Development of small molecules toward therapeutic applications for myotonic dystrophy and cancer

The projects described herein seek to gain structural insight into the development of therapeutics for myotonic dystrophy types 1 (DM1) and 2 (DM2) and cancer. The myotonic dystrophies are repeat expansion diseases that currently have no cure. The mismatched bases found in DM1 and DM2 DNA and RNA provide a unique structure for targeting small molecules selectively to inhibit transcription and protein sequestration to recover aberrant mis-splicing. Chapter 1 describes the challenges of targeting nucleic acids as well as the progress toward developing small molecules for myotonic dystrophy therapeutics. Chapter 2 describes our efforts to target DM. First, the development of a target-guided screen identified compounds that could self-assemble on a d(CTG) template in situ via “click” chemistry between azides and alkynes. Three hit compounds were identified via a MS screen and were capable of inhibiting transcription bidirectionally of d(CTG·CAG)90 with IC50 values in the low micromolar range. Second, two compounds were developed that undergo template-selective, reversible assembly in situ via aldehyde-amine condensation. These assembled oligomers could inhibit transcription of d(CTG)exp in a cooperative manner and rescue aberrant mis-splicing in a dose-dependent manner. Third, we aimed to develop Amiloride as a new recognition unit for T-T mismatches. A library of derivatives was developed and the effect of structure on binding affinity was investigated to gain insight on the structure-activity relationship. It was determined that maintaining proper conformation between amiloride and thymine has the largest effect on binding properties. Current treatments of cytotoxic agents for cancer cause unwanted, significant side-effects due to off-target effects. Cancer provides a unique microenvironment including low pH, and increased reactive oxygen species (ROS), that we can take advantage of for stimuli-responsive, selective-targeting agents. Chapter 3 describes these properties of cancer and current progress toward developing stimuli-responsive molecules. Specifically, the use of acetals as acid-responsive moieties and boronic acids as ROS-responsive moieties are reported. In chapter 4, we report our efforts to develop acid-responsive, acid-amplifying small molecules. Our compounds utilized an acetal moiety for acidic degradation along with benzyl chloride for acid generation. Under the current conditions, the acetal remained intact, but acid was generated via benzyl chloride hydrolysis. The rate of acid-production could be tuned by adding electron-withdrawing substituents. A dual-stimuli-responsive polymer was designed that could utilize these acid-generators. A boronate ester caged guanidinium was designed to provide a ROS-responsive moiety resulting in degradation of the polymer and delivery of a drug. The sum of these works provides structural information for future design of therapeutic compounds.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Lanzendorf, Amie Nicole

Contributors dc:contributor

• Zimmerman, Steven C
• Burke, Martin D
• Chan, Jefferson
• Kalsotra, Auinash

• Myotonic Dystrophy Type 1
• Myotonic Dystrophy Type 2
• Cancer
• Amiloride
• Target-guided Screen
• Transcription Inhibition
• Template Selective Assembly
• Stimuli-responsive
• Acetal

Statement dc:rights

• Copyright 2024 Amie Lanzendorf

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/125785

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F125785