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

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• 作者：Stefan Kwiatkowski^a ; ^b ; Vitaliy M. Sviripa^a ; ^b ; Zhaiyi Zhang^a ; Alison E. Wendlandt^a ; Claudia Hö ; bartner^c ; David S. Watt^a ; ^b ; ^d ; ^{dwatt@uky.edu" class="auth_mail" title="E-mail the corresponding author} ; Stefan Stamm^a ; ^{stefan.stamm@uky.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Norcantharidin analogs ; Protein phosphatase-1 (PP1) inhibitors ; Exon 7 inclusion ; Alternative pre-mRNA splicing ; SMN2 protein
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 February 2016
• 年：2016
• 卷：26
• 期：3
• 页码：965-968
• 全文大小：621 K

文摘

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.