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.     

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.     

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.     

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.     

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.     

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 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.     

新型吲唑-查尔酮杂合物的合成及抗肿瘤活性

设计并合成了一系列新型含查尔酮-吲唑杂合衍生物,并对其体外肿瘤活性进行初步研究。 先以2,6-二氟苯腈和吗啉为起始原料,经过取代和环合两步反应合成4-吗啉-3-氨基-1H-吲唑。 4-吗啉-3-氨基-1H-吲唑与含羧基的查尔酮中间体与经过酰胺化反应制备了9个新型含查尔酮-吲唑杂合衍生物,其结构经傅里叶变换红外光谱仪(FTIR)、核磁共振波谱仪(NMR)、质谱(MS)和元素分析确证。 采用MTT法,以索拉菲尼为阳性对照药,以人胃癌细胞株(MKN45)和人肺癌细胞株(A549)为测试细胞株对目标化合物进行抗肿瘤活性评价。 结果表明,大部分目标化合物显示了较好的抗肿瘤活性,其中化合物4a和4d活性较好,其抑制人胃癌细胞株MKN45的IC₅₀分别为2.65和3.55 μmol/L,均优于阳性对照药索拉菲尼(IC₅₀=4.69 μmol/L)。     

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.     

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.     

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.     

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.     

Syntheses and Anti-cancer Activities of Derivatives of Tetrandrine and Fangchinoline

A series of derivatives of tetrandrine and fangchinoline was designed and synthesized to find more active anti-cancer compounds. Their anti-cancer activities were tested against human hcpatocellular carcinoma BEL-7402 and PLC/PRF/5 cells, human lung adenocarcinoma A549 cells as well as human leukaemia K562 cells, and the structure-activity relationship（SAR） was also studied. All the compounds except BI exhibited superior inhibitory ac- tivities against PLC/PRF/5 cells with half maximal inhibitory conccntration（ICs0） values of less than 15 μmol/L, and compounds A2, A4, B2 and B4 showed IC50 values of less than 9 pmol/L. Compounds A2, A6, B2 and B4 showed potent anti-cancer activities against all the tested cells with 1C5o values of less than 10 pmol/L. The results show that terandrine and fangchinoline derivatives are potential suppressors to human cancer.     

Cytotoxic polyacetylenes isolated from the roots and rhizomes of Notopterygium incisum

Phytochemical investigation on the roots and rhizomes of Notopterygium incisum led to the isolation of a new polyacetylene, notopolyenol A (1), along with thirteen known analogues (2-14). Their structures were elucidated by extensive analyses of NMR and HRMS data, and the absolute configuration of 1 was unambiguously determined as 3 R by comparison of its retention time and ECD curve with those of synthetic enantiomers (-)-1 and (+)-1, whose absolute configurations were established by using the modified Mosher's method. Subsequent activity screening revealed that (3 S)-1 exhibited the most significant cytotoxicity against MCF-7, H1299, and HepG2 cancer cells with IC_(50) values of 1.3 μmol/L,0.6μmol/L and 1.4μmol/L, respectively.     

Microbial transformation of glycyrrhetinic acid and potent neural anti-inflammatory activity of the metabolites

The microbial transformation of glycyrrhetinic acid(1) by Cunninghamella blakesleana CGMCC 3.970 led to the production of five new metabolites(2-6).The structures of the metabolites were determined by extensive spectroscopic(HR-ESIMS,1D and 2D NMR) data analyses.The involved reactions exhibited specific hydroxylations at C-24,C-7,and C-15,and oxidation at C-3.Moreover,compounds 2,5,and 6showed significant neural anti-inflammatory activity by inhibiting lipopolysaccharide-induced NO production in mouse microglia BV2 cells with IC_(50) values of 0.76,0.94,and 0.16μmol/L,respectively.     

Isolation and Stucture Elucidation of Diterpenes from Wedelia prostrata and Their Cytotoxicity Activities

In this paper, a new diterpene together with seven known diterpenes was isolated from Wedelia prostrata. The chemical structure of the new compound was elucidated via 1D and 2D nuclear magnetic resonance(NMR) techniques and mass spectrometry and identified to be 3α-phenylpropionoyloxy-ent-kaur-16-en-oic acid(1). The isolated diterpenes were tested for their cytotoxicity activities via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. The results show that compounds 1, 2, 3, 4 and 6 exhibit different levels of cytotoxic activities. Especially, compound 2 shows significant cytotoxicity toward HeLa and A549 cell lines(IC₅₀=6.14 and 8.76 μmol/L).     

Synthesis and α-glucosidase inhibitory activity of chrysin,diosmetin, apigenin,and luteolin derivatives

Several derivatives have been synthesized from chrysin, diosmetin, apigenin, and luteolin, which were isolated from diverse natural plants. The α-glucosidase inhibitory activity of these compounds was evaluated. The glucosidase inhibitory activity of all derivatives （IC50 〈 24.396 μmol]L） was higher compared with that of the reference drug, acarbose （IC50=563.601 ±40.492μmol/L）, and 1- deoxynojirimycin （IC50 = 226.912± 12.573 μmol/L）. O3＇,O7-Hexyl diosmetin （IC50 = 2.406 ± 0.101μmol/L） was the most potent inhibitor identified. These compounds showed a higher inhibitory ability compared with their precursors except the luteolin derivatives. In general, the inhibitory activity of the synthetic derivatives was enhanced with long alkyl chains at positions 3＇, 4＇ and 7 of the flavonoid.     

Design,Synthesis and Activities of Aziridine Derivatives of N5-Methyltetrahydrofolate Against Methionine Synthase

Aziridine derivatives of N⁵-methyltetrahydrofolate were designed and synthesized based on the mechanism of methionine synthase, and their biological activities were investigated as well. The aziridine derivatives 1 and 6 exhibited superior inhibitory activities(IC₅₀: 5.05 and 4.15 μmol/L, respectively) compared to the corresponding chain analogue 4(IC₅₀=24.42 μmol/L). The results suggest that the aziridine derivatives can get potential activities against nucleophilic methionine synthase.     

Structure and Activity of a New Sapogenin from Chlorophytum laxum R. Br.

A new steroidal sapogenin named 25-R-spirosta-3,5-dien-12β-ol(1) was isolated from the dried roots of Chlorophytum laxum R. Br. along with five known compounds, namely, diosgenin(2), stigmasterol(3), β-sitosterols(4), estigmasterol-3-O-β-D-glicopyranoside(5) and 3-O-β-authemisol(6). The structure of compound 1 was elucidated by the analysis of IR, HRESI-MS, 1D and 2D NMR spectral data. Compounds 2-5 were isolated from Chlorophytum laxum R. Br. In addition, all the compounds were evaluated for cytotoxicity on the human nasopharyngeal carcinoma cancer cell line 5-8F. Among them, the newly identified 25-R-spirosta-3,5-dien-12β-ol(1) and diosgenin(2) exhibited high cytotoxicity on 5-8F cells, with IC₅₀ values of 24.8 and 41.9 μmol/L, respectively.     

Design,Synthesis and Biological Activity of Novel Chalcone Derivatives as Anti-influenza Agents

A series of novel chalcone derivatives was designed and synthesized via a suitable synthetic strategy in good yields using commercially available 2-amino-4-nitrophenol as an initiator. The structures of the target compounds were confirmed by means of ¹H NMR, ¹³C NMR and high-resolution mass spectrometry(HRMS). And the ability of the target compounds to inhibit influenza viruses was evaluated. These compounds showed moderate inhibitory activity against influenza A(H9N2 and H5N1) viruses. Within this series, compounds S14 and S15 with good potency(IC₅₀=40.3-51.5μmol/L) could be used as lead compounds in the future.