lignans and coumarin

The topoisomerase enzymes play an important role in DNA metabolism, and searching for enzyme inhibitors is an important target in the search for new anticancer drugs. Discovery of new anticancer chemotherapeutical capable of inhibiting topoisomerase enzymes is highlighted in anticancer research. Therefore, biologists, organic chemists and medicinal chemists all around the world have been identifying, designing, synthesizing and evaluating a variety of novel bioactive molecules targeting topoisomerase. This review summarizes types of topoisomerase inhibitors in the past decade, and divides them into nine classes by structural characteristics, including N-heterocycles compounds, quinone derivatives, flavonoids derivatives, coumarin derivatives, lignan derivatives, polyphenol derivatives, diterpenes derivatives, fatty acids derivatives, and metal complexes. Then we discussed the application prospect and development of these anticancer compounds, as well as concluded parts of their structural-activity relationships. We believe this review would be invaluable in helping to further search potential topoisomerase inhibition as antitumor agent in clinical usage.

Topics: Coumarins; Diterpenes; DNA Topoisomerases; Fatty Acids; Flavonoids; Heterocyclic Compounds; Humans; Lignans; Organometallic Compounds; Polyphenols; Quinones; Topoisomerase Inhibitors

Suppression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) along with nitric oxide reduction in RAW 264.7 cells by 7,8-dihydroxy-4-methylcoumarin, ethyl p-coumarate, ethyl caffeate and ethyl ferulate drove us to search structural-analogues of the aforementioned compounds through structure-based drug design. Docking studies revealed that substituted cinnamic acids and their ethyl esters (2-7c) showed higher GoldScore-fitness (GSF) and non-bonding interactions with target proteins than 7,8-dihydroxy-4-methylcoumarin (1a) and 7,8-dihydroxy-5-methylcoumarin (1b). With this background, the methylcoumarins (1a and 1b) and the cinnamic acid derivatives (2-7c) were fused in different permutations and combinations to generate sixty novel fused-cyclic coumarinolignans (FCLs) (8-13k). Docking studies on 8-13k indicated that several FCLs possess higher GSF, interesting active site interactions and distinctive π-π interactions compared to the standards (cleomiscosin A, diclofenac Na and prednisolone). Based on these findings, four novel FCLs (9d, 10d, 11d and 11e) were synthesized and tested for inhibition effect on TNF-α, IL-1β and IL-6 expressions in LPS and oxalate crystal-induced in-vitro models. Compound 10d exhibited significant effect (P < 0.0001 at 100 μM) with an IC

Topics: Animals; Anti-Inflammatory Agents; Binding Sites; Coumarins; Drug Design; Interleukin-1beta; Interleukin-6; Lignans; Lipopolysaccharides; Macrophages; Mice; Molecular Docking Simulation; NF-kappa B; Nitric Oxide; Protein Structure, Tertiary; RAW 264.7 Cells; Signal Transduction; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Genkwa Flos, a famous traditional Chinese medicine has been reported to have significant hepatotoxicity. A high-throughput and reliable method was established to explore potential toxic components by high-performance liquid chromatography coupled with a Q Exactive high-performance benchtop quadrupole-Orbitrap mass spectrometer. A total of 68 compounds including 22 chemical components and 46 metabolites were tentatively identified based on the accurately measured mass value, retention time, and fragmentation pattern. Besides, the metabolic pathways of main components in Genkwa Flos were also illustrated. The results indicated that hydroxylation, demethylation, methylation, glucuronidation, sulfation, cysteine conjugation, and glutathione conjugation participated in the metabolic reactions of Genkwa Flos. Moreover, 12 Genkwa Flos chemical components and 26 metabolites were detected in cell lysate, which were considered as the bound components to HL-7702 cells. In view of cell affinity theory, these compounds were preliminarily deduced to be potential toxic ingredients for the hepatotoxicity induced by Genkwa Flos. The results demonstrated that the developed method was a very feasible and efficient approach for the components identification even in the complex matrix. In conclusion, this study will provide a deep insight into the toxic substances of Genkwa Flos and lay a chemical basis for in-depth toxic studies on Genkwa Flos hepatotoxicity.

Topics: Animals; Cell Survival; Cells, Cultured; Chromatography, High Pressure Liquid; Coumarins; Diterpenes; Drugs, Chinese Herbal; Flavonoids; Glycosides; Humans; Lignans; Male; Mass Spectrometry; Medicine, Chinese Traditional; Molecular Structure; Rats; Rats, Sprague-Dawley

Topics: Amides; Apigenin; Benzodioxoles; Catechin; Chromatography, High Pressure Liquid; Coumarins; Dioxoles; Flavonoids; Furans; Hesperidin; Hydroxybenzoates; Lignans; Limit of Detection; Plant Leaves; Powders; Reproducibility of Results; Seasons; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Zanthoxylum

Herbal products have been widely used, and the safety of herb-drug interactions has aroused intensive concerns. This study aimed to investigate the effects of phytochemicals on the catalytic activities of human CYP2D6(*)1 and CYP2D6(*)10 in vitro.. HepG2 cells were stably transfected with CYP2D6(*)1 and CYP2D6(*)10 expression vectors. The metabolic kinetics of the enzymes was studied using HPLC and fluorimetry.. HepG2-CYP2D6(*)1 and HepG2-CYP2D6(*)10 cell lines were successfully constructed. Among the 63 phytochemicals screened, 6 compounds, including coptisine sulfate, bilobalide, schizandrin B, luteolin, schizandrin A and puerarin, at 100 μmol/L inhibited CYP2D6(*)1- and CYP2D6(*)10-mediated O-demethylation of a coumarin compound AMMC by more than 50%. Furthermore, the inhibition by these compounds was dose-dependent. Eadie-Hofstee plots demonstrated that these compounds competitively inhibited CYP2D6(*)1 and CYP2D6(*)10. However, their Ki values for CYP2D6(*)1 and CYP2D6(*)10 were very close, suggesting that genotype-dependent herb-drug inhibition was similar between the two variants.. Six phytochemicals inhibit CYP2D6(*)1 and CYP2D6(*)10-mediated catalytic activities in a dose-dependent manner in vitro. Thus herbal products containing these phytochemicals may inhibit the in vivo metabolism of co-administered drugs whose primary route of elimination is CYP2D6.

Topics: Berberine; Cell Line, Tumor; Chromatography, High Pressure Liquid; Coumarins; Cyclooctanes; Cyclopentanes; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Furans; Ginkgolides; Hep G2 Cells; Humans; Isoflavones; Kinetics; Lignans; Luteolin; Phytochemicals; Polycyclic Compounds

Three new lignans, erythro-strebluslignanol (1), threo-7'-methoxyl strebluslignanol (2) and erythro-7'-methoxyl strebluslignanol (3), together with twelve known compounds were isolated from the n-butanol and chloroform fractions of the heartwood of Streblus asper. Their structures were elucidated through extensive spectroscopic methods, including MS and 2D NMR experiments (HMQC and HMBC). The stereochemistry at the chiral center was determined using CD spectra, as well as analysis of coupling constants and optical rotation data, respectively. Primary bioassays showed that 6-hydroxyl-7-methoxyl-coumarin (5) and ursolic acid (10) showed anti-HBV activities, with IC(50) values of 29.60 μM and 89.91 μM for HBsAg at no cytotoxicity, and IC(50) values of 46.41 μM and 97.61 μM for HBeAg at no cytotoxicity, respectively.

Topics: Antiviral Agents; Biological Assay; Biphenyl Compounds; Cell Line; Cell Survival; Coumarins; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Inhibitory Concentration 50; Lignans; Moraceae; Plant Extracts; Triterpenes; Ursolic Acid; Wood