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DOI: 10.1055/s-0030-1258710
Synthesis of RKA 182
Contributor(s):Philip KocienskiUniversity of Liverpool, Liverpool School of Tropical Medicine, London School of Hygiene and Tropical Medicine, UK; Phramongkutklao College of Medicine, Bangkok, Thailand; Swiss Tropical and Public Health Institute, Basel and Carbogen AMCIS, Hunzenschwil, Switzerland
Identification of a 1,2,4,5-Tetraoxane Antimalarial Drug-Development Candidate (RKA 182) with Superior Properties to the Semisynthetic Artemisinins
Angew. Chem. Int. Ed. 2010, 49: 5693-5697
Publication History
Publication Date:
21 October 2010 (online)
Key words
RKA 182 - antimalarial - 1,2,4,5-tetraoxanes - gem-dihydroperoxides - rhenium oxide
Significance
RK 182 is a remarkably stable, orally available antimalarial agent selected for development from a library of over one hundred and fifty 1,2,4,5-tetraoxane analogues. As the water-soluble ditosylate salt, RKA 182, displayed an IC50 of 0.87 nM and an ED50/ED90 of 1.1/4.1 mg kg-¹, which is superior to the leading synthetic artemisinin analogues currently in phase II development. It also shows a long duration of action with 79% being recovered after four hours in infected blood.
Comment
The key step in the synthesis of RKA 182 was the formation of the dispirocyclic 1,2,4,5-tetraoxane E from the potentially hazardous gem-dihydroperoxide intermediate C employing Re2O7 as a mild Lewis acid catalyst according to the procedure of P. Ghorai and P. H. Dussault (Org. Lett. 2009, 11, 213). The synthesis depicted provided 1.2 kg of material.