Macrocycles with various applications including G-quadruplex stabilization and self-assembling into nanopores with ion channel activity
Rocabado, Guizella A.
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Macrocycles are molecules with a multiplicity of applications in medicine and other fields of industry. Many macrocyclic molecules are found in nature in a variety of systems. Similarly, other natural systems, while not made from macrocyclic structures, can be understood and simulated by macrocyclic arrangements. In the last two decades, the Gong laboratory has explored the design and synthesis of macrocycles for a variety of applications. In the first chapter of this work, tetraurea macrocycles are investigated as G-quadruplex stabilizing ligands. G-quadruplex binding ligands have gained a tremendous amount of attention in the last decade as potential anticancer therapeutics by inhibiting the activity of telomerase. Telomerase is a reverse transcriptase active in rapidly dividing cells, such as cancer cells. There are diverse ways to inhibit this enzyme; one of them is by stabilizing the telomeric G-quadruplex structure. Among the many types of G-quadruplex ligands, macrocycles have shown selective binding with high affinity to the G-quadruplex structure. The ability for the macrocycle to stack on the G-quadruplex creates a stabilizing interaction, determined through increasing optical thermal melts. These macrocycles are inspired by the structure of telomestatin; the first natural product shown to selectively bind the G-quadruplex; however, the total synthesis of this natural product is difficult and costly. Thus we model nature with tetraurea macrocycles with similar size and aromatic surface than that of telomestatin. Moreover, along with determining favorable stacking interactions between macrocycles and G-quads, studies are underway to better understand the importance and versatility of certain metal ions and their role in the potential added stability of macrocycle-quad interaction. In the second chapter, generation-four macrocycles are investigated for their self-assembling abilities into tubular arrangements that serve as transmembrane channels. These synthetic nanopores with selective transport properties have remarkable potential in research, medicine, and industry. However, challenges remain before such applications can be utilized. First, the design of the self-assembling structure is crucial; thus we chose macrocycles as our base material due to their shape-persistent structures. Macrocycles have the ability to self-assemble into tubular arrangements owing to side chain as well as π-π interactions due to large aromatic surfaces. The exterior of the tubular frame must be hydrophobic in order to penetrate and remain in the membrane. However, the interior can be designed to selectively allow the desired ions to pass through the pore. This leads to the second challenge: ion selectivity of the pores. Using fluorescence assays, ion selectivity can be assessed. Furthermore, channel activity and selectivity can be confirmed by single channel studies using a planar lipid bilayer instrument. These results enhance our understanding of macrocycle self-assembly and ion channel selectivity.