Anti-inflammatory dihydroxanthones from a Diaporthe species.

In a search for anti-inflammatory compounds from fungi inhibiting the promoter activity of the small chemokine CXCL10 (Interferon-inducible protein 10, IP-10) as a pro-inflammatory marker gene, the new dihydroxanthone methyl (1R, 2R)-1,2,8-trihydroxy-6-(hydroxymethyl)-9-oxo-2,9-dihydro-1H-xanthene-1-carboxylate (2) and the previously described dihydroxanthone AGI-B4 (1) were isolated from fermentations of a Diaporthe species. The structures of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy, mass spectrometry, and calculations using density functional theory (DFT). Compounds 1 and 2 inhibited the LPS/IFNγ induced CXCL10 promoter activity in transiently transfected human MonoMac6 cells in a dose-dependent manner with IC50 values of 4.1 µM (±0.2 µM) and 1.0 µM (±0.06 µM) respectively. Moreover, compounds 1 and 2 reduced mRNA levels and synthesis of pro-inflammatory mediators such as cytokines and chemokines in LPS/IFNγ stimulated MonoMac6 cells by interfering with the Stat1 and NFκB pathway.

Xylochemical Synthesis and Biological Evaluation of Shancigusin C and Bletistrin G.

The biological activities of shancigusin C (1) and bletistrin G (2), natural products isolated from orchids, are reported along with their first total syntheses. The total synthesis of shancigusin C (1) was conducted by employing the Perkin reaction to forge the central stilbene core, whereas the synthesis of bletistrin G (2) was achieved by the Wittig olefination followed by several regioselective aromatic substitution reactions. Both syntheses were completed by applying only renewable starting materials according to the principles of xylochemistry. The cytotoxic properties of shancigusin C (1) and bletistrin G (2) against tumor cells suggest suitability as a starting point for further structural variation.

Total Synthesis of epi-Trichosetin.

The natural 3-decalinoyltetramic acid epi-trichosetin was synthesized in ten steps starting from ( R)-(+)-citronellal using an intramolecular Diels-Alder reaction and a Lacey-Dieckmann cyclization as the key steps. The use of a 2-nitrobenzyl protecting group resulted in an efficient synthetic endgame. The natural product was obtained in 4.1% overall yield.

Total Synthesis of (-)-Hymenosetin.

The 3-decalinoyltetramic acid (-)-hymenosetin and its N-methyl analogue were prepared in 11 and 8 steps, respectively, from (+)-citronellal using an intramolecular Diels-Alder reaction as the key step. This method represents the first example for the synthesis of a 3-decalinoyltetramic acid with a free NH moiety. The stereochemistry of the title compound, an unnatural diastereomer, and of a decalin building block was studied in detail using circular dichroism spectroscopy in the IR and UV/VIS freqeuncy range. This allowed to determine the absolute configuration of the natural product and to plan the synthetic route.

Marine Isonitriles and Their Related Compounds.

Marine isonitriles represent the largest group of natural products carrying the remarkable isocyanide moiety. Together with marine isothiocyanates and formamides, which originate from the same biosynthetic pathways, they offer diverse biological activities and in spite of their exotic nature they may constitute potential lead structures for pharmaceutical development. Among other biological activities, several marine isonitriles show antimalarial, antitubercular, antifouling and antiplasmodial effects. In contrast to terrestrial isonitriles, which are mostly derived from α-amino acids, the vast majority of marine representatives are of terpenoid origin. An overview of all known marine isonitriles and their congeners will be given and their biological and chemical aspects will be discussed.

Identification of NF-κB as Determinant of Posttraumatic Stress Disorder and Its Inhibition by the Chinese Herbal Remedy Free and Easy Wanderer.

Posttraumatic stress disorder (PTSD) is a mental disorder developing after exposure to traumatic events. Although psychotherapy reveals some therapeutic effectiveness, clinically sustainable cure is still uncertain. Some Chinese herbal formulae are reported to work well clinically against mental diseases in Asian countries, but the safety and their mode of action are still unclear. In this study, we investigated the mechanisms of Chinese remedy free and easy wanderer (FAEW) on PTSD. We used a reverse pharmacology approach combining clinical data to search for mechanisms of PTSD with subsequent in vitro verification and bioinformatics techniques as follows: (1) by analyzing microarray-based transcriptome-wide mRNA expression profiling of PTSD patients; (2) by investigating the effect of FAEW and the antidepressant control drug fluoxetine on the transcription factor NF-κB using reporter cell assays and western blotting; (3) by performing molecular docking and literature data mining based on phytochemical constituents of FAEW. The results suggest an involvement of inflammatory processes mediated through NF-κB in the progression of PTSD. FAEW was non-cytotoxic in vitro and inhibited NF-κB activity and p65 protein expression. FAEW's anti-inflammatory compounds, i.e., paeoniflorin, isoliquiritin, isoliquiritin apioside and ononin were evaluated for binding to IκK and p65-RelA in a molecular docking approach. Paeoniflorin, albiflorin, baicalin, isoliquiritin and liquiritin have been reported to relieve depression in vivo or in clinical trials, which might be the active ingredients for FAEW against PTSD.

The Chinese herbal formula Free and Easy Wanderer ameliorates oxidative stress through KEAP1-NRF2/HO-1 pathway.

Posttraumatic stress disorder (PTSD) gains a lot of attention due to high prevalence and strong psychological upset, but the etiology remains undefined and effective treatment is quite limited. Growing studies demonstrated the involvement of oxidative stress in various psychiatry diseases, suggesting anti-oxidation therapy might be a strategy for PTSD treatment. Free and Easy Wanderer (FAEW) is a poly-herbal drug clinically used in China for hundreds of years in the treatment of psychiatric disorder. We hypothesized that FAEW exerts clinical effects through the activity against oxidative stress with fluoxetine as antidepressant control drug. Our results revealed that FAEW significantly reduced both endogenous and H2O2-induced exogenous ROS levels in the human glioblastoma T98G and neuroblastoma SH-SY5Y cell lines. Transcriptome-wide microarray analysis indicated NRF2/HO-1 as the common target of FAEW and fluoxetine. Western blotting assay proved that the two drugs promoted NRF2 release from KEAP1 in the cytoplasm and translocation to the nuclei in a KEAP1-dependent manner, the expression of the protein HO-1 increased accordingly, suggesting the participation of KEAP1-NRF2/HO-1 pathway. The chemical constituents of FAEW (i.e. paeoniflorin, baicalin) bound to KEAP1 in silico, which hence might be the effective substances of FAEW. In conclusion, FAEW counteracted H2O2-induced oxidative stress through KEAP1-NRF2/HO-1 pathway.