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Title:Macrocyclic linker modifications alter specificity and toxicity properties of DM1-targeting small molecules
Author(s):Schuster, Emma J.
Contributor(s):Zimmerman, Steve C.
Subject(s):Myotonic Dystrophy Type 1 (DM1)
Small molecule
Trinucleotide Repeat Disorder
Abstract:The rational design of small molecules for targeting of the CTG/CUG expansions [(CTG/CUG)exp] characteristic of myotonic dystrophy type I (DM1) has previously involved variations in recognition, intercalation, and linker units in the linear form (i.e., a single linker). This paper explores the cyclization of our small molecule using two linkers and how linkers of different lengths impact the macrocycle’s properties, especially specificity and toxicity when compared to the non-cyclized analog. Five variations of the small molecule were synthesized with various linkers of different carbon lengths A3D3, A4D4, A5D5, A3D4, and A4D3. To understand the basic toxicity and specificity properties of these different ligands, the cytotoxicity in HeLa cells of all compounds was measured and the specificity of A3D4 and A4D3 were compared in an in vitro transcription assay. In HeLa cells treated with A3D3 and A3D4, 36±15% and 42±23%, respectively of cells died at 10 mM compound exposure. A4D4, A5D5, and A4D3 were much more toxic at 10 mM with percent cell deaths at 99±1%, 100±2%, and 98±2%, respectively. Against a non-cyclic control, cell death was 99±0.6% at 10 mM. The specificity testing for (CTG)exp of A3D4 and A4D3 showed that at 100 μM, A4D3 showed an 85±35% efficiency of transcription of a random duplex compared to 22±13% efficiency in A3D4, indicating greater non-specific binding of A3D4. Compound A4D3, although more toxic at high concentrations, appears to be non-toxic at therapeutic concentrations and more specific than A3D4 for the CTG expansion, suggesting a possible structure that can be used in further characterization.
Issue Date:2017
Genre:Dissertation / Thesis
Rights Information:Copyright 2017 Emma J. Schuster
Date Available in IDEALS:2017-05-04

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