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An effective reagent to functionalize alcohols with phosphocholine.

ABSTRACT: Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids and oligosaccharides. In this study, an air and bench stable phosphocholine donor has been developed and evaluated with a number of alcohol acceptors. Using a one-pot, three-step sequence, (phosphitylation, oxidation, and phosphate deprotection) phosphocholine derivatives are synthesized in high yields. Of particular interest is the synthesis of miltefosine, the lone oral drug approved to treat leishmaniasis. Due to its prohibitive expense ($1500 per g), miltefosine is not accesable for the majority of the world's patients. Based on the described reaction sequence, this drug can be produced for $25 per g.

SUBMITTER: Xu LL

PROVIDER: S-EPMC7047658 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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An effective reagent to functionalize alcohols with phosphocholine.

Xu Lianyan L LL Berg Lawrence J LJ Jamin Keith D D Townsend Steven D SD

Organic & biomolecular chemistry 20200108 4

Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids and oligosaccharides. In this study, an air and bench stable phosphocholine donor has been developed and evaluated with a number of alcohol acceptors. Using a one-pot, three-step sequence, (phosphitylation, oxidation, and phosphate deprotection) phosphocholine derivatives are synthesized in high yields. Of particular interest is th ...[more]

PMID: 31912847

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Project description:BackgroundEvidence indicates that Bax functions as a "lipidic" pore to regulate mitochondrial outer membrane permeabilization (MOMP), the apoptosis commitment step, through unknown membrane elements. Here we show mitochondrial ceramide elevation facilitates MOMP-mediated cytochrome c release in HeLa cells by generating a previously-unrecognized mitochondrial ceramide-rich macrodomain (MCRM), which we visualize and isolate, into which Bax integrates.Methodology/principal findingsMCRMs, virtually non-existent in resting cells, form upon irradiation coupled to ceramide synthase-mediated ceramide elevation, optimizing Bax insertion/oligomerization and MOMP. MCRMs are detected by confocal microscopy in intact HeLa cells and isolated biophysically as a light membrane fraction from HeLa cell lysates. Inhibiting ceramide generation using a well-defined natural ceramide synthase inhibitor, Fumonisin B1, prevented radiation-induced Bax insertion, oligomerization and MOMP. MCRM deconstruction using purified mouse hepatic mitochondria revealed ceramide alone is non-apoptogenic. Rather Bax integrates into MCRMs, oligomerizing therein, conferring 1-2 log enhanced cytochrome c release. Consistent with this mechanism, MCRM Bax isolates as high molecular weight "pore-forming" oligomers, while non-MCRM membrane contains exclusively MOMP-incompatible monomeric Bax.Conclusions/significanceOur recent studies in the C. elegans germline indicate that mitochondrial ceramide generation is obligate for radiation-induced apoptosis, although a mechanism for ceramide action was not delineated. Here we demonstrate that ceramide, generated in the mitochondrial outer membrane of mammalian cells upon irradiation, forms a platform into which Bax inserts, oligomerizes and functionalizes as a pore. We posit conceptualization of ceramide as a membrane-based stress calibrator, driving membrane macrodomain organization, which in mitochondria regulates intensity of Bax-induced MOMP, and is pharmacologically tractable in vitro and in vivo.

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An effective reagent to functionalize alcohols with phosphocholine.

Publications

An effective reagent to functionalize alcohols with phosphocholine.

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