Synthesis of [15,15,15-2H3]-Dihydroartemisinic Acid and Isotope Studies Support a Mixed Mechanism in the Endoperoxide Formation to Artemisinin
Autor: | Hadi D. Arman, Francis K. Yoshimoto, Kaitlyn Varela |
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Rok vydání: | 2021 |
Předmět: |
Antiparasitic
medicine.drug_class Stereochemistry Pharmaceutical Science 01 natural sciences Analytical Chemistry chemistry.chemical_compound Biosynthesis parasitic diseases Drug Discovery Kinetic isotope effect medicine Artemisinin Ene reaction Bond cleavage Pharmacology Natural product 010405 organic chemistry Organic Chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry Complementary and alternative medicine chemistry Yield (chemistry) Molecular Medicine medicine.drug |
Zdroj: | Journal of Natural Products. 84:1967-1984 |
ISSN: | 1520-6025 0163-3864 |
Popis: | Artemisinin is the plant natural product used to treat malaria. The endoperoxide bridge of artemisinin confers its antiparasitic properties. Dihydroartemisinic acid is the biosynthetic precursor of artemisinin that was previously shown to nonenzymatically undergo endoperoxide formation to yield artemisinin. This report discloses the synthesis of [15,15,15-2H3]-dihydroartemisinic acid and its use to determine the mechanism of endoperoxide formation. Several new observations were made: (i) Ultraviolet-C (UV-C) radiation initially accelerates artemisinin formation and subsequently promotes homolytic cleavage of the O-O bond and rearrangement of artemisinin to a different product, and (ii) dideuterated and trideuterated dihydroartemisinic acid isotopologues at C3 and C15 converted to artemisinin at a slower rate compared to nondeuterated dihydroartemisinic acid, revealing a kinetic isotope effect in the initial ene reaction toward endoperoxide formation (kH/kD ∼ 2-3). (iii) The rate of conversion from dihydroartemisinic acid to artemisinin increased with the amount of dihydroartemisinic acid, suggesting an intermolecular interaction to promote endoperoxide formation, and (iv) 18O2-labeling showed incorporation of three and four oxygen atoms from molecular oxygen into the endoperoxide bridge of artemisinin. These results reveal new insights toward understanding the mechanism of endoperoxide formation in artemisinin biosynthesis. |
Databáze: | OpenAIRE |
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