Comparison of the Reactivity of Antimalarial 1,2,4,5-Tetraoxanes with 1,2,4-Trioxolanes in the Presence of Ferrous Iron Salts, Heme, and Ferrous Iron Salts/Phosphatidylcholine

• Published in: Journal of medicinal chemistry Vol. 54; no. 19; pp. 6443 - 6455
• Main Authors: Bousejra-El Garah, Fatima, Wong, Michael He-Long, Amewu, Richard K, Muangnoicharoen, Sant, Maggs, James L, Stigliani, Jean-Luc, Park, B. Kevin, Chadwick, James, Ward, Stephen A, O’Neill, Paul M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.10.2011; Amer Chemical Soc
• Subjects: Alkylation; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Chemical Sciences; Chemistry, Medicinal; Ferrous Compounds - chemistry; Heme - chemistry; Life Sciences & Biomedicine; Models, Molecular; Parasitic Sensitivity Tests; Peroxides - chemical synthesis; Peroxides - chemistry; Peroxides - pharmacology; Pharmacology & Pharmacy; Phosphatidylcholines - chemistry; Plasmodium berghei - drug effects; Plasmodium falciparum - drug effects; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Stereoisomerism; Structure-Activity Relationship; Tetraoxanes - chemical synthesis; Tetraoxanes - chemistry; Tetraoxanes - pharmacology; DRUG; OXIDATION; MECHANISM; TETRAOXANE; ALKYLATION; IDENTIFICATION; ARTEMISININ; MASS-SPECTROMETRY; DISPIRO-1,2,4-TRIOXOLANE; DISPIRO-1,2,4,5-TETRAOXANES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200768h

Dispiro-1,2,4,5-tetraoxanes and 1,2,4-trioxolanes represent attractive classes of synthetic antimalarial peroxides due to their structural simplicity, good stability, and impressive antimalarial activity. We investigated the reactivity of a series of potent amide functionalized tetraoxanes with Fe(II)gluconate, FeSO4, FeSO4/TEMPO, FeSO4/phosphatidylcholine, and heme to gain knowledge of their potential mechanism of bioactivation and to compare the results with the corresponding 1,2,4-trioxolanes. Spin-trapping experiments demonstrate that Fe(II)-mediated peroxide activation of tetraoxanes produces primary and secondary C-radical intermediates. Reaction of tetraoxanes and trioxolanes with phosphatidylcholine, a predominant unsaturated lipid present in the parasite digestive vacuole membrane, under Fenton reaction conditions showed that both endoperoxides share a common reactivity in terms of phospholipid oxidation that differs with that of artemisinin. Significantly, when tetraoxanes undergo bioactivation in the presence of heme, only the secondary C-centered radical is observed, which smoothly produces regioisomeric drug derived-heme adducts. The ability of these tetraoxanes to alkylate the porphyrin ring was also confirmed with FeIITPP and MnIITPP, and docking studies were performed to rationalize the regioselectivity observed in the alkylation process. The efficient process of heme alkylation and extensive lipid peroxidation observed here may play a role in the mechanism of action of these two important classes of synthetic endoperoxide antimalarial.