-231, IC₅₀=2.59 μmol/L against H460, IC₅₀=1.50 μmol/L against HT-29) by 4.4, 46.3 and 83.3 fold.     

Electrochemical non-enzymatic glucose sensors based on nano-composite of Co3O4 and multiwalled carbon nanotube

Nanocomposite of Co₃O₄ and MCNT was synthesised using one step solvothermal method, and an electrochemical non-enzymatic glucose sensor (Co₃O₄-MCNT/GCE) was successfully constructed. This sensor was used successfully for the quantitative analysis of trace glucose in serum sample.     

Expeditious synthesis,antileishmanial and antioxidant activities of novel 3-substituted-4-hydroxycoumarin derivatives

A series of novel 3-substituted-4-hydroxycoumarin derivatives 6(a–1) were synthesized in high yield using one-pot three component coupling reaction catalyzed by ceric ammonium nitrate. These compounds were evaluated for antileishmanial activity against Leishmania donovani promastigotes and antioxidant activity(DPPH-radical scavenging activity). Two compounds, 6h(IC_(50)= 9.90 μmol/L) and 6i(IC_(50)= 6.90 μmol/L) displayed potent antileishmanial activity when compared with standard antileishmanial agents pentamidine(IC_(50)= 16.15 μmol/L) and miltefosine(IC_(50)= 12.50 μmol/L). Three compounds, 6c(IC_(50)= 10.79 μmol/L), 6h(IC50= 10.60 μmol/L), and 6i(IC_(50)= 10.73 μmol/L) showed significant antioxidant activity favorably with the antioxidant standards butylated hydroxy toluene(IC_(50)= 16.47 μmol/L) and ascorbic acid(IC_(50)= 12.69 μmol/L). A molecular docking study of compounds 6(a–1) suggested a possible mode of binding with the Adenine phosphoribosyltransferase enzyme of L.donovani. ADME properties were predicted in silico and support the potential of 6(a–1) to show favorable drug-like properties.     

6,7-seco-ent-Kaurane diterpenoids from lsodon sculponeatus and their bioactivity

One new 6,7-seco-enr-kaurane diterpenoid,sculponin T(1),was isolated from the aerial parts of Isodon sculponeatus,along with four known analogs,sculponeatin J(2),sculponeatin K(3),sculponeatin C(4),and sculponeatin Q(5).Their structures were elucidated by extensive spectroscopic analysis and by comparison with data reported in the literature.Significant cytotoxic activity was observed for compound 2 against five human tumor cell lines with IC_(50) values ranging from 1.8 μmol/L to 3.3 μmol/L,and it also inhibited NO production in LPS-stimulated RAW264.7 cells,with IC_(50) value of 3.3 μmol/L.     

Synthesis and in vitro antitumor activity of novel naphthyridinone derivatives

A series of naphthyridinone derivatives based on la(a precursor of Voreloxin) were designed and synthesized.Seven compounds having 70%inhibition against HL60 at 30 μmol/L were further evaluated for their in vitro antitumor activity by SRB assay.Results reveal that thiazol-2-yl and 3-aminomethyl-4-benzyloxyimino-3-methylpyrrolidin-l-yl groups are optimal at the N-1 and C-7positions of naphthyridinone core,respectively.10 j exhibits broad-spectrum activity(IC_(50):0.5-6.25 μmol/L) against all of the tested cell lines including Etoposide- and/or la-resistant ones,and is 1.3-fold to 100-fold more potent than the two references against eight of these cell lines.     

土壤中典型人工甜味剂的前处理方法优化及高效液相色谱-串联质谱分析

优化了同时提取土壤中4种典型人工甜味剂的前处理与净化方法,并结合高效液相色谱-串联质谱（HPLC-MS/MS）技术,建立了一种快速高效的分析方法。样品采用25 mL 0.01 mol/L醋酸-醋酸钠溶液（pH 4）提取2次,每次提取20 min;萃取样品进一步采用CNW Poly-Sery PWAX固相萃取小柱净化浓缩;最后采用HPLC-MS/MS进行测定。在干燥土壤中添加1、10、100 μg/kg标准品时,4种甜味剂的平均回收率为86.5%~105%,日内精密度（RSD）≤5.94%,日间精密度（RSD）≤6.53%;在1~100 μg/kg范围内的线性关系良好（r²>0.995）;方法的检出限为0.01~0.21 μg/kg,定量限为0.03~0.70 μg/kg。利用该方法对天津某污水灌溉的农田土壤进行了分析测定,结果表明该方法快捷可靠,可用于土壤中人工甜味剂的环境调查。