PDF file - 303K, Supplemental Figure 1. Chemical structure of licochalcone E (LicE). Supplemental Figure 2. Licochalcone E decreases the tube formation of endothelial cells. Supplemental Figure 3. Licochalcone E decreases the secretion of urokinase-type plasminogen activator (uPA), VEGF-A, and MMP-9 in MDA-MB-231 breast cancer cells.

PDF file - 167K, Supplemental Table 1. Effect of licochalcone E (LicE) on body weights and organ weights in BALB/c mice injected with 4T1 cells. Supplemental Table 2. Effect of licochalcone E (LicE) on the levels of creatinine and the activity of AST and ALT in the sera of BALB/c mice injected with 4T1 cells. Supplemental Table 3. Oral administration of licochalcone E (LicE) decreases the levels of various cytokines in the lung lysates from 4T1 tumor-bearing BALB/c mice. Supplemental Table 4. Oral administration of licochalcone E (LicE) decreases the levels of various proteins involved in the regulation of angiogenesis/metastasis in the lung lysates from 4T1 tumor-bearing BALB/c mice. Supplemental Table 5. Licochalcone E (LicE) does not inhibit the viability of MDA-MB-231 cells. Supplemental Table 6. Licochalcone E (LicE) does not reduce the viability of 4T1 cells.

Human immunodeficiency virus-1 (HIV-1) transactivator of transcription (Tat) is an important viral factor in neuro-inflammation. Hindsiipropane B, present in Celastrus hindsii, possesses various biological mechanisms including anti-inflammatory activity. In this report, we explored the regulatory activity of hindsiipropane B on HIV-1 Tat-mediated chemokine production and its mode of action in astrocytes. Hindsiipropane B significantly alleviated HIV-1 Tat-mediated production of inflammatory chemokines, CCL2, CXCL8, and CXCL10. Hindsiipropane B inhibited expression of HDAC6, which is important regulator in HIV-1 Tat-mediated chemokine production. Hindsiipropane B diminished HIV-1 Tat-mediated reactive oxygen species (ROS) generation and NADPH oxidase activation/expression. Furthermore, hindsiipropane B inhibited HIV-1 Tat-mediated signaling cascades including MAPK, NF-kappa B, and AP-1. These data suggest that hindsiipropane B exerts its inhibitory effects on HIV-1 Tat-mediated chemokine production via down-regulating the HDAC6-NADPH oxidaseMAPK-NF-kappa B/AP-1 signaling axis, and could serve as a therapeutic lead compound against HIV-1 Tat-associated neuro-inflammation.

A Facile synthesis of natural benzoxazoles, nocarbenzoxazoles F (1), G (5) and their derivatives (2–4 and 6–8) was achieved from the commercially available inexpensive precursors with overall yields ranging from 15 to 49%. Our strategy to access this family of benzoxazoles was enabled by POCl3‐mediated cyclodehydration, selective and/or complete demethylation and reduction as the key steps. Their in vitro nitric oxide (NO) inhibitory effect was further evaluated as an indicator of anti‐inflammatory activity in LPS‐induced RAW 264.7 cells and found to display weak to moderate activity in a concentration‐dependent manner without marked cytotoxicity. Overall, compound 8 (53.5% at 10 μM; IC50 = 8.17 μM) followed by compound 6 (12.7% at 10 μM; IC50 = 28.26 μM) exhibited significant activity, being more active than the positive control, L‐NMMA (19.5% at 10 μM; IC50 = 18.77 μM).

Syntheses of natural homoisoflavonoids, (+/-)-portulacanones A-C (4, 8 and 9), portulacanone D (6), isolated from Portulaca oleracea L. (POL) and their derivatives (3, 5 and 7) have been achieved for the first time along with the synthesis of known derivatives (1 and 2) and their in vitro inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages was evaluated as an indicator of anti-inflammatory activity. All the compounds tested had a concentration-dependent inhibitory effect on NO production by RAW-264.7 macrophages without obvious cytotoxicity. Compounds 3 (97.2% at 10 mu M; IC50 = 1.26 mu M) followed by 6 (portulacanone D) (92.5% at 10 mu M; IC50 = 2.09 mu M), 1 (91.4% at 10 mu M; IC50 = 1.75 mu M) and 7 (83.0% at 10 mu M; IC50 = 2.91 mu M) were the most potent from the series. This finding was further correlated with the suppressed expression of iNOS induced by LPS. Our promising preliminary results may provide the basis for the assessment of compound 3 as a lead structure for a NO production-targeted anti-inflammatory drug development and also could support the usefulness of POL as a folklore medicinal plant in the treatment of inflammatory diseases. (C) 2018 Elsevier Ltd. All rights reserved.

An efficient first synthesis of 2,5‐diaryloxazoles 1–5 was accomplished from commercially inexpensive precursors and in overall yields of 38–48%. The synthesis proceeds via α‐aminoketones and cyclodehydration (Robinson–Gabriel reaction) as key step. Next, these oxazoles were examined for their inhibitory effect against nitric oxide (NO) production in lipopolysaccharide (LPS)‐induced RAW 264.7 cells and were found to display concentration‐dependent inhibition of NO production without cytotoxicity. Of note, compound 3 (70.7%; IC50 = 2.33 μM) was identified as a potent inhibitor in view of its comparable inhibitory effect with the positive control, N G‐monomethyl‐L‐arginine acetate (L‐NMMA) (79.3%; IC50 = 4.51 μM) followed by compounds 5 (68.3%; IC50 = 2.30 μM) and 2 (53.9%; IC50 = 6.31 μM). As a whole, compound 3 may hold great promise for further development of NO production targeted anti‐inflammatory agent.

A general and efficient method for C-3 functionalization of 2-phenylimidazo[1,2-a]pyridine has been developed. The reaction employs Cu(OTf)(2) as a catalyst at 10 mol% loading, proceeds in dimethyl sulfoxide solvent, and utilizes bench-stable solid N-benzyloxycarbonylamino sulfones derived from aromatic and aliphatic aldehydes as N-acyliminium ion precursors. The imidazo[1,2-a]pyridine products are obtained in moderate to good yields.

A modular and efficient synthesis of the biologically significant C-methylisoflavones isosideroxylin (1), 6,8-dimethylgenistein (2) and their analogues (3–8) is established for the first time. The synthesis is realized in 7-8 steps in overall yields of 16%-24% from commercially inexpensive phloroglucinol and features a high yielding Vilsmeier–Haack reaction, Friedel-Crafts acylation, Gammill’s protocol and Suzuki coupling as the pivotal transformations. Next, these compounds evaluated for their inhibitory potency on the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated RAW-264.7 cells as an indicator of anti-inflammatory activity. The results showed that all the compounds decreased NO production in a dose-dependent manner without marked cytotoxicity and IC50 values are found in the range of 10.17–33.88μmol/L. Of note, compounds 3 followed by 1, 7 and 8 show comparable inhibitory activity with positive control (N-monomethyl-l-arginine, L-NMMA).

The present study describes the synthesis of piceatannol (2) and its analogs (3–8) using Wittig‐Horner reaction, Colvin rearrangement, and Sonogashira reaction as key steps and also evaluation of their inhibitory potency on the production of inflammatory mediator nitric oxide (NO) in lipopolysaccharide (LPS)‐induced RAW‐264.7 macrophages. Three compounds 7 (90.1%), 8 (60.8%), and 6 (55.2%) were found to potently inhibit NO production induced by LPS without affecting the viability of RAW‐264.7 cells. In addition, their Arginase I and II inhibition activity was also evaluated. In this study, three compounds, i.e., compounds 2–4 were showed good inhibition activity to both arginase I and II. Of the synthesized compounds, compound 2 exhibited maximum inhibitory activity of 28% (arginase I) and 26% (arginase II) at 10 μM concentration followed by compounds 3 and 4 of 20 and 22% to arginase I, 22 and 23% to arginase II, respectively.

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.

The first syntheses of natural benzofurans, gramniphenols F and G, morunigrol C and its 3′,5′-di-O-methyl analogue along with the synthesis of cicerfuran are achieved by a unified synthetic sequence using 7-hydroxycoumarin, 5-bromoresorcinol, 2,4-dihydroxybenzaldehyde, and sesamol as building blocks. Ramirez gem-dibromoolefination, Miyaura borylation, Suzuki coupling have been successfully exploited in the synthesis. Additionally, their anti-inflammatory effects were also investigated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages. The compounds exhibited significant inhibition of iNOS mediated nitric oxide (NO) production with no cytotoxicity at 10μM concentration and IC50 values are found in the range from 9.1 to 25.2μM.

First syntheses of five natural 1,3-diarylpropenes (cinnamylphenols) 2-4, 7, and 8 along with synthesis of two other natural 1,3-diarylpropenes 1 and 5 and E-isomer of mucronulastyrene (6) were achieved by Friedel-Crafts alkylation as a key step. Subsequently, their anti-inflammatory effects were also investigated in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. The compounds exhibited significant inhibition of inflammatory mediated nitric oxide (NO) production with no cytotoxicity except compound 8 (dalberatin B) at 10 mu m concentration and IC50 values were found in the range from 4.05 to 16.76 mu m.

Diversity oriented synthesis of natural 2-arylbenzofuran, moracin F (1) has been carried out from the commercially available starting materials using Sonogashira coupling, Suzuki coupling, neutral Al2O3 mediated cyclization, and intramolecular Wittig reaction as key steps.

Facile synthesis of natural aurones, rugaurone A (1a), gramflavonoid A (1b) and their novel derivatives (1c-1o) is accomplished in good to high yields with exceptional Z-selectivity (>= 97%) from the commercially available starting materials. Herein, practically improved method was developed for the synthesis of common key intermediate, 5,6-dimethoxybenzofuran-3(2H)-one (5). Later, their nitric oxide (NO) production inhibition effects were estimated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages as an indicator of anti-inflammatory activity. All compounds exhibited weak to good strength against NO production in a concentration-dependent manner and none of the compound showed significant cytotoxicity against macrophages at the highest (10 mu M) concentration. The IC50 values are showed in the range from 3.39 to 19.55 mu M. Among the 15 aurones synthesized in this study, 3 compounds that is compound 1g (63.98%) followed by compound 1o (49.07%) and rugaurone A (1a) (41.72%) showed the maximum inhibitory activity with respective IC50 values of 4.50 mu M, 4.98 mu M and 3.39 mu M compared to L-NMMA (IC50 = 5.19 mu M), which was used as a standard NO inhibitor. This study suggests that compounds 1g, 1o and 1a may serve as favorable structures for further development of NO production-targeted anti-inflammatory agents.

An expeditious stereoselective synthesis of a naturally occurring 2,6‐disubstituted piperidine alkaloid, (−)‐pinidinone, has been accomplished with an overall yield of 31% in total eight steps. The synthesis involves ethyl acetoacetate as the starting material and the stereoselective α‐aminoallylation of aldehyde with (S)‐tert‐butanesulfinamide, allyl bromide, and indium and Grubbs’ olefin cross‐metathesis as the pivotal steps.

An efficient synthesis of 2-aroylbenzofurans, rugchalcones A, B and their derivatives was accomplished in excellent yields by the Rap–Stoermer reaction between substituted salicylaldehydes and phenacyl bromides. Later their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages. The compounds were exhibited exceptional potency against inflammatory mediated NO production with no cytotoxicity at 10μM concentration and IC50 values are found in the range from 0.75 to 13.27μM. Among the 2-aroylbenzofurans prepared in this study, compounds 4 (99.6%; IC50=0.57), rugchalcone B (2) (99.3%; IC50=4.13), 7 (96.8%; IC50=1.90) and 8 (74.3%; IC50=0.99) were showed the maximum inhibitory activity. This study suggests that compounds 2, 4, 7 and 8 which are having 4-hydroxyphenyl group and/or hydroxy (–OH) group at 5- and/or 6-position of benzofuran motif could be considered as a promising scaffolds for the further development of iNOS inhibitors for potential anti-inflammatory applications.

An efficient first synthesis of biologically significant natural butenolides, rubrolides F (1f); R (1r), S (1s) & its 7 '',8 ''-didehydro derivative (1sa), and 3 ''-bromo rubrolide (1fa) along with the synthesis of rubrolide E (1e) and its di-O-methyl derivative (1ea) is accomplished in a collective fashion from commercially available and inexpensive precursors in overall yields of 14-48.5%. Key features are Wittig-Horner reaction, SeO2-induced tandem allylic hydroxylation/intramolecular cyclization and Knoevenagel condensation. Next, in their inhibitory activity towards nitric oxide (NO) production in lipopolysaccharide-induced RAW 264.7 macrophages as an indicator of anti-inflammatory activity, all compounds displayed good inhibitory activity in a concentration-dependent manner. None of the compound exhibited notable cytotoxicity at the highest concentration (10 mu M) and IC50 values are found in the range from 8.53 to 17.85 mu M. (C) 2016 Elsevier Ltd. All rights reserved.

An efficient synthesis of dihydrostilbenes (1-5) and diarylpropanes (6-10) is achieved from the commercially available starting materials and Wittig-Horner reaction, Claisen-Schmidt condensation and hydrogenation as key steps. Later, their nitric oxide (NO) production inhibition effects were evaluated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages as an indicator of anti-inflammatory activity. All the tested compounds significantly decreased NO production in a concentration-dependent manner except compounds 2, 6 and 8 and did not show notable cytotoxicity except compound 1. Two compounds i.e., compound 9 (hindsiipropane B) (100%; IC50=1.84μM) possessed the most potent NO inhibitory activity which was even stronger than the positive control, L-NMMA (90.1%; IC50=2.73μM) followed by compound 4 (75.5%; IC50=2.98μM) at 10μM concentration and this finding was also further correlated by suppressed expression of LPS stimulated inducible NO synthase. Our study revealed that compound 9, a 1,3-diarylpropane scaffold with 3″,4″-dimethoxyphenyl and 3',4'-dihydroxy-2'-methoxyphenyl motifs could be considered as potential compound or lead compound for further development of NO production-targeted anti-inflammatory agents.

E-mail: jgjun@hallym.ac.krReceived September 5, 2014, Accepted September 25, 2014Simple and practical synthesis of natural benzofuran derivative eupomatenoid-6 via Horner-Emmons typecondensation as the key step is described. The umpolung property of aldehyde derivative, α-aminophosphonatewas efficiently employed in this reaction. α-Aminophosphonate of anisaldehyde subjected to Horner-Emmonstype condensation with 5-bromo-2-methoxybenzaldehyde to yield the deoxybenzoin, which was furthermethylated and then underwent tandem demethylation-cyclodehydration to afford the benzofuran scaffold inexcellent yield. Finally Suzuki coupling with propenyl boronic acid afforded eupomatenoid-6 with an overallyield of 56.8%.Key Words : α-Aminophosphonate, Kebachnik-Fields reaction, Horner-Emmons type condensation, Suzukicoupling, Eupomatenoid-6IntroductionSubstituted benzofurans are attractive targets of organicsynthesis because of their physiological, pharmacologicaland therapeutic properties.

The total synthesis of puerariafuran and its derivatives was achieved for the first time by the direct reaction between substituted α‐bromoacetophenones and resorcinol. The reaction was mediated by neutral alumina and was fully regio‐controlled. Subsequently, the Sonogashira coupling method was applied for puerariafuran preparation. Finally, the anti‐inflammatory effects of these prepared compounds were evaluated in lipopolysaccharide ( LPS ) stimulated RAW 264.7 macrophages. The results revealed that puerariafuran and its derivatives show weak inhibition activity on the production of inflammatory‐mediated nitric oxide.