ABSTRACT
Hybrid molecules are composed of two pharmacophores with different biological activities. Here, we conjugated phthalazine moieties (antiangiogenetic pharmacophore) and bis(hydroxymethyl)pyrrole moieties (DNA cross-linking agent) to form a series of bis(hydroxymethyl)pyrrolo[2,1- a]phthalazine hybrids. These conjugates were cytotoxic to a variety of cancer cell lines by inducing DNA damage, arresting cell cycle progression at the G2/M phase, triggering apoptosis, and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2) in endothelial cells. Among them, compound 29d encapsulated in a liposomal formulation (e.g., 29dL) significantly suppressed the growth of small-cell lung cancer cell (H526) xenografts in mice. Based on immunohistochemical staining, the tumor xenografts in mice treated with 29dL showed time-dependent decreases in the intensity of CD31, a marker of blood vessels, whereas the intensity of γ-H2AX, a marker of DNA damage, increased. The present data revealed that the conjugation of antiangiogenic and DNA-damaging agents can generate potential hybrid agents for cancer treatment.
Subject(s)
Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , DNA Damage/drug effects , Phthalazines/chemistry , Phthalazines/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Humans , Mice , Neovascularization, Pathologic/prevention & control , Phosphorylation , Phthalazines/chemical synthesis , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/drug effects , Vascular Endothelial Growth Factor Receptor-2/metabolism , Xenograft Model Antitumor AssaysABSTRACT
A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of ß-carboline (topoisomerase I/II inhibition) and bis(hydroxymethyl)pyrrole (DNA cross-linking) are synthesized for antitumor evaluation. Of tumor cell lines tested, small cell lung cancer (SCLC) cell lines are the most sensitive to the newly synthesized compounds. These hybrids induce cell cycle arrest at the G2/M phase, trigger tumor cell apoptotic death, and display diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Intriguingly, the substituent at N11 (H or Me) plays a critical role in modulating Topo II inhibition and DNA cross-linking activities. N11-Me derivatives predispose to induce DNA crosslinks, whereas N11-H derivatives potently inhibit Topo II. Computational analysis implicates that N11-Me restrict the torsion angles of the two adjacent OH on pyrrole resulting in a favorable of DNA cross-linking. Among these hybrids, compound 17a with N11-H is more effective than cisplatin and etoposide, but as potent as irinotecan, against the growth of SCLC H526 cells in xenograft model.
Subject(s)
DNA Topoisomerases, Type II/metabolism , DNA/metabolism , Drug Design , Indoles/chemical synthesis , Indoles/pharmacology , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/pathology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Humans , Indoles/chemistry , Indoles/metabolism , Mice , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/metabolism , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/metabolism , Topoisomerase II Inhibitors/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
We developed a facile synthesis to yield orthogonally protected mannose building blocks with high overall yields. The protection/glycosylation steps can be carried out in a successive manner without purification of intermediate products. This developed synthesis led to formation of linear/branched tri-, penta- and heptasaccharides.
Subject(s)
Monosaccharides/chemistry , Oligosaccharides/chemistry , Benzoic Acid/chemistry , Catalysis , Glycosylation , Hydrolysis , Oligosaccharides/chemical synthesis , Pyridines/chemistry , Sulfonic Acids/chemistryABSTRACT
Infecting about one-half of the global human population, Helicobacter pylori is well established as the primary cause of gastritis, duodenal ulcer, and gastric cancer. Currently there is no clear information regarding if and how host cells interact with H. pylori, and if such interactions are dependent on the type of gastric disease. Using fluorescently labeled fucose-containing glycoconjugates, we provide evidence observing both the uptake of L-fucose from gastric cancer cells to H. pylori and that human alpha-L-fucosidase 2 (FUCA2) is secreted only under coculture conditions (i.e., host cells infected with H. pylori). Upon depletion of FUCA2 by RNA interference and detection of translocated CagA (a virulence factor of H. pylori) in host cells, FUCA2 was found to be essential for H. pylori adhesion, in particular to the gastric cancer- and duodenal ulcer-specific strains. Additionally FUCA2 was shown to significantly enhance the expression of Lewis x antigen in H. pylori, which is critical for bacterial cell adhesion in the pathogenesis and defense strategy to escape host surveillance. These findings not only demonstrate an important connection between FUCA2 and the adhesion, growth, and pathogenicity of H. pylori, but also support the idea that FUCA2 is a potential target for clinical diagnosis and therapeutic intervention of H. pylori-related diseases.
Subject(s)
Fucose/metabolism , Helicobacter pylori/physiology , alpha-L-Fucosidase/metabolism , Adenocarcinoma/enzymology , Adenocarcinoma/microbiology , Adenocarcinoma/pathology , Amino Acid Sequence , Antigens, Bacterial/metabolism , Bacterial Proteins/metabolism , Cell Line , Cell Line, Tumor , Electrophoresis, Polyacrylamide Gel , Fucose/chemistry , Helicobacter pylori/metabolism , Host-Pathogen Interactions , Humans , Immunoblotting , Isoenzymes/genetics , Isoenzymes/metabolism , Kinetics , Lewis X Antigen/metabolism , Mass Spectrometry , Microscopy, Confocal , Molecular Sequence Data , Molecular Structure , RNA Interference , Sequence Homology, Amino Acid , Stomach Neoplasms/enzymology , Stomach Neoplasms/microbiology , Stomach Neoplasms/pathology , Substrate Specificity , alpha-L-Fucosidase/geneticsABSTRACT
Five new sesquiterpene lactones, spicatolides D-H (1-5), along with four known compounds, pitocarphin D (6), 8 alpha-acetoxy-10 alpha-hydroxy-13-O-methylhirsutinolide (7), spicatolide A (8), and 13-O-methylvernojalcanolide 8-O-acetate (9), were isolated from an ethyl acetate extract of the aerial parts of Pseudoelephantopus spicatus. The structures of the new compounds were elucidated on the basis of spectroscopic data interpretation. All of the compounds isolated were evaluated for their cytotoxic effects against five human cancer cell lines. Compounds 1, 3, and 4 showed cytotoxicity (IC50 < 5 micro g/mL) against the Hep3B and MCF-7 cancer cell lines.
Subject(s)
Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Asteraceae/chemistry , Lactones/isolation & purification , Lactones/pharmacology , Plants, Medicinal/chemistry , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Drug Screening Assays, Antitumor , Humans , Lactones/chemistry , Molecular Conformation , Molecular Structure , Sesquiterpenes/chemistry , TaiwanABSTRACT
Two new sesquiterpene lactones, spicatolide C (1) and spicatocadinanolide A (2), have been isolated along with the known piptocarphol isomers (3, 4) and one eudismane type sesquiterpene (5) from the EtOAc extract of the aerial parts of Pseudoelephantopus spicatus. The structures and the relative stereochemistries of the new metabolites were determined by spectroscopic methods.
Subject(s)
Asteraceae/chemistry , Lactones/chemistry , Plant Components, Aerial/chemistry , Plants, Medicinal/chemistry , Sesquiterpenes/chemistry , Lactones/isolation & purification , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Models, Molecular , Molecular Conformation , Reference Standards , Sesquiterpenes/isolation & purification , StereoisomerismABSTRACT
A novel anti-HIV alkaloid, drymaritin (1), and a new C-glycoside flavonoid, diandraflavone (2), along with eight known compounds, torosaflavone A, isovitexin, spinasterol beta-d-glycoside, p-hydroxybenzoic acid, p-hydroxybenzaldehyde, cis-p-coumarate, methyl 5-hydroxy-4-oxopentanoate, and glycerol-alpha-lignocerate, were isolated from Drymaria diandra. Drymaritin (1) exhibited anti-HIV effects in H9 lymphocytes with an EC(50) value of 0.699 microg/mL and a TI of 20.6. Compound 2 showed significantly selective inhibition on superoxide anion generation from human neutrophils stimulated by fMLP/CB with an IC(50) value of 10.0 microg/mL.
