Enantioselective Synthesis of Spliceostatin E and Evaluation of Biological Activity

Ghosh, Arun K.; Veitschegger, Anne M.; Sheri, Venkata Reddy; Effenberger, Kerstin A.; Prichard, Beth E.; Jurica, Melissa S.

doi:10.1021/ol503127r

Cited by 24 publications

(30 citation statements)

References 30 publications

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“…The inhibition zones were more evident since the concentration of 250 μg/mL and the severe inhibitory effect was recorded at the concentration of 500 μg/mL with all tested compounds. Our results were concordance with that cited in the literature [27][28][29][30][31][32][33][34][35][36][37][38][39].…”

Section: Biological Activitiessupporting

confidence: 93%

“…The various biological activities of tetrahydropyran [29][30][31][32], thiazole [33][34][35][36], benzthiazole [37][38][39] and benzimidazole derivatives [40,41] and other hetertocyclic compounds [42,43] prompted us to study the antimicrobial activities of our newly synthesized products. The in vitro antibacterial activities of compounds 9 and 10a-10f were evaluated against Gram positive and Gram negative bacteria (S. aureus, B. subtilis, E. coli and B. cereus) and fungus (Candida albicans) are reported in Table 5.…”

Section: Biological Activitiesmentioning

confidence: 99%

See 1 more Smart Citation

An unexpected tandem cycloaddition reaction of α,β-unsaturated acid chloride with amines: Synthesis of dihydropyrancarboxamide derivatives and biological activity

Elassar

2015

Eur. J. Chem.

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Section: Biological Activitiessupporting

confidence: 93%

Section: Biological Activitiesmentioning

confidence: 99%

An unexpected tandem cycloaddition reaction of α,β-unsaturated acid chloride with amines: Synthesis of dihydropyrancarboxamide derivatives and biological activity

Elassar

2015

Eur. J. Chem.

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“…SSA (1) has a very different architecture, and the shared characteristics with PB (2) and HB (3) are not obvious. The inactivating change in SSA (4) is localized to the ring containing an epoxide (note that iSSA is equivalent to SSE) (Ghosh et al 2014c). Our data indicate a shared interaction site, and it will be very interesting to determine how these three compounds with very different structures interact with SF3B1.…”

Section: Discussionmentioning

confidence: 78%

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

Effenberger

Urabe

Prichard

et al. 2016

RNA

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102

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The protein SF3B1 is a core component of the spliceosome, the large ribonucleoprotein complex responsible for pre-mRNA splicing. Interest in SF3B1 intensified when tumor exome sequencing revealed frequent specific SF3B1 mutations in a variety of neoplasia and when SF3B1 was identified as the target of three different cancer cell growth inhibitors. A better mechanistic understanding of SF3B1's role in splicing is required to capitalize on these discoveries. Using the inhibitor compounds, we probed SF3B1 function in the spliceosome in an in vitro splicing system. Formerly, the inhibitors were shown to block early steps of spliceosome assembly, consistent with a previously determined role of SF3B1 in intron recognition. We now report that SF3B1 inhibitors also interfere with later events in the spliceosome cycle, including exon ligation. These observations are consistent with a requirement for SF3B1 throughout the splicing process. Additional experiments aimed at understanding how three structurally distinct molecules produce nearly identical effects on splicing revealed that inactive analogs of each compound interchangeably compete with the active inhibitors to restore splicing. The competition indicates that all three types of compounds interact with the same site on SF3B1 and likely interfere with its function by the same mechanism, supporting a shared pharmacophore model. It also suggests that SF3B1 inhibition does not result from binding alone, but is consistent with a model in which the compounds affect a conformational change in the protein. Together, our studies reveal new mechanistic insight into SF3B1 as a principal player in the spliceosome and as a target of inhibitor compounds.

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“…In vitro assays bypass some of these issues by more directly measuring splicing activity. Several FR901464, pladienolide B, and herboxidiene derivatives have been tested for effects on in vitro splicing in HeLa cell extract . Generally, in vitro data correlate well with cell‐based assay results.…”

Section: Sars Of Sf3b1 Inhibitorsmentioning

confidence: 77%

“…However, the complex chemical structures of SF3B1 inhibitors, in particular, make total synthesis very challenging. Nonetheless, several groups successfully generated SF3B1 inhibitors and derivatives for the three main structural families: FR901464, pladienolides (including FD‐985), and herboxidiene . Taking SAR analysis another step further, the Webb lab compared the structures of FR901464 and pladienolide B to predict common pharmacophore consisting of epoxy and carbonyloxy groups joined and relatively positioned by a diene linker .…”

Section: Sars Of Sf3b1 Inhibitorsmentioning

confidence: 99%

Modulating splicing with small molecular inhibitors of the spliceosome

2016

Self Cite

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Small molecule inhibitors that target components of the spliceosome have great potential as tools to probe splicing mechanism and dissect splicing regulatory networks in cells. These compounds also hold promise as drug leads for diseases in which splicing regulation plays a critical role, including many cancers. Because the spliceosome is a complicated and dynamic macromolecular machine comprised of many RNA and protein components, a variety of compounds that interfere with different aspects of spliceosome assembly is needed to probe its function. By screening chemical libraries with high-throughput splicing assays, several labs have added to the collection of splicing inhibitors, although the mechanistic insight into splicing yielded from the initial compound hits is somewhat limited so far. In contrast, SF3B1 inhibitors stand out as a great example of what can be accomplished with small molecule tools. This group of compounds were first discovered as natural products that are cytotoxic to cancer cells, and then later shown to target the core spliceosome protein SF3B1. The inhibitors have since been used to uncover details of SF3B1 mechanism in the spliceosome and its impact on gene expression in cells. Continuing structure activity relationship analysis of the compounds is also making progress in identifying chemical features key to their function, which is critical in understanding the mechanism of SF3B1 inhibition. The knowledge is also important for the design of analogs with new and useful features for both splicing researchers and clinicians hoping to exploit splicing as pressure point to target in cancer therapy.

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Enantioselective Synthesis of Spliceostatin E and Evaluation of Biological Activity

Cited by 24 publications

References 30 publications

An unexpected tandem cycloaddition reaction of α,β-unsaturated acid chloride with amines: Synthesis of dihydropyrancarboxamide derivatives and biological activity

An unexpected tandem cycloaddition reaction of α,β-unsaturated acid chloride with amines: Synthesis of dihydropyrancarboxamide derivatives and biological activity

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

Modulating splicing with small molecular inhibitors of the spliceosome

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