Chemistry and Biology of the Caged <i>Garcinia</i> Xanthones

Chantarasriwong, Oraphin; Batova, Ayse; Chavasiri, Warinthorn; Theodorakis, Emmanuel A.

doi:10.1002/chem.201000741

Cited by 124 publications

(61 citation statements)

References 193 publications

(284 reference statements)

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“…Plants of the genus Garcinia produce an intriguing family of caged-xanthonederived natural products that have a documented value in traditional Eastern medicine (10). Collectively referred to as caged Garcinia xanthones (CGXs), these compounds are structurally defined by an unusual motif in which the C ring of an allylated xanthone has been converted into a tricyclic cage (Fig.…”

mentioning

confidence: 99%

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Morrisey

et al. 2017

Antimicrob Agents Chemother

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Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ϳ10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

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confidence: 99%

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Morrisey

et al. 2017

Antimicrob Agents Chemother

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“…This compound has been shown to affect growth of cancer cells in multiple ways against multiple targets, including gene regulation, as an antiapoptosis agent, by inducing production of reactive oxygen species, and as a cell cycle modifier. This compound has also been shown to inhibit bacterial growth, in particular Gram-positive; however, the mechanism of action is unknown (47). We have shown here that at least one target in bacteria is PheRS.…”

Section: Discussionmentioning

confidence: 78%

“…The compound library investigated here is no exception and contains both known and unknown compounds. BM03E08 is a compound known as acetyl isogambogic acid and is a member of a group of compounds known as caged Garcinia xanthones, which is a family of plant metabolites isolated from a variety of Garcinia trees (47). Gambogic acid has been shown to have both anticancer and anti-infective properties.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Analysis of Natural-Product Compounds Inhibiting Protein Synthesis in Pseudomonas aeruginosa

Keniry

Palmer

et al. 2016

Antimicrob Agents Chemother

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bBacterial protein synthesis is the target for numerous natural and synthetic antibacterial agents. We have developed a poly(U) mRNA-directed aminoacylation/translation (A/T) protein synthesis system composed of phenylalanyl-tRNA synthetases (PheRS), ribosomes, and ribosomal factors from Pseudomonas aeruginosa. This system has been used for high-throughput screening of a natural-compound library. Assays were developed for each component of the system to ascertain the specific target of inhibitory compounds. In high-throughput screens, 13 compounds were identified that inhibit protein synthesis with 50% inhibitory concentrations ranging from 0.3 to >80 M. MICs were determined for the compounds against the growth of a panel of pathogenic organisms, including Enterococcus faecalis, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, P. aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Three of the compounds were observed to have broad-spectrum activity and inhibited a hypersensitive strain of P. aeruginosa with MICs of 8 to 16 g/ml. The molecular target of each of the three compounds was determined to be PheRS. One compound was found to be bacteriostatic, and one compound was bactericidal against both Gram-positive and Gram-negative pathogens. The third compound was observed to be bacteriostatic against Gram-positive and bactericidal against Gram-negative bacteria. All three compounds were competitive with the substrate ATP; however, one compound was competitive, one was uncompetitive, and one noncompetitive with the amino acid substrate. Macromolecular synthesis assays confirm the compounds inhibit protein synthesis. The compounds were shown to be more than 25,000-fold less active than the control staurosporine in cytotoxicity MTT testing in human cell lines. Bacterial infections are a continuing major worldwide health problem. Infections can be minor, such as skin rashes and common ear infections in infants, or potentially lethal, such as those in many immunocompromised patients. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen and the causative agent in a wide range of infections and is responsible for one-seventh of all nosocomial infections (1, 2). Among clinical isolates of P. aeruginosa, antimicrobial resistance is increasing (3) and has become a major problem in the hospital setting (4). However, the most serious medical problem caused by P. aeruginosa is chronic lung colonization associated with cystic fibrosis patients (5), and it is the leading cause of morbidity and mortality in these patients (6).Antibiotics block cellular processes which are essential for bacterial survival. Many of the current antibiotics, both naturally occurring and synthetic, target protein synthesis as a mechanism of action (for a complete list, see reference 7). Antibiotics that target protein synthesis include the macrolides, clindamycin, chloramphenicol, the aminoglycosides, and the tetracyclines (8-10). Linezolid, one of the newest antibiotics and a protein synthesis inhi...

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“…Reaction of 131 with coenzyme A (HSCoA) can produce activated ester 132 that can further react with three units of malonyl-coenzyme A to yield intermediate 133. A Dieckmann condensation gives rise to benzophenones, such as maclurin (134). Depending upon the benzophenone produced, this is a branch point in the biogenesis of other benzophenone-type natural products.…”

Section: Biosynthesis Of Polyprenylated Xanthonesmentioning

confidence: 99%

Polyprenylated Phloroglucinols and Xanthones

Theodorakis

2011

Biomimetic Organic Synthesis

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Chemistry and Biology of the Caged Garcinia Xanthones

Cited by 124 publications

References 193 publications

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Discovery and Analysis of Natural-Product Compounds Inhibiting Protein Synthesis in Pseudomonas aeruginosa

Polyprenylated Phloroglucinols and Xanthones

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