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Journal Article

Synthesis of a norcantharidin-tethered guanosine: Protein phosphatase-1 inhibitors that change alternative splicing.

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Höbartner,  C.
Research Group of Nucleic Acid Chemistry, MPI for biophysical chemistry, Max Planck Society;

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2248945.pdf
(Publisher version), 622KB

Supplementary Material (public)

2248945_Suppl.docx
(Supplementary material), 135KB

Citation

Kwiatkowski, S., Sviripa, V. M., Zhang, Z. Y., Wendlandt, A. E., Höbartner, C., Watt, D. S., et al. (2016). Synthesis of a norcantharidin-tethered guanosine: Protein phosphatase-1 inhibitors that change alternative splicing. Bioorganic and Medicinal Chemistry Letters, 26(3), 965-968. doi:10.1016/j.bmcl.2015.12.054.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0029-AFFA-B
Abstract
Phosphorylation and dephosphorylation of splicing factors play a key role in pre-mRNA splicing events, and cantharidin and norcantharidin analogs inhibit protein phosphatase-1 (PP1) and change alternative pre-mRNA splicing. Targeted inhibitors capable of selectively inhibiting PP-1 could promote exon 7 inclusion in the survival-of-motorneuron-2 gene (SMN2) and shift the proportion of SMN2 protein from a dysfunctional to a functional form. As a prelude to the development of norcantharidin-tethered oligonucleotide inhibitors, the synthesis a norcantharidin-tethered guanosine was developed in which a suitable tether prevented the undesired cyclization of norcantharidin monoamides to imides and possessed a secondary amine terminus suited to the synthesis of oligonucleotides analogs. Application of this methodology led to the synthesis of a diastereomeric mixture of norcantharidin-tethered guanosines, namely bisammonium (1R,2S,3R,4S)- and (1S,2R,3S,4R)-3-((4-(2-(((((2R,3R,4R,5R)-5-(2-amino-6-oxo-1,6- dihydro-9H-purin-9-yl)-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-yl) oxy) oxidophosphoryl) oxy) ethyl)-phenethyl)(methyl)carbamoyl)-7-oxabicyclo[2.2.1] heptane-2-carboxylate, which showed activity in an assay for SMN2 pre-mRNA splicing