Abstract
A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Binding Sites
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Cell Line, Tumor / chemistry*
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Cell Line, Tumor / drug effects*
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Cell Proliferation / drug effects*
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Epoxy Compounds / chemical synthesis*
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Epoxy Compounds / chemistry
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Epoxy Compounds / metabolism*
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Humans
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Macrolides / chemical synthesis*
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Macrolides / chemistry
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Macrolides / metabolism*
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Phosphoproteins / antagonists & inhibitors*
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Phosphoproteins / chemistry*
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RNA Splicing / drug effects*
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RNA Splicing Factors
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Ribonucleoprotein, U2 Small Nuclear / antagonists & inhibitors*
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Ribonucleoprotein, U2 Small Nuclear / chemistry*
Substances
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6-deoxypladienolide D
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Antineoplastic Agents
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Epoxy Compounds
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Macrolides
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Phosphoproteins
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RNA Splicing Factors
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Ribonucleoprotein, U2 Small Nuclear
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SF3B1 protein, human