Inhibition of HIF-1α through Suppression of NF-κB Activation by Compounds Isolated from Senecio graveolens

One of the characteristics of cancer is that the lack of oxygen in the cancer cells triggers changes in their gene expression. This hypoxia activates hypoxia-inducible factor 1-alpha and this in turn sets in motion the whole family of important angiogenic genes for the tumour. Hypoxia-inducible factor 1-alpha therefore increases the density and vascular permeability within the tumours, facilitating their rapid growth and, later, the metastasis. Senecio graveolens is a South American medicinal plant commonly used for mountain sickness (lack of adaptation of the organism to hypoxia). Additionally, pharmacological studies showed that its alcoholic extracts have cytotoxic properties. This research aimed to perform a guided phytochemical study of S. graveolens to identify compounds capable of inhibiting hypoxia-inducible factor 1-alpha through suppression of nuclear factor kappa-light-chain-enhancer of activated B cell activation. The isolation led to the characterisation of phanurane (1), damsine (2), and scoparone (3), first reported in the S. graveolens species. Phanurane (1) showed inhibitory activity of hypoxia-inducible factor 1-alpha on the cancer cell lines U-373 MG (IC50 = 20.66 ± 0.04 μM), A549 (IC50 =25.80 ± 0.04 μM), Hep G2 (IC50 =29.21 ± 0.03 μM), and Caco-2 (IC50 =38.58 ± 0.02 μM). Damsine (2) hypoxia-inducible factor 1-alpha displayed inhibitory activity of hypoxiainducible factor 1-alpha on the cancer cell lines U-373 MG (IC50 =2.29 ± 0.07 μM), A549 (IC50 =4.13 ± 0.04 μM), Hep G2 (IC50 =6.40 ± 0.03 μM), and Caco-2 (IC50 =9.80 ± 0.04 μM). Finally, scoparone (3) displayed inhibitory activity of y poxiainducible factor 1-alpha on the cancer cell lines U-373 MG (IC50 =15.22±0.01μM), A549 (IC50 =17.47±0.02μM), Hep G2 (IC50=18.26±0.06μM), and Caco-2 (IC50=19.75±0.04μM). In addition, phanurane (1) displayed inhibitory activity over nuclear factor kappa-light-chain-enhancer of activated B cells on cancer cell lines U-373 MG (IC50 =7.13 ± 0.03 μM), A549 (IC50 = 8.64 ± 0.03 μM), Hep G2 (IC50 = 8.87 ± 0.04 μM), and Caco-2 (IC50 =15.11 ± 0.01 μM). Likewise, damsine (2) showed inhibitory activity over nuclear factor kappa-light-chainenhancer of activated B cells on cancer cell lines U-373 MG (IC50 =2.28 ± 0.01 μM), A549 (IC50 =3.79 ± 0.02 μM), Hep G2 (IC50 = 3.98 ± 0.05 μM), and Caco-2 (IC50 = 6.41 ± 0.02 μM). Lastly, scoparone (3) displayed inhibitory activity of nuclear factor kappa-light-chain-enhancer of activated B cells on cancer cell lines U-373 MG (IC50 = 3.62 ± 0.06 μM), A549 (IC50 = 4.48 ± 0.03 μM), Hep G2 (IC50 = 5.25 ± 0.01 μM), and Caco-2 (IC50 =11.90 ± 0.02 μM). This study corroborates the cytotoxic activity of the isolated compounds through the inhibition of hypoxia-inducible factor 1-alpha as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cellsThis work was supported by the National Herbarium of Bolivia, the Fundación de la Universidad Autónoma de Madrid (FUAM

Anti-inflammatory Potential of Macamides Isolated from Yellow Tubers of Mashua (Tropaeolum Tuberosum)

AbstractAlthough Tropaeolum tuberosum tubers have been consumed cooked as a folk remedy for the treatment of skin, lungs, liver and kidneys diseases, these uses have very limited scientific basis. Therefore, this article develops a phytochemical analysis of the yellow tubers of T. tuberosum with the objective to assess whether the isolated compounds have anti-inflammatory potential in the CCD-1109Sk, MRC-5 and RWPE-1 cell lines. We performed an extraction of T. tuberosum tubers using different organic solvents, followed by a bioguided chromatographic separation. Four macamides were identified by LC/MS techniques, but only N-benzyllinoleamide (1) and N-benzyloleamide (2) were isolated and elucidated by NMR/MS techniques, given that they were present in a larger proportion in the tubers. The anti-inflammatory potential of macamides was evaluated by the inhibition of NF-κB and STAT3 activation. Both compounds displayed inhibition of NF-κB activation with IC50 values of 2.28±0.54 µM; 3.66±0.34 µM and 4.48±0.29 µM for compound (1) and 6.50±0.75 µM; 7.74±0.19 µM and 8.37 ±0.09 µM for compound (2) in CCD-1109Sk, MRC-5 and RWPE-1 cell lines, respectively. Moreover, both compounds inhibited the STAT3 activation with IC50 of 0.61±0.76 µM; 1.24±0.05 µM and 2.10±0.12 µM for compound (1) and 5.49±0.31 µM; 7.73 ±0.94 µM and 7.79±0.30 µM for compound (2). Therefore, isolated macamides of T. tuberosum tubers showed promising anti-inflammatory effects, suggesting a possible beneficial use to combat inflammatory processes of skin, lung and prostate

Hydroalcoholic extract of Tagetes minuta L. inhibits inflammatory bowel disease through the activity of pheophytins on the NF-κB signalling pathway

Ethno-pharmacological relevance: Species of the genus Tagetes are well known for their anti-inflammatory properties. Tagetes minuta “Huacatay” is an endemic species of South America that has been used in traditional medicine since ancient times as a remedy for stomach and intestinal discomfort. Aim of the study: The aim of this study is to investigate the anti-inflammatory activity of the aqueous and hydroalcoholic extracts of the Huacatay, identifying the compounds responsible for this activity. Materials and methods: Anti-inflammatory activity of the compounds, fractions and extracts was evaluated in Hs 746T (stomach), HIEC-6 (intestine) and THP-1 (monocytes peripheral blood) cells by measuring their inhibitory capacity against the NF-κB production. Results: Aqueous and hydroalcoholic extracts of Tagetes minuta displayed anti-inflammatory activity in vitro, the hydroalcoholic extract being the most active (IC50 between 59.72 and 66.42 μg/mL) in all cell lines. Bio-guided hydroalcoholic extract fractionation led to the isolation and characterisation of two pheophytins, pheophytin a (1) and 132-hydroxy pheophytin a (2). Both compounds inhibited the production of NF-κB with IC50 values in the low micromolar range, with an IC50 between 12.32 and 16.01 μM for compound 1 and 7.91–9.87 μM for compound 2. Conclusions: The two pheophytins isolated in this study inhibit the production of NF-κB, thus showing that the traditional anti-inflammatory use of Tagetes minuta can be proved through pharmacological assays. This contributes to understanding the anti-inflammatory activity of the Huacatay extracts and their use in the treatment of stomach and intestinal discomfortThis work was supported by the National Herbarium of Bolivia and the Fundación de la Universidad Autónoma de Madrid (FUAM

Enzymatic synthesis and molecular modelling studies of rhamnose esters using lipase from Pseudomonas stutzeri

Rhamnolipids are becoming an important class of glycolipid biosurfactants. Herein, we describe for the first time the enzymatic synthesis of rhamnose fatty acid esters by the transesterifica-tion of rhamnose with fatty acid vinyl esters, using lipase from Pseudomonas stutzeri as a biocatalyst. The use of this lipase allows excellent catalytic activity in the synthesis of 4-O-acylrhamnose (99% conversion and full regioselectivity) after 3 h of reaction using tetrahydrofuran (THF) as the reaction media and an excess of vinyl laurate as the acyl donor. The role of reaction conditions, such as temperature, the substrates molar ratio, organic reaction medium and acyl donor chain-length, was studied. Optimum conditions were found using 35 ºC, a molar ratio of 1:3 (rhamnose:acyldonor), solvents with a low logP value, and fatty acids with chain lengths from C4 to C18 as acyl donors. In hydrophilic solvents such as THF and acetone, conversions of up to 99–92% were achieved after 3 h of reaction. In a more sustainable solvent such as 2-methyl-THF (2-MeTHF), high conversions were also obtained (86%). Short and medium chain acyl donors (C4–C10) allowed maximum conversions after 3 h, and long chain acyl donors (C12–C18) required longer reactions (5 h) to get 99% conversions. Furthermore, scaled up reactions are feasible without losing catalytic action and regioselectivity. In order to explain enzyme regioselectivity and its ability to accommodate ester chains of different lengths, homology modelling, docking studies and molecular dynamic simulations were performed to explain the behaviour observe

Synthesis and biological screening of a library of macamides as TNF-α inhibitors

Thirty-five macamide analogues were synthesised by modifying the initial molecular structure. The resulting structures were confirmed using NMR and MS. Cytotoxicity and the anti-inflammatory activity of these synthetic macamides were evaluated in the THP-1 cell line. Preliminary biological evaluation indicated that most of these synthetic macamides did not present cytotoxicity (MTT assay) in the tested cell line with respect to the control (actinomycin D). Regarding the anti-inflammatory activity, several analogues had a greater potential for inhibition of TNF-α than natural macamides. Synthetic macamide 4a was the most active (IC50 = 0.009 ± 0.001 μM) compared to the C87 (control). Through looking at the link between the chemical structure and the activity, our study proves that changes made to natural macamides at the level of the alkyl chain, the benzyl position, the amide bond, and the addition of two methyl groups to the aromatic ring (meta position) lead us to obtaining new macamides with greater anti-inflammatory activityThis work was supported by the Fundación de la Universidad Autónoma de Madrid (FUAM

Triterpenoids isolated from Jatropha macrantha (Müll. Arg.) inhibit the NF-κB and HIF-1α pathways in tumour cells

“This is an Accepted Manuscript version of the following article, accepted for publication in Natural Product Research. Natural Product Research 35.24 (2021): 5843-5847. It is deposited under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way”Activity-guided fractionations of Jatropha macrantha Müll. Arg. led to the isolation of pomolic acid (1) and euscaphic acid (2). The potential for inhibition against NF-κB and HIF-1α production of these two compounds was tested in different tumour cell lines. Compounds 1 and 2 showed an inhibitory activity of HIF-1α in the SK-MEL-28 (IC50=3.01 ± 0.02 μM and 3.78 ± 0.02 μM), A549 (IC50=9.97 ± 0.01 μM and 10.25 ± 0.01 μM) and U-373 MG (IC50=6.34 ± 0.02 μM and 8.85 ± 0.02 μM) cell lines. In addition, compounds 1 and 2 showed an inhibitory activity on NF-κB in SK-MEL-28 (IC50=1.05 ± 0.02 μM and 2.71 ± 0.01 μM), A549 (IC50=3.63 ± 0.01 μM and 3.73 ± 0.02 μM) and U-373 MG (IC50=2.55 ± 0.02 μM and 3.39 ± 0.01 μM) cell lines. This is the first report that isolates these compounds from J. macrantha and tests their antitumor potentia

Anti-inflammatory effects of TNF-α and ASK1 inhibitory compounds isolated from Schkuhria pinnata used for the treatment of dermatitis

2023 Acuerdos transformativos CRUEEthno-pharmacological relevance: The Andean Schkuhria pinnata species commonly known as ‘Canchalagua’ is used as an infusion in Andean countries to treat various anti-inflammatory and skin-related pathologies. Aim of the study: This study determined the anti-inflammatory activity of the aqueous extract from Schkuhria pinnata, identified compounds with high biological activity and performed a structure-activity relationship analysis to determine their binding mechanism. Materials and methods: A bio-guided isolation of the active compounds of Schkuhria pinnata was carried out by selecting the most active sub-extracts and fractions to test their anti-inflammatory activity against the ASK1 and TNF-α cytokines. Results: Three compounds were obtained, and their structures were elucidated by nuclear magnetic resonance. The compounds were (3R,4R)-4-(3,4-dimethoxybenzyl)-3-(4-hydroxy-3-methoxybenzyl) dihydrofuran-2(3H)-one (1), N-[2,3-dihydro-1,3-dimethyl-6-[(2R)-2-methyl-1-piperazinyl]-2-oxo-1H-benzimidazol-5-yl]-2-methoxybenzamide (2), and N-hydroxy-1-cyclopentene-1-carboxamide (3). Regarding their anti-inflammatory activity, the three compounds inhibited the TNF-α and ASK1 cytokines, however, compound 2 was the most active, with an IC50 of 19.08 and 8.94 nM, respectively. Conclusion: The anti-inflammatory activity of the aqueous extract of Schkuhria pinnata was evaluated, followed by the isolation of three compounds and the study of their pharmacological activity. The three compounds have been shown as promising treatment against dermatitis, confirming at the same time their traditional use.Universidad Autónoma de MadridDepto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpubAPC financiada por la UC

Alkaloids isolated from Tropaeolum tuberosum with cytotoxic activity and apoptotic capacity in tumour cell lines

Two alkaloids were isolated and identified for the first time in the black tubers of Tropaeolum tuberosum, collected from the Titicani-Taca, Ingavi province in La Paz, Bolivia. Their structures were elucidated by extensive NMR and MS spectroscopic analyses. The isolated compounds were evaluated for their cytotoxicity and apoptotic capacity against four human cancer cell lines. 2-Benzyl-3-thioxohexahydropyrrolo[1,2-c]imidazole-1-one (1) showed slight cytotoxic activity against all the cancer cell lines which were tested, with IC50 values ranging from 27.45 ± 0.80 to 31.07 ± 0.87 μM. Moreover, N-(4-acetyl-5-methyl-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl) acetamide (2) showed significant anti-cancer potential, with IC50 values between 1.26 ± 0.57 μM and 1.37 ± 0.09 μM against all human cancer cell lines which were tested. Treatment of tumour cell lines with the compounds caused an increase in the apoptotic rate of these cells, observing that compound 2 presented an apoptotic effect which was double with respect to the control (Dimethylenastron

Antitumoral potential of carbamidocyclophanes and carbamidocylindrofridin A isolated from the cyanobacterium Cylindrospermum stagnale BEA 0605B

Three carbamidocyclophanes, A, F and V, and carbamidocylindrofridin A were isolated from the cultured freshwater cyanobacterium Cylindrospermum stagnale, collected in the Canary Islands. The chemical structures of these compounds were elucidated through NMR, HRMS and ECD spectroscopy. The absolute configuration of carbamidocyclophane A was confirmed using X-ray-diffraction. All compounds showed apoptotic capacity against the SK-MEL-1, SK-MEL-28 and SK-MEL-31 tumour cells. Carbamidocylindrofridin A had the highest anti-tumour potential, with an IC50 of 1 ± 0.3 μM in the SK-MEL-1 cell lineThis work was supported by the Fundación de la Universidad Autónoma de Madrid (FUAM

Isolation of Nocuolin A and Synthesis of New Oxadiazine Derivatives. Design, Synthesis, Molecular Docking, Apoptotic Evaluation, and Cathepsin B Inhibition

2022 Descuento MDPINocuolin A (1), an oxadiazine, was isolated from the cyanobacterium Nostoc sp. Its chemical structure was elucidated using NMR and mass spectroscopic data. From this compound, two new oxadiazines, 3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropyl acetate (2) and 4-{3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropoxy}-4-oxobutanoic acid (3), were synthesised. The chemical structures of these two compounds were elucidated by a combination of NMR and MS analysis. Compound 3 showed cytotoxicity against the ACHN (0.73 ± 0.10 μM) and Hepa-1c1c7 (0.91 ± 0.08 μM) tumour cell lines. Similarly, compound 3 significantly decreased cathepsin B activity in ACHN and Hepa-1c1c7 tumour cell lines at concentrations of 1.52 ± 0.13 nM and 1.76 ± 0.24 nM, respectively. In addition, compound 3 showed no in vivo toxicity in a murine model treated with a dose of 4 mg/kg body weight.VALORALIA I MÁS DDepto. de Farmacología, Farmacognosia y BotánicaFac. de FarmaciaTRUEpubDescuento UC