Alpha-Diaminobutyric Acid-Linked Hairpin Polyamide-Alklylator Conjugates

Citation

Tsai, Sherry Mon-Yue (2008) Alpha-Diaminobutyric Acid-Linked Hairpin Polyamide-Alklylator Conjugates. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/3S8Y-YD79. https://resolver.caltech.edu/CaltechETD:etd-10152007-175458

Abstract

The ability to control gene expression through the use of DNA sequence-specific, cell-permeable molecules holds therapeutic promise. Pyrrole-imidazole polyamides are a class of synthetic ligands that can be programmed to bind a broad repertoire of DNA sequences with affinities and specificities comparable to natural DNA-binding proteins. These ligands are generally linked via a turn moiety, resulting in a ‘hairpin’ structure. Conjugation of polyamides to the non-specific DNA alkylator chlorambucil produces molecules capable of the sequence-specific alkylation of DNA that can arrest gene transcription. We have identified α-diaminobutyric acid (α-DABA) as a new turn moiety that can give polyamide-chlorambucil conjugates distinctive biological properties in cellular and small animal models; this may be due to their increased DNA alkylation specificities relative to the standard γ-DABA-linked conjugates. A general characterization of α-DABA-linked polyamides and their conjugates is reported.

Also described is the development of a modular synthesis of chondroitin sulfate (CS) glycosaminoglycans — a class of linear, sulfated oligosaccharides that play critical roles in neuronal development, cell division, and spinal cord injury. CS structure in vivo is complex and heterogeneous, hampering efforts to understand its precise biological roles. Access to CS molecules of precisely defined structures is critical to understanding their structure-function relationships. The reported synthetic route is capable of accessing CS structures of defined lengths and sulfation motifs, providing a new approach to understanding these important molecules.

Thesis Files