Date of Graduation

5-2022

Document Type

Thesis

Degree Name

Bachelor of Science

Degree Level

Undergraduate

Department

Biological Sciences

Advisor/Mentor

Adams, Paul D.

Committee Member/Reader

Tipsmark, Christian

Committee Member/Second Reader

Du, Yuchun

Committee Member/Third Reader

Aloia, Lindsey

Abstract

Microtubules are cytoskeletal filaments that play a role in essential functions within the cell such as cell motility, intracellular transport, structural support and chromosome segregation. Tubulin is a heterodimeric protein that exhibits GTP dependent polymerization and self- assembles into polar microtubule filaments. Microtubules are dynamic polymers corresponding to their role in separation of duplicated chromosomes during mitosis. As the polymers cycle through rounds of polymerization and depolymerization based on their nucleotide state, the chromosomes are pulled towards the poles in the mitotic cell. Their normal function and dynamics can be disrupted in highly proliferative cells that interrupt cell cycle progression revealing microtubules as an antimitotic cancer therapy target protein. Paclitaxel, also known as Taxol, is a current chemotherapeutic agent that binds microtubules and stabilizes the polymerized state, disrupting their dynamic action, stalling the cell cycle, and leading to apoptosis. Ruthenium-Polypyridyl Complexes (RPCs) are metalloorganic compounds with aromatic ring structures complexed to a center Ruthenium cation, some of which have been identified as a Microtubule Stabilizing Agent (MSA). The novel RPCs under investigation in this research are ([Ru(dip)2bpy]Cl2) (DB) and ([Ru(dip)2phen]Cl2 (DP). The first goal of this research was to determine if these novel compounds bind to microtubules. Fluorescence titrations between the microtubules and each small molecule were performed with increasing concentration of the RPC to measure the binding affinity (Kd). Polymerization data reveals that each novel small molecule enhances the rate and degree of polymerization in a similar manner as Paclitaxel. Circular Dichroism reveals the binding of the novel small molecule to MTs does not result in any significant secondary structural changes. ITC data further supports the notion that the novel RPCs are tightly binding to MTs and binding to a similar degree as other known MSAs, showing the importance in further research endeavors on these novel RPCs to determine their potential in antimitotic chemotherapy.

Keywords

Microtubule-Stabilizing Agents; Ruthenium-Polypyridyl Complexes

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