title: Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity.
abstract: 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 ∼10 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.
authors: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA hangjun.ke@drexelmed.edu.
authors: Hangjun
authors: H
authors: Ke
authors: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors: Joanne M
authors: JM
authors: Morrisey
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA.
authors: Shiwei
authors: S
authors: Qu
authors: Department of Chemistry, Faculty of Science, King Mongkut's University of Technology Thonburi, Bangmod, Thungkru, Bangkok, Thailand.
authors: Oraphin
authors: O
authors: Chantarasriwong
authors: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors: Michael W
authors: MW
authors: Mather
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA.
authors: Emmanuel A
authors: EA
authors: Theodorakis
authors: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors: Akhil B
authors: AB
authors: Vaidya
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D029760:Garcinia / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D015394:Molecular Structure; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects; D052939:Schizonts / Q000187:drug effects; D013329:Structure-Activity Relationship; D053058:Trophozoites / Q000187:drug effects; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D044004:Xanthones
keywords: Giemsa stain-negative body; Plasmodium falciparum; caged Garcinia xanthones; malaria; mitochondria