Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics.
The semisynthetic artemisinin derivatives such as artesunate and artemether, along with the fully synthetic endoperoxide antimalarials (e.g., OZ277, Nature 2004, 430, 900-904), are believed to mediate their antimalarial effects by iron-induced formation of carbon-centered radicals capable of alkylating heme and/or protein. Here, we describe the design and synthesis of a series of biotinylated endoperoxide probe molecules for use in proteomic studies. The target molecules include derivatives of the artemisinin and OZ families, and we demonstrate that these conjugates express nanomolar in vitro activity versus cultured strains of Plasmodium falciparum. We also describe the synthesis of chemically cleavable linked conjugates designed to enable mild elution of labeled proteins during target protein identification.
Barton
Victoria
V
Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L697ZD, UK.
Ward
Steven A
SA
Chadwick
James
J
Hill
Alasdair
A
O'Neill
Paul M
PM
D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019921:Biotinylation; D002244:Carbon / Q000737:chemistry*; D015195:Drug Design; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D040901:Proteomics / Q000379:methods*
D000962:Antimalarials; D037621:Artemisinins; D011355:Prodrugs; D002244:Carbon