ABSTRACT
Biogenesis-inspired chemical research of the leaves of Taiwania cryptomerioides afforded four unprecedented dimeric diterpenes, featuring a tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane core: taiwanoids A-D (1-4). The structures of these compounds were determined on the basis of comprehensive spectral analysis, chemical conversions and X-ray crystallography. A possible biosynthetic pathway for compounds 1-4 was proposed. Compounds 2 and 3 exerted a 5.37 and 6.26-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration of 20 µM, respectively.
Subject(s)
Abietanes/chemistry , Cupressaceae/chemistry , Abietanes/pharmacology , Antineoplastic Agents/pharmacology , Bortezomib/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Dimerization , Drug Resistance, Neoplasm/drug effects , Humans , Models, Molecular , Neoplasms/drug therapy , Plant Extracts/chemistry , Plant Extracts/pharmacologyABSTRACT
A new method based on ligand fishing combined with high-performance liquid chromatography quadrupole-time-of-flight mass spectrometer and molecular docking was established to screen α-glucosidase inhibitors from a traditional Chinese medicine Morus alba root bark. α-Glucosidase was immobilized on magnetic nanoparticles, used as a solid support to incubate with crude extract. After ligand fishing, the eluates were analyzed by high-performance liquid chromatography quadrupole-time-of-flight mass spectrometer, obtaining eleven ligands (1-4, 6-12) eventually. In order to discriminate the non-specific binders and discover powerful enzyme inhibitors, molecular docking was further performed and three of the eleven ligands were optimized to be excellent α-glucosidase inhibitors by the confirmation of isolation and bioassay of individual compounds. These three ligands, sanggenons G (6), O (7) and sanggenol G (12) exhibited striking inhibitory activities with extremely low IC50 values. The results suggest that established method will be applied to a wide range of target protein to screen potential bioactive constituents from herbal medicines.
Subject(s)
Drug Evaluation, Preclinical/methods , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Morus/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Chromatography, High Pressure Liquid/methods , Enzyme Assays/methods , Enzymes, Immobilized/metabolism , Ligands , Magnetite Nanoparticles/chemistry , Molecular Docking Simulation , Plant Bark/chemistry , Plant Roots/chemistry , Saccharomyces cerevisiae/enzymology , Tandem Mass Spectrometry/methods , alpha-Glucosidases/metabolismABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is a well-known antitumor target. Exogenous ROS insult can lead to selective cytotoxicity against cancer cells. A combination of STAT3 inhibition and "oxidation therapy" may be a new strategy to address the multidrug-resistance issue due to their important roles in the survival and drug resistance of cancer cells. Here, a series of novel curcumin-BTP hybrids were designed and evaluated as STAT3 inhibitors with ROS production activity. Compound 6b exerted the best antitumor activity and selectivity for MCF-7 and MCF-7/DOX cells (IC50 = 0.52 µM and 0.40 µM, respectively), while its IC50 value for MCF-10A breast epithelial cells was 7.72 µM. Furthermore, compound 6b suppressed STAT3 phosphorylation, nuclear translocation and DNA-binding activity and the expression of STAT3 specific oncogenes. Increases in the level of IL-6-induced p-STAT3 were also inhibited by 6b without influencing IFN-γ-induced p-STAT1 expression. Additionally, 6b effectively promoted intracellular ROS accumulation, induced cancer cell apoptosis and cell cycle arrest, abolished the colony formation ability of breast cancer cells, and inhibited P-gp expression in MCF-7/DOX cells. Finally, 6b suppressed the growth of implanted human breast cancer in vivo. Our findings highlight that 6b may be a promising therapeutic agent for drug-sensitive and drug-resistant breast cancers.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzyl Compounds/chemistry , Benzyl Compounds/pharmacology , Curcumin/chemistry , Curcumin/pharmacology , Drug Resistance, Neoplasm/drug effects , STAT3 Transcription Factor/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Benzyl Compounds/chemical synthesis , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Curcumin/chemical synthesis , Disease Models, Animal , Drug Design , Drug Resistance, Neoplasm/genetics , Female , Humans , MCF-7 Cells , Mice , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Phosphorylation/drug effects , Protein Binding , Protein Transport/drug effects , Reactive Oxygen Species , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Two new seco-prezizaane-type sesquiterpenes, 3,4-dehydroneomajucin (1) and 1,2,3,4-tetradehydroneomajucin (2), were isolated from the fruits of Illicium jiadifengpi. The structure of these compounds was determined using 1D and 2D NMR and ESI-MS. The isolates were evaluated for their anti-hepatitis B virus activities on the Hep G2.2.15 cell line. The inhibitory rates of compounds 1 and 2 on the HBeAg and HBsAg expression were 30.08 ± 3.09% and 11.43 ± 1.92% at a concentrations of 68.00 µM and 7.88 ± 1.21% and 16.96 ± 4.24% at a concentration of 68.50 µM, respectively.
Subject(s)
Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Illicium/chemistry , Sesquiterpenes/chemistry , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Fruit/chemistry , Hep G2 Cells/drug effects , Hep G2 Cells/virology , Humans , Lactones/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Spectrometry, Mass, Electrospray IonizationABSTRACT
A multi-channel counter-current chromatography (CCC) method has been designed and fabricated for the high-throughput fractionation of natural products without complications sometimes encountered with other conventional chromatographic systems, such as irreversible adsorptive constituent losses and deactivation, tailing of solute peaks and contamination. It has multiple independent CCC channels and each channel connects independent separation column(s) by parallel flow tubes, and thus the multi-channel CCC apparatus can achieve simultaneously two or more independent chromatographic processes. Furthermore, a high-throughput CCC fractionation method for natural products has been developed by a combination of a new three-channel CCC apparatus and conventional parallel chromatographic devices including pumps, sample injectors, effluent detectors and collectors, and its performance has been displayed on the fractionation of ethyl acetate extracts of three natural materials Solidago canadensis, Suillus placidus, and Trichosanthes kirilowii, which are found to be potent cytotoxic to tumor cell lines in the course of screening the antitumor candidates. By combination of biological screening programs and preparative high-performance liquid chromatography (HPLC) purification, 22.8 mg 6 beta-angeloyloxykolavenic acid and 29.4 mg 6 beta-tigloyloxykolavenic acid for S. canadensis, 25.3mg suillin for S. placidus, and 6.8 mg 23,24-dihydrocucurbitacin B for T. Kirilowii as their major cytotoxic principles were isolated from each 1000 mg crude ethyl acetate extract. Their chemical structures were characterized by electrospray ionization mass spectrometry, one- and two-dimensional nuclear magnetic resonance. The overall results indicate the multi-channel CCC is very useful for high-throughput fractionation of natural products for drug discovery in spite of the solvent balancing requirement and the lower resolution of the shorter CCC columns.