Jatrophane diterpenoids with multidrug-resistance modulating activity from the latex of Euphorbia nicaeensis.

Seven previously undescribed jatrophane diterpenoids, nicaeenin A-G, with eight known jatrophane diterpenoids, namely euphodendrophanes A-C, F, N, O, Q, S, were isolated from latex of Euphorbia nicaeensis collected in Serbia. The chemical structures of the compounds were determined by spectroscopic analysis including 1D and 2D NMR and HRESIMS experiments. All but one of the previously undescribed jatrophanes, showed significant potential to inhibit P-glycoprotein (P-gp) activity in two MDR cancer cells (NCI-H460/R and DLD1-TxR). The most powerful were nicaeenin F and nicaeenin G. Moreover nicaeenin G significantly stronger sensitized NCI-H460/R cells to DOX than Dex-VER.

Research on Chemical Composition and Biological Properties Including Antiquorum Sensing Activity of Angelica pancicii Vandas Aerial Parts and Roots.

The essential oil, different extracts, and isolated compounds of Angelica pancicii Vandas (Apiaceae) were investigated for the first time. The GC-FID and GC-MS analyses revealed sesquiterpenoids as the main constituents of A. pancicii essential oil of aerial parts with bornyl acetate (8.08%), n-octanol (5.82%), kessane (4.26%), and ß-selinene (4.26%) as the main constituents. Analysis of methanol extracts, using an HPLC-DAD/ESI-ToF-MS system, showed a total of 52 compounds in the aerial parts and 53 in the roots, indicating coumarins as the main constituents. In addition, new chromone (1) and six known furanocoumarins (2-7) were isolated from the roots and structurally elucidated by combined spectroscopic methods. The aerial part extracts exhibited higher polyphenolic contents and antioxidant activity evaluated by three radical scavenging assays. Using a microwell dilution method, the strongest antibacterial activity profiles were determined for ethanol and methanol root extracts (minimum bactericidal concentrations (MBCs) = 0.25-3.00 mg/mL), which were comparable to the activity of streptomycin (MBCs = 0.34-1.24 mg/mL), while the strongest antibacterial compound of A. pancicii was oxypeucedanin hydrate (MBCs = 0.50-8.00 mg/mL). Antifungal potential was in moderate extent, and the highest activity was obtained for root methanol extract (minimum fungicidal concentrations (MFCs) = 4.00-14.00 mg/mL). Tested sub-minimum inhibitory concentrations (subMICs) of the extracts and isolated compounds inhibited selected Pseudomonas aeruginosa PAO1 virulence determinants. The most reduced growth of P. aeruginosa colony was in the presence of isolated oxypeucedanin. Ethanol (17.36-46.98%) and methanol (34.54-52.43%) root extracts showed higher anti-biofilm activity compared to streptomycin (49.40-88.36%) and ampicillin (56.46-92.16%).

Chemistry of the sternal gland secretion of the Mediterranean centipede Himantarium gabrielis (Linnaeus, 1767) (Chilopoda: Geophilomorpha: Himantariidae).

The geophilomorph centipede, Himantarium gabrielis, when disturbed, discharges a viscous and proteinaceous secretion from the sternal glands. This exudate was found by gas chromatography-mass spectrometry, liquid chromatography-high resolution mass spectrometry, liquid chromatography-mass spectrometry-mass spectrometry and NMR analyses to be composed of hydrogen cyanide, benzaldehyde, benzoyl nitrile, benzyl nitrile, mandelonitrile, mandelonitrile benzoate, 3,7,6O-trimethylguanine (himantarine), farnesyl 2,3-dihydrofarnesoate and farnesyl farnesoate. This is the first report on the presence of benzyl nitrile and mandelonitrile benzoate in secreted substances from centipedes. Farnesyl 2,3-dihydrofarnesoate is a new compound, while himantarine and farnesyl farnesoate were not known as natural products. A post-secretion release of hydrogen cyanide by reaction of mandelonitrile and benzoyl nitrile was observed by NMR, and hydrogen cyanide signals were completely assigned. In addition, a protein component of the secretion was analysed by electrophoresis which revealed the presence of a major 55 kDa protein. Analyses of the defensive exudates of other geophilomorph families should produce further chemical surprises.

Jatrophane diterpenoids from the latex of Euphorbia dendroides and their anti-P-glycoprotein activity in human multi-drug resistant cancer cell lines.

Thirteen jatrophane diterpenoids (1-10, 13-15), three previously isolated (11, 12, 16) and a known tigliane (17) were isolated from the latex of Euphorbia dendroides. The structures and relative configurations of compounds were elucidated by spectroscopic techniques. The P-glycoprotein (P-gp) inhibiting activities of the representative set of jatrophanes (1-6 and 11-16) have been assessed. Jatrophanes 2 and 5 demonstrated the most powerful inhibition of P-gp, higher than R(+)-verapamil and tariquidar in colorectal multi-drug resistant (MDR) cells (DLD1-TxR).

New anti-cancer characteristics of jatrophane diterpenes from Euphorbia dendroides.

Jatrophane diterpenes were shown to be inhibitors of P-glycoprotein (P-gp). There are also evidences on their microtubule-interacting activity in cancer cells. We evaluated new anti-cancer characteristics of two jatrophane type compounds from Euphorbia dendroides. For that purpose, the model system of sensitive non-small cell lung cancer cell line (NCI-H460) and its resistant counterpart (NCI-H460/R) was used. Although both jatrophanes showed inhibitory effect on cancer cell growth, they were non-toxic for peripheral blood mononuclear cells (PBMC). We examined their effects in combination with paclitaxel (PTX), a well-known mitotic spindle interacting chemotherapeutic. Jatrophanes overcome PTX resistance in concentration-dependent manner in MDR cancer cell line (NCI-H460/R). We observed that this synergistic effect is not caused merely by P-gp inhibition. In combination with PTX, jatrophanes induce cell killing and change cell cycle distribution leading to G2/M arrest. Furthermore, they exert an anti-angiogenic effect by decreasing the vascular endothelial growth factor (VEGF) secretion. The reduction of the level of mdr1 mRNA expression in sensitive cells, suggests that these compounds could not contribute to the development of resistance. In conclusion, present study provides a rational basis for the new cancer treatment approach with jatrophanes that are non-toxic to normal cells and have new favorable anti-cancer characteristics.

Isolation and biological evaluation of jatrophane diterpenoids from Euphorbia dendroides.

From the Montenegrin spurge Euphorbia dendroides, seven new diterpenoids [jatrophanes (1-6) and a tigliane (7)] were isolated and their structures elucidated by spectroscopic techniques. The biological activity of the new compounds was studied against four human cancer cell lines. The most effective jatrophane-type compound (2) and its structurally closely related derivative (1) were evaluated for their interactions with paclitaxel and doxorubicin using a multi-drug-resistant cancer cell line. Both compounds exerted a strong reversal potential resulting from inhibition of P-glycoprotein transport.