Biomimetic Synthesis of Rhytidenone†A and Mode of Action of Cytotoxic Rhytidenone†F.

The rhytidenone family comprises spirobisnaphthalene natural products isolated from the mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of rhytidenone A was achieved by a Michael reaction/aldol/lactonization cascade in a single step from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F was investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ lead to the accumulation of p53, which is an essential tumor suppressor in humans. Consequently, the Fas-dependent signaling pathway is activated to initiate cellular apoptosis. These studies have identified the first small-molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development.

Identification of spirobisnaphthalene derivatives with anti-tumor activities from the endophytic fungus Rhytidhysteron rufulum AS21B.

The cultivation of the mangrove-derived fungus Rhytidhysteron rufulum AS21B in acidic condition changed its secondary metabolite profile. Investigation of the culture broth extract led to the isolation and identification of two new spirobisnaphthalenes (1 and 2) together with eleven known compounds (3-13) from the crude extract of the fungus grown under an acidic condition as well as six known compounds (4, 10, 14-17) were isolated from the crude extract of the fungus grown under a neutral condition. Their structures were elucidated on the basis of extensive spectroscopic data. The isolated compounds were evaluated for their cytotoxicity against two human cancer cell lines, Ramos lymphoma and drug resistant NSCLC H1975. Compounds 2 and 10 displayed the most promising anti-tumor activity against both cancer cell lines.

Bioactive prenylated xanthones from the young fruits and flowers of Garcinia cowa.

Five new xanthones, garciniacowones A-E (1-5), together with 14 known xanthones, 6-19, were isolated from the young fruits and fresh flowers of Garcinia cowa. The structures of 1-5 were elucidated by analysis of their 1D and 2D NMR spectra and mass spectrometric data. The compounds 1-19 were tested in vitro for their antimicrobial activity and for their ability to inhibit α-glucosidase. Compounds 16 and 17 showed the most potent α-glucosidase inhibitory activity, with IC50 values of 7.8 ± 0.5 and 8.7 ± 0.3 µM, respectively. Compounds 8, 9, and 19 showed antibacterial activity against Bacillus subtilis TISTR 088 with identical MIC values of 2 µg/mL, while 8, 10, and 19 exhibited antibacterial activity against Bacillus cereus TISTR 688 with identical MIC values of 4 µg/mL.

Synergistic impact of arbutin and kaempferol-7-O-α-L-rhamnopyranoside from Nephelium lappaceum L. on whitening efficacy and stability of cosmetic formulations.

Four flavonoid glycosides, namely quercetin-3-O-rhamnoside (1), kaempferol-3-O-ß-D-glucopyranosyl (2), kaempferol-7-O-α-L-rhamnopyranoside (3), and kaempferol-3-O-ß-D-glucopyranosyl-7-O-α-L-rhamnopyranoside (4), from Nephelium lappaceum L. seeds were evaluated for their efficacy against melanin inhibition in B16F10 melanoma cells and tyrosinase inhibition. Among them, kaempferol-7-O-α-L-rhamnopyranoside (3) displayed the highest potency in both activities without any significant cytotoxicity. The combination of compound 3 and arbutin in specific proportions demonstrated a synergistic effect (CI < 1) in inhibiting melanin production in B16F10 cells and tyrosinase inhibition. Additionally, a cosmetic formulation containing compound 3 and arbutin as active ingredients exhibited favorable stability under accelerated storage conditions. Quantitative analysis indicated that compound 3 and arbutin levels in the formulation were above 90% after one month of storage. Determination of the formulation's shelf life using the Q10 method, estimating it to be around 5.2 months from the date of manufacture. The synergy between arbutin and kaempferol-7-O-α-L-rhamnopyranoside (3) extracted from N. lappaceum substantially enhances both the whitening effectiveness and the stability of cosmetic formulations.

Inhibitory efficiency of Andrographis paniculata extract on viral multiplication and nitric oxide production.

Andrographis paniculata (Burm. F.) Nees is a medicinal plant previously reported with broad-spectrum antivirals but the mode of inhibition remains elusive. The objective of this study was to identify the most active fraction from A. paniculata ethanol extract (APE, APE-2A, APE-2B and APE-2C) and dry powder extract (APSP) against influenza A (H3N2), representing RNA viruses, and herpes simplex virus-1 (HSV-1), representing DNA viruses. The results showed that the fractions APSP, APE, APE-2B, and APE-2C directly neutralized the HSV-1 and influenza A (H3N2) when incubated at room temperature for 60 min before infecting the cells. The results also showed that the additional APE-2A fraction also directly neutralized the influenza A (H3N2), but not the HSV-1. The APE, APE-2B and APE-2C inhibited the HSV-1 by more than 0.5 log when the fractions were introduced after infection. Similarly, the APSP and APE inhibited the influenza A (H3N2) more than 0.5 log after infection. Only 50 µg/mL APE-2C inhibited the viruses greater than 0.5 log. In addition, A. paniculata extracts were also evaluated for their interfering capacities against nitric oxide (NO) production in LPS-activated RAW 264.7 macrophages. As well, APE-2C potently inhibited NO production at the IC50 of 6.08 µg/mL. HPLC and LC-MS analysis indicated that the most actively antiviral fractions did not contain any andrographolide derivatives, whereas the andrographolide-rich fractions showed moderate activity.

Kinetics of CBD, Δ9-THC Degradation and Cannabinol Formation in Cannabis Resin at Various Temperature and pH Conditions.

Introduction: Cannabidiol (CBD), cannabinol (CBN), and Δ9-tetrahydrocannabinol (Δ9-THC) are major cannabinoids in cannabis resin and products. The kinetic of the chemical reaction of resin cannabis is important for product development and storage. A few reports are available in the literature on the rate of CBD and Δ9-THC degradation, and CBN formation in dried resin and solutions of various pH. Materials and Methods: Thermal degradation of CBD, Δ9-THC, and formation of CBN was studied at 50°C, 60°C, 70°C, and 80°C for dried cannabis resin. The effect of pH and temperature on cannabinoids transformation in cannabis solution was also examined at pH 2, 4, 6, 8, 10, and 12 and at 40°C, 50°C, 60°C, and 70°C. High-performance chromatography coupled with diode-array detection (HPLC-DAD) was used for the analysis of CBD, CBN, and Δ9-THC transformation. The values of activation energies (Ea), shelf-life (t90% - t110%), and rate constant (k) were calculated for the CBD, Δ9-THC, and CBN. The effect of temperature and pH on the dried cannabis resin was adequately modeled with the Arrhenius equation. Results: The results indicated that the chemical kinetics in the thermal degradation of CBD, Δ9-THC, and formation of CBN were the zero-order, pseudo-zero-order, and first-order reactions, respectively, in cannabis resin. The first-order and pseudo-first-order degradation kinetics were evidenced for CBD and Δ9-THC, respectively, in cannabis solutions, whereas the zero-order formation kinetic was detected for the CBN. The transformation rate of the CBD, CBN, and Δ9-THC increased with increasing temperature, especially as temperature increased to 70°C at pH 2.0. The optimum pH for CBD stability was between pH 4 and 6, whereas the optimum pH for Δ9-THC stability was between pH 4 and 12. Conclusion: The major cannabinoids (CBD, CBN, and Δ9-THC) reacted more quickly at high temperature and in an acidic solution. Especially, the minimum transformation of CBD, CBN, and Δ9-THC was achieved by using on a low temperature, slightly to moderately acidic pH values, and short-time processing. These results may help to improve the storage condition of CBD, CBN, and Δ9-THC products and in the manufacturing process.

Absolute configuration of micromelin.

The title compound {systematic name: 7-meth-oxy-6-[(1R,2R,5R)-5-methyl-4-oxo-3,6-dioxabicyclo-[3.1.0]hexan-2-yl]-2H-chromen-2-one}, C(15)H(12)O(6), is a coumarin, which was isolated from the roots of Micromelum glanduliferum. There are two mol-ecules in the asymmetric unit with slight differences in bond angles. In both mol-ecules, the furan ring adopts a flattened envelope conformation. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions into chains along the a axis. Aromatic π-π stacking inter-actions with centroid-centroid distances in the range 3.6995 (11)-3.8069 (11) Šand C⋯O short contacts [3.030 (2)-3.171 (3) Å] also occur.

De novo synthesis, structural assignment and biological evaluation of pseudopaline, a metallophore produced by Pseudomonas aeruginosa.

Pseudopaline is an opine carboxylate metallophore produced by Pseudomonas aeruginosa for harvesting divalent metals. However, the structure of pseudopaline is not fully elucidated. Herein, we report the first de novo total synthesis and isolation of pseudopaline, which allows unambiguous determination and confirmation of both the absolute and the relative configuration of the natural product. The synthesis highlights an efficient and stereocontrolled route using the asymmetric Tsuji-Trost reaction as the key step. The preliminary structure-activity relationship study indicated that one pseudopaline derivative shows comparable activity to pseudopaline. Moreover, a pseudopaline-fluorescein conjugate was prepared and evaluated, which confirmed that pseudopaline could be transported in the bacteria. Since the metal acquisition by P. aeruginosa is crucial for its ability to cause diseases, our extensive structural and functional studies of pseudopaline may pave the way for developing new therapeutic strategies such as the "Trojan horse" antibiotic conjugate against P. aeruginosa.

Antibacterial dihydrobenzopyran and xanthone derivatives from Garcinia cowa stem barks.

Two new compounds, garciniacowol (1) and garciniacowone (2) along with 15 knowncompounds were isolated from the stem barks of Garcinia cowa. Their structures weredetermined by intensive spectroscopic methods. The structure of 1 was a symmetrical dimericdihydrobenzopyran derivative, whereas the framework of 2 was a triprenyl caged-xanthoneprecursor. The antibacterial activities against Escherichia coli TISTR 780, Salmonellatyphimurium TISTR 292, Staphylococcus aureus TISTR 1466, and methicillin-resistant S. aureus(MRSA) SK1 of the isolated compounds were also evaluated. Compounds 2 and 9 exhibitedgood antibacterial activity against MRSA SK1 with the same minimum inhibitory concentration(MIC) value of 2 µg/mL. Moreover, compound 2 also showed good antibacterial activityagainst S. aureus with an MIC value of 2 µg/mL.