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Stereospecific Synthesis of 23-Hydroxyundecylprodiginines and Analogues and Conversion to Antimalarial Premarineosins via a Rieske Oxygenase Catalyzed Bicyclization
journal contribution
posted on 2015-12-17, 06:09 authored by Papireddy Kancharla, Wanli Lu, Shaimaa M. Salem, Jane Xu Kelly, Kevin A. ReynoldsFacile
and highly efficient synthetic routes for the synthesis
of (S)- and (R)-23-hydroxyundecylprodiginines
((23S)-2, and (23R)-2), 23-ketoundecylprodiginine (3), and deuterium-labeled
23-hydroxyundecylprodiginine ([23-d]-2) have been developed. We demonstrated a novel Rieske oxygenase MarG
catalyzed stereoselective bicyclization of (23S)-2 to premarineosin A (4), a key step in the tailoring
process of the biosynthesis of marineosins, using a marG heterologous expression system. The synthesis of various A–C-ring
functionalized prodiginines 32–41 was achieved to investigate the substrate promiscuity of MarG. The
two analogues 32 and 33 exhibit antimalarial
and cytotoxic activities stronger than those of the marineosin intermediate 2, against Plasmodium falciparum strains (CQS-D6, CQR-Dd2, and 7G8) and hepatocellular
HepG2 cancer cell line, respectively. Feeding of 34–36 to Streptomyces venezuelae expressing marG led to production of novel premarineosins,
paving a way for the production of marineosin analogues via a combinatorial
synthetic/biosynthetic approach. This study presents the first example
of oxidative bicyclization mediated by a Rieske oxygenase.
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substrate promiscuityhepatocellular HepG 2 cancer cell lineanalogues 32Rieske oxygenasestereoselective bicyclizationoxidative bicyclizationStereospecific SynthesisStreptomyces venezuelaemarineosin analoguesAntimalarial Premarineosinssynthesisnovel premarineosinsnovel Rieske oxygenase MarGPlasmodium falciparum strainscytotoxic activitiesmarG heterologous expression systemRieske Oxygenase Catalyzed BicyclizationFacile33 exhibit antimalarial
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