Cytotoxic activity of dimeric acridone alkaloids derived from Citrus plants towards human leukaemia HL-60 cells.

OBJECTIVES: Acridone alkaloids from Citrus and their derivatives show various kinds of biological activity. However, the anticancer activities of dimeric acridone alkaloids with unique structures and the molecular mechanism of these effects are poorly understood. METHODS: We investigated the cytotoxicity effects of dimeric acridone alkaloids isolated from Marsh grapefruit on human myeloid leukaemia HL-60 cells. KEY FINDINGS: Of the six dimeric acridone alkaloids tested, citbismine-E, the most potent, dose- and time-dependently decreased HL-60 cell viability by inducing apoptosis. The treatment of HL-60 cells with citbismine-E yielded a significant increase in levels of intracellular reactive oxygen species (ROS). Citbismine-E lowered the mitochondrial membrane potential and increased the activities of caspase-9 and -3. In addition, citbismine-E-induced apoptosis, decrease in mitochondrial membrane potential and caspase activation were significantly alleviated by pretreatment of the cells with antioxidant N-acetylcysteine (NAC). Citbismine-E induced intrinsic caspase-dependent apoptosis through ROS-mediated c-Jun N-terminal kinase activation. Citbismine-E-induced production of oxidative stress biomarkers, malondialdehyde and 8-hydroxy-2'-deoxyguanosine was also attenuated by pretreatment with NAC. CONCLUSIONS: Citbismine-E is a powerful cytotoxic agent against HL-60 cells that acts by inducing mitochondrial dysfunction-mediated apoptosis through ROS-dependent JNK activation. Citbismine-E also induced oxidative stress damage via ROS-mediated lipid peroxidation and DNA damage in HL-60 cells.

Acridone Alkaloids.

There have been substantial developments in the chemistry and biology of the acridone alkaloids in the 16years since the topic was last reviewed in this series of monographs (2000). The present survey covers the literature from mid-1999 to 2016. A brief overview of the biosynthesis of acridone alkaloids is followed by details of the occurrence and characterization of known alkaloids from new sources, and of novel alkaloids. The classes covered include simple acridone alkaloids, C-prenylacridones, furo[3,2-b]- and furo[2,3-c]acridones, pyrano[3,2-b]- and pyrano[2,3-c]acridones, and dimeric alkaloids containing acridone moieties. Syntheses of acridone alkaloids and certain analogs reported during the review period are comprehensively covered. The final section summarizes aspects of their bioactivity, including cytotoxicity and anticancer activity, antimicrobial and antiparasitic properties, and enzyme inhibition. The chapter concludes with a brief description of important bioactive synthetic analogs.

Oxidative burst inhibition, cytotoxicity and antibacterial acriquinoline alkaloids from Citrus reticulate (Blanco).

Two novel acridone-quinoline alkaloids, acriquinoline A (1) and acriquinoline B (2), together with twenty-two known compounds were isolated from the methanol extract of the root of Citrus reticulata Blanco. The structures of all compounds were determined by comprehensive analyses of their 1D and 2D NMR and mass spectral (EI and ESI) data. The possible biosynthesis for the formation of above compounds is proposed, based on close examination of their structures. Compounds 1, 2, 6, 10 and 14-17 exhibited strong suppressive effect on phagocytosis response upon activation with serum opsonized zymosan in the range of IC50 0.2-10.5µM, which was tested in vitro for oxidative burst studies of whole blood. However, compounds displayed low cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3, with IC50 between 30.8 and 60.5µM compared to the standard doxorubicin with IC50 0.9µM. These compounds, tested against bacteria, fungi and plant pathogen oomycetes by the paper disk agar diffusion assay, resulting in missing to low activities corresponding with MICs>1mg/mL.

Acridone alkaloids from Glycosmis chlorosperma as DYRK1A inhibitors.

Two new acridone alkaloids, chlorospermines A and B (1 and 2), were isolated from the stem bark of Glycosmis chlorosperma, together with the known atalaphyllidine (3) and acrifoline (4), by means of bioguided isolation using an in vitro enzyme assay against DYRK1A. Acrifoline (4) and to a lesser extent chlorospermine B (2) and atalaphyllidine (3) showed significant inhibiting activity on DYRK1A with IC50's of 0.075, 5.7, and 2.2 µM, respectively. Their selectivity profile was evaluated against a panel of various kinases, and molecular docking calculations provided structural details for the interaction between these compounds and DYRK1A.

Acridanone alkaloid in Baliospermum montanum--evaluation of its effect against anaphylaxis.

Baliospermum montanum leaves yielded 3-hydroxy-2,4-dimethoxy-10-methyl-9-acridanone (1), an alkaloid from the CHCl3 fraction. Spectroscopic analysis was performed to assign the structure of the new compound (1) and its absolute configuration. The compound was evaluated for its effect in anaphylaxis by estimation of the release of histamine in systemic anaphylaxis model. The acridanone alkaloid significantly inhibited the degranulation of mast cells up to 65.22 % and 75.12 % at a dose of 50 and 75 mg/kg, respectively.

Complete 1H and 13C NMR data assignment of new constituents from Severinia buxifolia.

Phytochemical analysis of different organs of the rutaceaeous plant Severinia buxifolia led to the isolation of a new limonoid, a new acridone alkaloid, and a new flavone. Structure elucidation and signal assignment were achieved by the extensive use of 1D and 2D NMR experiments (selective 1D NOE, COSY, NOESY, HSQC, HMBC).

Algicide constituents from Swinglea glutinosa.

Oscillatoria perornata, a cyanobacterium (blue-green alga), common in catfish production ponds in the southeastern United States, produces the monoterpene 2-methylisoborneol (MIB), which is absorbed into catfish flesh and imparts a "musty" taste, rendering them unpalatable and unmarketable. Algicides that are currently in the commercial market to control O. perornata have broad-spectrum toxicity toward other beneficial phytoplankton, such as the green alga Selenastrum capricornutum, as well as low biodegradability. As part of our continuing efforts to search for natural-product-based algicides, the ethyl acetate extract of the roots of Swinglea glutinosa was investigated. This report describes isolation and structure elucidation of one novel coumarin, two known coumarins, and nine acridone alkaloids from S. glutinosa root extracts and the evaluation of these compounds for algicidal activity against O. perornata.

Isolation of acridone alkaloids and N-[(4-monoterpenyloxy)phenylethyl]-substituted sulfur-containing propanamide derivatives from Glycosmis parva and their anti-herpes simplex virus activity.

Six acridone alkaloids including a new glycosparvarine (1), three limonoids, and four N-[(4-monoterpenyloxy)phenylethyl]-substituted sulfur-containing propanamide derivatives including two new species, (+)-S-deoxydihydroglyparvin (10) and (+)-S-deoxytetrahydroglyparvin (11), were isolated from the branches and the leaves of Glycosmis parva CRAIB collected in the east of Thailand. Antiviral activity evaluation of isolates against herpes simplex virus (HSV) type 1 and 2 disclosed that two acridone alkaloids, glycosparvarine (1) and glycofolinine (4), showed moderate inhibitory activities with 50% effective concentration (EC50) of 348 microM and 151 microM, respectively; as well, (+)-S-deoxydihydroglyparvin (10) exhibited anti-HSV activity at the lower concentration.

[Search of novel bioactive natural products from plant sources--novel structures and biological activities--].

Over 30 years, our laboratory has been involved in the search of bioactive natural products from plant sources of several plant families, Rutaceae, Guttiferae, Avicenniaceae, and so on. In this review, novel structures of acridone alkaloids, carbazole alkaloids, coumarins, depsidones, and so on isolated in our laboratory will be showed. In addition, some results of assay of biological activities of the isolated compounds also will be described.