Organic and Metallo-Organic Platforms for Nucleic Acid Recognition: Synthesis, Self-Assembly, and Biophysical Studies

Abstract

In biological systems, the self-assembly of intricate three-dimensional nucleic acid architectures, from double-stranded DNA duplexes to four-stranded DNA and RNA guanine quadruplexes, is driven by non-covalent interactions. The selective recognition of guanine quadruplexes by artificial binders through such interactions is a rapidly expanding field of research, inspired by the growing awareness of the regulatory roles these structures play in essential biological processes associated with the development of diseases such as cancer. This thesis describes three classes of organic and metallo-organic guanine quadruplex binders, many of which are obtained from organic chelates that either undergo dynamic self-assembly in the presence of labile or semi-labile metal ions or form inert coordination complexes. An alternate synthesis of a known binder is also reported.

In Chapters 2 and 3, the synthesis of four novel ligands comprised of two 2-(1,2,3-triazol-4-yl)pyridine “Click” chelates connected to an aromatic unit by hinges of controlled length and flexibility has been reported. An exploration of the self-assembly of acridine-based ligands with semi-rigid or flexible hinges into dinuclear metallo-cylinders or mononuclear metallo-macrocycles in the presence of zinc(II), iron(II), copper(II), and copper(I) in Chapter 2 will inform the rational design of future ligands for predictable self-assembly into either architecture. In Chapter 3, the coordination geometries of zinc(II), copper(II), and palladium(II) have been used to tune metallo-macrocycle topologies, thereby creating a library of possible guanine quadruplex binders from a single ligand.

In Chapter 4, an alternate synthesis of “gold standard” guanine quadruplex binder Phen-DC3 is described. This route minimizes the use of hazardous reagents and doubles the overall synthetic yield, promoting its use as a standard in biophysical assays.

In Chapters 5 to 7, a novel platinum(II) platform has been identified as the first example of a planar metal complex capable of selectively recognizing quadruplexes with high affinity on a level comparable to Phen-DC3. The synthesis and biophysical studies of second-generation binders demonstrate that this platform can be readily derivatized with various chemical functionalities to enhance quadruplex binding affinity and selectivity. In the future, this may enable the specific targeting of particular quadruplexes and allow binder properties to be tuned for therapeutic applications.