Manadoperoxides A−D from the Indonesian Sponge Plakortis cfr. simplex. Further Insights on the Structure−Activity Relationships of Simple 1,2-Dioxane Antimalarials

• Published in: Journal of natural products (Washington, D.C.) Vol. 73; no. 6; pp. 1138 - 1145
• Main Authors: Fattorusso, Caterina, Persico, Marco, Calcinai, Barbara, Cerrano, Carlo, Parapini, Silvia, Taramelli, Donatella, Novellino, Ettore, Romano, Adriana, Scala, Fernando, Fattorusso, Ernesto, Taglialatela-Scafati, Orazio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 25.06.2010; Amer Chemical Soc; American Society of Pharmacognosy
• Subjects: Animals; Antimalarials - chemistry; Antimalarials - isolation & purification; Antimalarials - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Dioxanes - chemistry; Dioxanes - isolation & purification; Dioxanes - pharmacology; General pharmacology; Life Sciences & Biomedicine; Medical sciences; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Parasitic Sensitivity Tests; Pharmacognosy. Homeopathy. Health food; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plakortis - chemistry; Plant Sciences; Plasmodium falciparum - drug effects; Science & Technology; Structure-Activity Relationship; Asia; Indonesia; DRUG; METABOLITES; ACIDS; PLASMODIUM-FALCIPARUM; FIELD; ABSOLUTE STEREOCHEMISTRY; MALARIA; ARTEMISININ; CORAL LOBOPHYTUM SP; MARINE SPONGE; Endoperoxide; Antimalarial; Dioxane derivatives; Pharmacognosy; Animal origin; In vitro; Marine environment; Antiprotozoal agent; Peracetal; Structure activity relation; Porifera; Parasiticide; Isolation; Sponge; Invertebrata; Mechanism of action; Structural analysis
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np100196b

The new endoperoxyketal polyketides manadoperoxides A−D (2−5) have been isolated from the Indonesian sponge Plakortis cfr. simplex and their stereostructures established by means of spectroscopic data and semisynthetic transformations. Manadoperoxides were assayed in vitro against D10 and W2 strains of Plasmodium falciparum and showed moderate antimalarial activity compared to that of plakortin (1) and peroxyplakoric B3 ester (9), the latter differing from manadoperoxide B only by minor structural details. This unexpected difference in the antimalarial activity has been rationalized on the basis of our recently published model for the interaction of 1,2-dioxanes with heme and production of C-centered radicals toxic to the parasite. For the manadoperoxides, either the endoperoxide linkage is inaccessible to the heme iron or the O1 radical cannot evolve to produce a C-centered radical.