Synthesis of a norcantharidin-tethered guanosine: Protein phosphatase-1 inhibitors that change alternative splicing. Issue 3 (1st February 2016)

• Record Type: Journal Article
• Authors: Kwiatkowski, Stefan; Sviripa, Vitaliy M.; Zhang, Zhaiyi; Wendlandt, Alison E.; Höbartner, Claudia; Watt, David S.; Stamm, Stefan
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 3(2016)
• Page Start: 965
• Page End: 968
• Publication Date: 2016-02-01
• Subjects: Norcantharidin analogs -- Protein phosphatase-1 (PP1) inhibitors -- Exon 7 inclusion -- Alternative pre-mRNA splicing -- SMN2 protein; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.12.054
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: A tethered isocantharidin-guanosine adduct that affects PP1-inhibition promotes alternative splicing in the survival-of-motoneuron-2 ( SMN2 ) gene. 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 (1 R, 2 S, 3 R, 4 S )- and (1 S, 2 R, 3 S, 4 R )-3-((4-(2-(((((2 R, 3 R, 4 R, 5 R )-5-(2-amino-6-oxo-1, 6-dihydro-9 H -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.