Abstract
Pladienolide B (PB) is a potent cancer cell growth inhibitor that targets the SF3B1 subunit of the spliceosome. There is considerable interest in the compound as a potential chemotherapeutic, as well as a tool to study SF3B1 function in splicing and cancer development. The molecular structure of PB, a bacterial natural product, contains a 12-member macrolide ring with an extended epoxide-containing side chain. Using a novel concise enantioselective synthesis, we created a series of PB structural analogs and the structurally related compound herboxidiene. We show that two methyl groups in the PB side chain, as well as a feature of the macrolide ring shared with herboxidiene, are required for splicing inhibition in vitro. Unexpectedly, we find that the epoxy group contributes only modestly to PB potency and is not absolutely necessary for activity. The orientations of at least two chiral centers off the macrolide ring have no effect on PB activity. Importantly, the ability of analogs to inhibit splicing in vitro directly correlated with their effects in a series of cellular assays. Those effects likely arise from inhibition of some, but not all, endogenous splicing events in cells, as previously reported for the structurally distinct SF3B1 inhibitor spliceostatin A. Together, our data support the idea that the impact of PB on cells is derived from its ability to impair the function of SF3B1 in splicing and also demonstrate that simplification of the PB scaffold is feasible.
Highlights
Pladienolide B is a complex natural product that potently inhibits pre-mRNA splicing
Synthesis of Pladienolide B (PB) Structural Analogs— it is established that PB targets the spliceosomal core protein SF3B1 and inhibits pre-mRNA splicing, the structural elements of PB responsible for this biological activity are unknown
PB is a member of a family of several pladienolide natural products from Streptomyces platensis, all of which share a complex macrolide ring structure [7, 26]
Summary
Pladienolide B is a complex natural product that potently inhibits pre-mRNA splicing. SF3B1 is the target of pladienolide B (PB), a natural product with potent cytotoxicity and antitumor activity both in cancer cell lines and mouse xenograft models [7,8,9]. Our data point toward more straightforward synthetic pathways and modifications in PB, which will be key to dissecting the function of its target SFB1 in the spliceosome and studying the relationship between splicing pathways and cancer cell growth. They may lead to structurally less complex new PB analogs that are better tuned to selectively target cancer cell growth and increase the therapeutic potential of the drug
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