forbesione and gambogic-acid

Total of 22 caged xanthones were subjected to susceptibility testing of global epidemic MRSA USA300. Natural morellic acid showed the strongest potency (MIC of 12.5μM). However, its potent toxicity diminishes MRSA therapeutic potential. We synthetically modified natural morellic acid to yield 13 derivatives (3a-3m). Synthetically modified 3b retained strong potency in MRSA growth inhibition, yet the toxicity was 20-fold less than natural morellic acid, permitting the possibility of using caged xanthones for MRSA therapeutic.

Topics: A549 Cells; Amino Acids; Ampicillin; Anti-Bacterial Agents; Bacterial Adhesion; Garcinia; HEK293 Cells; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxacillin; Xanthones

To investigate the growth inhibitory mechanism of four caged xanthones from Garcinia hanburyi in cholangiocarcinoma (CCA) KKU-100 and KKU-M156 cells.. Four caged xanthones, selected on the basis of their anticancer potency and chemical structure diversities (i.e. isomorellin, isomorellinol, forbesione and gambogic acid) were used in this study. Growth inhibition of these caged xanthones was determined using the sulforhodamine B assay. Induction of apoptosis was assessed by observing cell morphology, ethidium bromide and acridine orange staining and DNA fragmentation assay. Levels of apoptotic-related gene and protein expressions were determined by a real-time reverse transcriptase polymerase chain reaction and Western blotting analysis, respectively.. The compounds were found to inhibit growth of both cell lines in a dose-dependent manner and also showed selective cytotoxicity against the cancer cells when compared with normal peripheral blood mononuclear cells. Growth suppression by these compounds was due to apoptosis, as evidenced by the cell morphological changes, chromatin condensation, nuclear fragmentation, and DNA ladder formation. At the molecular level, these compounds induced down-regulation of Bcl-2 and survivin proteins with up-regulation of Bax and apoptosis-inducing factor proteins, leading to the activation of caspase-9 and -3 and DNA fragmentation. The functional group variations did not appear to affect the anticancer activity with regard to the two CCA cell lines; however, at a mechanistic level, isomorellinol exhibited the highest potency in increasing the Bax/Bcl-2 protein expression ratio (120 and 41.4 for KKU-100 and KKU-M156, respectively) and in decreasing survivin protein expression (0.01 fold as compared to control cells in both cell lines). Other activities at the molecular level indicate that functional groups on the prenyl side chain may be important.. Our findings for the first time demonstrate that four caged xanthones induce apoptosis in CCA cells which is mediated through a mitochondria-dependent signaling pathway.

Topics: Apoptosis; Base Sequence; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma; DNA Primers; Garcinia; Gene Expression; Heterocyclic Compounds; Humans; Xanthones

A unified synthetic strategy toward caged Garcinia natural products has been designed and implemented. Central to the strategy is a tandem Claisen/Diels-Alder/Claisen rearrangement of a suitably substituted xanthone precursor to form forbesione (1a). Serving as a template, forbesione is then used to deliver representative members of this family, including desoxygaudichaudione A (4), desoxymorellin (5), and gambogin (10). Studies on the timing of this reaction cascade suggest that the C-ring Claisen/Diels-Alder rearrangement proceeds initially and is followed by the A-ring Claisen reaction. The electronic and steric effects that govern the outcome of this cascade are presented.

Topics: Biological Products; Bridged-Ring Compounds; Chemistry, Organic; Garcinia; Heterocyclic Compounds; Indicators and Reagents; Molecular Structure; Xanthenes; Xanthones