ABSTRACT
Ovarian carcinoma remains the most lethal among gynecological cancers. Chemoresistance is a clinical problem that severely limits treatment success. To identify potent anticancer agents against the cisplatin-resistant human ovarian cancer cell line A2780/Cis, 26 polyphenols bearing a cinnamaldehyde scaffold were synthesized. Structural differences in their inhibitory effect on clonogenicity of A2780/Cis cells were elucidated using comparative molecular field analysis and comparative molecular similarity indices analysis. Structural conditions required for increased inhibitory activity can be derived based on the analysis of their contour maps. The two most active compounds (16 and 19) were selected and further characterized their biological activities. We found that compounds 16 and 19 trigger cell cycle arrest at the G2/M phase and apoptotic cell death in cisplatin-resistant A2780/Cis human ovarian cancer cells. The molecular mechanism of compound 16 was elucidated using in vitro aurora A kinase assay, and the binding mode between the compound 16 and aurora A kinase was interpreted using in silico docking experiments. The findings obtained here may help us develop novel plant-derived polyphenols used for potent chemotherapeutic agents. In conclusion, compounds 16 and 19 could be used as promising lead compounds for the development of novel anticancer therapies in the treatment of cisplatin-resistant ovarian cancers.
Subject(s)
Acrolein/analogs & derivatives , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Ovarian Neoplasms/drug therapy , Polyphenols/pharmacology , Acrolein/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Molecular Structure , Ovarian Neoplasms/pathology , Polyphenols/chemical synthesis , Polyphenols/chemistry , Structure-Activity RelationshipABSTRACT
Colorectal cancer is the third and fourth leading cause of cancer in males and females, respectively. Flavonoids, including chalcones, are secondary metabolites in plants that exhibit diverse biological activities, including antibacterial, antimalarial, and antitumor activities. In order to find potent and novel chemotherapy drugs for colorectal cancer, a series of benzochalcone derivatives, in which an α,ß-unsaturated carbonyl group was replaced with a pyrazoline, was designed and synthesized. A clonogenic survival assay was performed with each derivative to evaluate antitumor activity. 1-(5-(2,4-Dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)naphthalen-2-ol (derivative 7) had the most potent inhibitory effect on the long-term clonogenicity of HCT116 human colorectal cancer cells (IC50=2.4 µM). The results of Western blot and flow cytometric analyses suggested that derivative 7 could inhibit the proliferation of colorectal cancer cells through inhibition of cell cycle progression and induction of apoptosis. To elucidate its molecular mechanism, in vitro kinase binding assays were carried out, which demonstrated that derivative 7 inhibited aurora kinases A and B selectively. The binding modes between the compound and aurora kinases were interpreted using in silico docking experiments to explain the selective inhibitory effects on aurora kinases A and B. These findings will facilitate the design of potent novel benzochalcones as anticancer agents.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aurora Kinases/antagonists & inhibitors , Chalcones/chemistry , Chalcones/pharmacology , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Aurora Kinases/metabolism , Binding Sites , Chalcones/therapeutic use , Colorectal Neoplasms/drug therapy , Enzyme Activation/drug effects , HCT116 Cells , Humans , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Structure, TertiaryABSTRACT
To find potent new chemotherapy drugs, we designed and synthesized a series of naphthochalcones bearing naphthalenyl-phenyl-pyrazoline moieties. The complete (1)H and (13)C NMR data for these compounds are reported here and can be used to identify further new naphthochalcones bearing the desired pyrazoline moieties.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/chemical synthesis , Chalcones/chemistry , Chalcones/chemical synthesis , Pyrazoles/chemistry , Antineoplastic Combined Chemotherapy Protocols/chemistry , Carbon Isotopes , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Protons , Reference StandardsABSTRACT
Chalcones are of interest to medicinal chemists because their structures can be easily modified with various functional groups. The syntheses and biological activities of chalcones from natural sources are well known. In this study, 24 2'-hydroxychalcones bearing methoxy substituents were synthesized, among which five are new. The NMR data for all synthesized chalcones are described for the first time. The complete assignments of the (1)H and (13)C NMR data can be used for the identification of newly discovered and widely isolated, synthesized chalcones.
Subject(s)
Chalcones/chemistry , Carbon Isotopes , Magnetic Resonance Spectroscopy/standards , Protons , Reference StandardsABSTRACT
Mast cells are primarily responsible for IgE-mediated allergic responses. The activation level of mast cells is reflected in their degree of degranulation. This can in turn be determined by measuring the amount of ß-hexosaminidase release, a key parameter in degranulation. In this study, 40 flavone derivatives, including flavone, 14 methoxyflavones, 13 hydroxyflavones, and 12 hydroxymethoxyflavones, were evaluated for their inhibition of degranulation in rat basophilic leukemia RBL-2H3 cells. 3',7-Dihydroxyflavone inhibited degranulation (IC(50) = 13.56 µM), which was comparable to PP2 (3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) used as a control. In addition, we report quantitative relationships between the structural properties of flavones and their inhibitory effects on degranulation.
Subject(s)
Antigens/metabolism , Flavones/pharmacology , Mast Cells/drug effects , Animals , Binding Sites , Cell Degranulation/drug effects , Cell Line, Tumor , Flavones/chemistry , Hydrogen Bonding , Immunoglobulin E/immunology , Mast Cells/physiology , Rats , Structure-Activity Relationship , beta-N-Acetylhexosaminidases/metabolismABSTRACT
Several types of chalcones containing 2H-chromen group were synthesized. Claisen-Schmidt condensation of 2H-chromen-3-carbaldehydes (I) with methoxy substituted acetophenones afforded (E)-3-(2H-chromen-3-yl)-1-(methoxyphenyl)prop-2-en-1-ones (chromenylchalcones, 1-7). Other types of chromenylchalcone, (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(methoxyphenyl)prop-2-en-1-ones (8-13) were also obtained between reaction of methoxy substituted benzaldehydes and 1-(6-methoxy-2H-chromen-3-yl)ethanone (II). Dichromenylchalcones (14-16) were also synthesized through the same reaction between aldehydes (I) and ketone (II). Their complete (1)H-NMR and (13)C-NMR assignments are reported here and more polysubstituted chromenylchalcones synthesized or isolated from the natural sources in the future can be identified on the basis of the NMR data reported here.
Subject(s)
Chalcones/chemistry , Carbon Isotopes , Chalcones/chemical synthesis , Chalcones/isolation & purification , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Protons , Reference StandardsABSTRACT
A phytotoxic root exudate from Acroptilon repens was identified as 7,8-benzoflavone, an inhibitor of cytochrome P450 1A2 and activator of cytochrome P450 3A4. The synthetic 5,6-benzoflavone also is a potent phytotoxin. Six 7,8-benzoflavones and eight 5,6-benzoflavones were synthesized in this study. The NMR data for a few of these compounds have been previously reported; however, the NMR data for most of them have not been reported. For reference purposes, the complete NMR data for the 14 benzoflavones are described.
Subject(s)
Benzoflavones/chemical synthesis , Benzoflavones/chemistry , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Reference StandardsABSTRACT
A toxin produced by Pseudomonas tolaasii, tolaasin, causes brown blotch disease in mushrooms. Tolaasin forms pores on the cellular membrane and destroys cell structure. Inhibiting the ability of tolaasin to form ion channels may be an effective method to protect against attack by tolaasin. However, it is first necessary to elucidate the three-dimensional structure of the ion channels formed by tolaasin. In this study, the structure of the tolaasin ion channel was determined in silico based on data obtained from nuclear magnetic resonance experiments.
Subject(s)
Bacterial Proteins/chemistry , Bacterial Toxins/chemistry , Depsipeptides/chemistry , Ion Channels/chemistry , Pseudomonas/metabolism , Amino Acid Sequence , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Bacterial Toxins/genetics , Bacterial Toxins/metabolism , Depsipeptides/genetics , Depsipeptides/metabolism , Ion Channels/genetics , Ion Channels/metabolism , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Sequence Data , Pseudomonas/chemistry , Pseudomonas/geneticsABSTRACT
Schizandra chinensis has been known to have five predominant tastes: salty, sweet, sour, astringent, and bitter. It has also been shown to have various effects on the cardiovascular system, gastrointestinal system, anti-inflammatory, central nervous system, endocrine system, and stress protect. However, its anti-cancer activity on colon carcinoma HCT-116 cells has not been yet been examined. Thus, in this study, we attempted to isolate a compound from Schisandra chinensis that induced apoptosis in HCT-116 cells. An active compound was found and identified to be Gomisin A. It displayed apoptotic activity through caspase-7 cleavage in colon carcinoma HCT-116 cells. In addition, we further assessed the effects of this compound using long-term survival clonogenic assay with HCT116 cells.
Subject(s)
Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cyclooctanes/isolation & purification , Cyclooctanes/pharmacology , Dioxoles/isolation & purification , Dioxoles/pharmacology , Lignans/isolation & purification , Lignans/pharmacology , Schisandra/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Caspase 7/metabolism , Colonic Neoplasms/drug therapy , Cyclooctanes/chemistry , Dioxoles/chemistry , HCT116 Cells , Humans , Lignans/chemistryABSTRACT
Resveratrol is a polyphenol isolated from many natural sources including grapes, mulberries, eucalyptus, spruce, lilies, and peanuts. The hydroxyl groups in polyphenols can be substituted with various functional groups, allowing production of multiple derivatives. NMR spectroscopy is used to identify new derivatives. Since the complete NMR data of the known derivatives can be useful for identification of the newly isolated derivatives, here, we report the synthesis of 14 methoxylated stilbenes and four 1,2-diphenylethanes and their NMR data.
Subject(s)
Stilbenes/chemistry , Stilbenes/chemical synthesis , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Reference Standards , StereoisomerismABSTRACT
Chalcones, intermediates in flavonoid biosynthesis, can exhibit antibacterial, antiproliferative, and anti-inflammatory properties. Chalcones contain two benzene rings and both hydroxylated and methoxylated analogs are frequently produced by hydroxylases and O-methyltransferases in plant biosynthetic pathways. Assignments of NMR peaks in the spectra of hydroxylated and/or methoxylated chalcones can help in identifying novel chalcone derivatives isolated from natural sources by referencing these data against NMR spectra obtained from known chalcones. We report here the syntheses of 20 chalcones and complete assignments of (1)H and (13)C NMR spectra.
Subject(s)
Chalcones/chemistry , Chalcones/chemical synthesis , Carbon Isotopes , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Protons , Reference Standards , StereoisomerismABSTRACT
Even hydroxyflavones show diverse biological functions, they have two common features such as showing antioxidative effects and containing hydroxyl groups. The authors tested the antioxidative effects of thirty hydroxyflavones using 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. While the scavenging activity of galangin, 3,5,7-trihydroxyflavone was 52.5%, fisetin, 3,7,3',4'-tetrahydroxyflavone showed 85.2%. To investigate the relationships between the structures of hydroxyflavones and their antioxidative effects, the three-dimensional quantitative structure-activity relationships were examined.