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

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-AFFA-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-879C-C
Genre: Journal Article

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Kwiatkowski, S., Author
Sviripa, V. M., Author
Zhang, Z. Y., Author
Wendlandt, A. E., Author
Höbartner, C.1, Author              
Watt, D. S., Author
Stamm, S., Author
Affiliations:
1Research Group of Nucleic Acid Chemistry, MPI for biophysical chemistry, Max Planck Society, ou_578605              

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Free keywords: Norcantharidin analogs; Protein phosphatase-1 (PP1) inhibitors; Exon 7 inclusion; Alternative pre-mRNA splicing; SMN2 protein
 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

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Language(s): eng - English
 Dates: 2015-12-182016-02-01
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.bmcl.2015.12.054
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Title: Bioorganic and Medicinal Chemistry Letters
Source Genre: Journal
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Pages: - Volume / Issue: 26 (3) Sequence Number: - Start / End Page: 965 - 968 Identifier: -