Novel 1,2,4-oxadiazole compounds as PPAR-α ligand agonists: a new strategy for the design of antitumour compounds.

Modulation of PPAR-α by natural ligands is a novel strategy for the development of anticancer therapies. A series of 16 compounds based on the structure of 3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole (natural compound) with antitumour potential were designed and synthesised. The cytotoxicity and PPAR agonist activity of these synthetic 1,2,4-oxadiazoles were evaluated in the A-498 and DU 145 tumour cell lines. Preliminary biological evaluation showed that most of these synthetic 1,2,4-oxadiazoles are less cytotoxic (sulforhodamine B assay) than the positive control WY-14643. Regarding the PPAR-α modulation, compound 16 was the most active, with EC50 = 0.23-0.83 µM (PPAR-α). Additionally, compound 16 had a similar activity to the natural compound (EC50 = 0.18-0.77 µM) and was less toxic in the RPTEC and WPMY-1 cell lines (non-tumour cells) (CC50 = 81.66-92.67 µM) than the natural compound. Looking at the link between chemical structure and activity, our study demonstrates that changes to the natural 1,2,4-oxadiazole at the level of the thiophenyl residue can lead to new agonists of PPAR-α with promising anti-tumour activity.

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

Nocuolin 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.

Antitumoral activity of 1,2,4-oxadiazoles compounds isolated from the Neowerdermannia vorwerkii in liver and colon human cancer cells.

Two unknown 1,2,4-oxadiazoles (3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole and 5-(3-hydroxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole) and one known 1,2,4-oxadiazole (5-(3-methoxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole) were isolated from tubers of Neowerdermannia vorwerkii, collected from the San Juan Huancollo, Ingavi province, La Paz, Bolivia. The chemical structures of these compounds were elucidated through NMR and HRMS spectroscopic analyses. All compounds showed apoptotic capacity against the SK-HEP-1 and Caco-2 tumour cells. 5-(3-methoxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole and 5-(3-hydroxyphenyl)-3-(pyridin-3-yl)-1,2, 4-oxadiazole showed slight apoptotic capacities, with an IC50 between 17.46 ± 0.75 to 15.91 ± 0.62 µM and 39.29 ± 0.98 to 34.81 ± 0.70 µM, respectively. 3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole showed a higher apoptotic capacity with an IC50 in the range of 0.98 ± 0.11 to 0.76 ± 0.03 µM, similar to that of the positive control (Dimethylenastron).

Anti-inflammatory properties of Neowerdermannia vorwerkii Fric 'Achacana' used in treating stomach-related ailments.

ETHNO-PHARMACOLOGICAL RELEVANCE: The tuber of Neowerdermannia vorwerkii commonly known as 'Achacana' is used as an infusion in Andean countries to treat various gastrointestinal ailments, kidney and liver diseases. AIM OF THE STUDY: This study determined the anti-inflammatory activity of the aqueous extract from Neowerdermannia vorwerkii and identified the compounds related to this activity. MATERIALS AND METHODS: A bio-guided isolation of the active compounds of Neowerdermannia vorwerkii was carried out, selecting the sub-extracts and fractions depending on their anti-inflammatory activity in the Hs 738.St/Int, Hs 746T and NCI-N87 cells. RESULTS: Three compounds were obtained and characterised by nuclear magnetic resonance and mass spectrometry. These compounds are (3-(pyridin-3-yl)-5-(tiophen-3-yl)-1,2,4-oxadiazole (1), 5-(3-methoxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole (2) and 5-(3-hydroxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole (3). Regarding their anti-inflammatory activity, the three compounds inhibited the production of cytokines (IL-1ß, IL-6 and TNF-α), however, compound 1 was the most active, with an IC50 of 0.87 µM in all cell lines. CONCLUSION: In the present study, the anti-inflammatory activity of the aqueous extract of Neowerdermannia vorwerkii was tested and analysed, following the isolation of three 1,2,4-oxadiazoles type compounds with similar pharmacological properties.

Anti-inflammatory activity of glycolipids isolated from cyanobacterium Nodularia harveyana.

Activity-guided fractionations from the freshwater cyanobacterium Nodularia harveyana led to the isolation of two monogalactosyldiacylglycerols (MGDG), two digalactosyldiacylglycerols (DGDG), two monoglucosyldiacylglycerols (MGlcDG) and 1-(O-hexose)-3,25-hexacosanediol (HG). Structures were elucidated by a combination of 1D and 2D NMR analysis, HRMS and GC-MS. The potential for inhibition against TNF-α and NF-κB production of these seven compounds was tested in THP-1 cells. All compounds showed activity, but compound 7 showed higher inhibitory activity of TNF-α and NF-κB, with IC50 of 4.88 ± 0.13 and 3.64 ± 0.45 µM, respectively.

Inhibition of melanin production and tyrosinase activity by flavonoids isolated from Loranthus acutifolius.

Activity-guided fractionations of leaves and stems from Loranthus acutifolius led to the isolation of 2',4',6-trimethoxyflavone (1), 3',4',5-trihydroxy-6,7,8-trimethoxyflavone (2), 2'4'-dihydroxy-6'-methoxy-chalcone (3) and 4',5-dihydroxy-6,7,8-trimethoxyflavone (4). The potential for inhibition against melanin production and tyrosinase activity of these 4 compounds was tested in B16-F10 cells. 2',4',6-trimethoxyflavone, 3',4',5-trihydroxy-6,7,8-trimethoxyflavone, 2'4'-dihydroxy-6'-methoxy-chalcone and 4',5-dihydroxy-6,7,8-trimethoxyflavone showed an inhibitory activity of melanin production with IC50 of 3.6 ± 0.05 µM, 8.1 ± 0.05 µM, 1.6 ± 0.03 µM and 6.5 ± 0.05 µM, respectively. In addition, 2',4',6-trimethoxyflavone, 3',4',5-trihydroxy-6,7,8-trimethoxyflavone, 2'4'-dihydroxy-6'-methoxy-chalcone and 4',5-dihydroxy-6,7,8-trimethoxyflavone were able to inhibit tyrosinase activity with IC50 of 4.0 ± 0.03 µM, 11.3 ± 0.05 µM, 5.7 ± 0.02 µM and 8.6 ± 0.04 µM, respectively. This is the first time that these compounds are reported in the L. acutifolius species showing anti-melanogenic activities.

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 discomfort.

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

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 potential.

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).

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 activity.

Cybastacines A and B: Antibiotic Sesterterpenes from a Nostoc sp. Cyanobacterium.

Cybastacines A (1) and B (2) were discovered as a novel pentacyclic sesterterpenoid-alkaloid skeleton structure, with a guanidinium group. These molecules were isolated from a Nostoc sp. cyanobacterium collected in the Canary Islands. Their structures were elucidated primarily by a combination of spectroscopic analyses and X-ray diffraction. These compounds showed antibiotic activities against several clinically relevant bacterial strains.