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Salinipostins A–K, Long-Chain Bicyclic Phosphotriesters as a Potent and Selective Antimalarial Chemotype

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† Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, United States
‡ Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, United States
*E-mail: [email protected]
*E-mail: [email protected]
Cite this: J. Org. Chem. 2015, 80, 3, 1312–1320
Publication Date (Web):January 13, 2015
https://doi.org/10.1021/jo5024409
Copyright © 2015 American Chemical Society
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    Abstract

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    Despite significant advances in antimalarial chemotherapy over the past 30 years, development of resistance to frontline drugs remains a significant challenge that limits efforts to eradicate the disease. We now report the discovery of a new class of antimalarials, salinipostins A–K, with low nanomolar potencies and high selectivity indices against mammalian cells (salinipostin A: Plasmodium falciparum EC50 50 nM, HEK293T cytotoxicity EC50 > 50 μM). These compounds were isolated from a marine-derived Salinospora sp. bacterium and contain a bicyclic phosphotriester core structure, which is a rare motif among natural products. This scaffold differs significantly from the structures of known antimalarial compounds and represents a new lead structure for the development of therapeutic targets in malaria. Examination of the growth stage specificity of salinipostin A indicates that it exhibits growth stage-specific effects that differ from compounds that inhibit heme polymerization, while resistance selection experiments were unable to identify parasite populations that exhibited significant resistance against this compound class.

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    HPLC trace for salinipostin A–K isolation; comparison of key NMR chemical shifts for salinipostin A, 2-epicyclipostin P and cyclipostin P; 1H, 13C, COSY, HSQC, HMBC, and 31P NMR data and MS2 data for salinipostin A; 1H, 13C, COSY, and MS2 data for salinipostins B and C; 1H, COSY, and MS2 spectra for salinipostins D–K; VCD data for configurational determination of salinipostin A; NMR table for salinipostins A–K; growth curves for mammalian cell lines This material is available free of charge via the Internet at http://pubs.acs.org.

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