citrusinine-i and acridone

A new flavonoid, atalantraflavone (1) as well as eight known compounds including atalantoflavone (2), racemoflavone (3), 5,4'-dihydroxy-(3″,4″-dihydro-3″,4″-dihydroxy)-2″,2″-dimethylpyrano-(5″,6″:7,8)-flavone (4), lupalbigenin (5), anabellamide (6), citrusinine I (7), p-hydroxybenzaldehyde (8), and frideline (9), were isolated from the leaves of Atalantia monophylla (L.) DC. Focusing on Alzheimer's disease, acetylcholine esterase (AChE) inhibition and antioxidant activity were evaluated using the modified Ellman's method and the ABTS scavenging assay, respectively. It was found that isoflavonoid 5, lupalbigenin, showed 79% inhibition to AChE and was 1.4-fold stronger than the tacrine standard. In addition, acridone 7, citrusinine I, displayed 90.68% antioxidant activity.

Topics: Acridones; Alkaloids; Antioxidants; Cholinesterase Inhibitors; Drug Evaluation, Preclinical; Flavonoids; Isoflavones; Magnetic Resonance Spectroscopy; Molecular Structure; Plant Extracts; Plant Leaves; Rutaceae

Cathepsin V is a lysosomal cysteine peptidase highly expressed in thymus, testis and corneal epithelium. Eleven acridone alkaloids were isolated from Swinglea glutinosa (Bl.) Merr. (Rutaceae), with eight of them being identified as potent and reversible inhibitors of cathepsin V (IC(50) values ranging from 1.2 to 3.9 μM). Detailed mechanistic characterization of the effects of these compounds on the cathepsin V-catalyzed reaction showed clear competitive inhibition with respect to substrate, with dissociation constants (K(i)) in the low micromolar range (2, K(i)=1.2 μM; 6, K(i)=1.0 μM; 7, K(i)=0.2 μM; and 11, K(i)=1.7 μM). Molecular modeling studies provided important insight into the structural basis for binding affinity and enzyme inhibition. Experimental and computational approaches, including biological evaluation, mode of action assessment and modeling studies were successfully employed in the discovery of a small series of acridone alkaloid derivatives as competitive inhibitors of catV. The most potent inhibitor (7) has a K(i) value of 200 nM.

Topics: Acridines; Acridones; Alkaloids; Cathepsins; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Humans; Kinetics; Models, Molecular; Molecular Structure; Structure-Activity Relationship

Two new tetranortriterpenoids, 7-isovaleroylcycloseverinolide (1) and 7-isovaleroylcycloepiatalantin (2), together with 28 known compounds, were isolated and characterized from the root bark of Severinia buxifolia collected in Hainan. The structures of 1 and 2 were elucidated on the basis of spectral evidence including 2D NMR and X-ray techniques. The cytotoxicity of several acridone alkaloid isolates (3-8) was evaluated against a small tumor cell panel.

Topics: Acridines; Acridones; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Colonic Neoplasms; Crystallography, X-Ray; Drugs, Chinese Herbal; Humans; KB Cells; Magnetic Resonance Spectroscopy; Molecular Structure; Plant Roots; Plants, Medicinal; Taiwan; Triterpenes; Tumor Cells, Cultured

Fifteen acridone alkaloids were examined for their antiproliferative activity toward monolayers and suspension of several types of cancer and normal human cell lines. As a result, atalaphyllidine (9), 5-hydroxy-N-methylseverifoline (11), atalaphyllinine (12), and des-N-methylnoracronycine (13) showed potent antiproliferative activity against tumor cell lines, whereas they have weak cytotoxicity on normal human cell lines. The structure-activity relationship established from the results revealed that a secondary amine, hydroxyl groups at C-1 and C-5, and a prenyl group at C-2 played an important role for antiproliferative activities of the tetracyclic acridones.

Topics: Acridines; Acridones; Alkaloids; Animals; Antineoplastic Agents; Cell Division; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Mice; Structure-Activity Relationship; Tumor Cells, Cultured

Citrusinine-I, a new acridone alkaloid isolated from the root bark of the citrus plant (Rutaceae), exhibited potent activity against herpes simplex virus (HSV) type 1 and type 2 at low concentrations relative to their cytotoxicity; 50% effective concentrations (ED50) of citrusinine-I were 0.56 micrograms/ml and 0.74 micrograms/ml against HSV-1 and HSV-2, respectively. Inhibitory action was also demonstrated against cytomegalovirus (CMV) and thymidine kinase-deficient or DNA polymerase mutants of HSV-2. The compound markedly suppressed HSV-2 and CMV DNA synthesis at concentrations which did not inhibit the synthesis of virus-induced early polypeptides. However, citrusinine-I had no inhibitory activity against HSV and CMV DNA polymerases in cell-free extracts. Although the target of this inhibitor remains to be elucidated, the most plausible candidate is a virus-coded ribonucleotide reductase. Citrusinine-1, when combined with acyclovir or ganciclovir, synergistically potentiated the antiherpetic activity of these agents. Based on a comparative study of the antiherpetic activity of citrusinine-1 and 28 related compounds, a structure-activity relationship could be established.

Topics: Acridines; Acridones; Alkaloids; Animals; Antiviral Agents; Cells, Cultured; Cytomegalovirus; DNA-Directed DNA Polymerase; DNA, Viral; Humans; Mutation; Simplexvirus; Tumor Cells, Cultured; Viral Proteins; Virus Replication