Open Access Dissertation
Date of Award
Christine S. Chow
DNA serve as an ideal target where drugs such as cisplatin (cisPt) bind and exert their anticancer activities. CisPt is known to preferentially coordinate with DNA leading to formation of cisPt-deoxyguanosine (dGuo) adducts. The adducts distort the DNA structure and contribute to inhibition of DNA-mediated cellular functions and ultimately cancer cell death. Despite its utilization as an anticancer drug, cisPt has a number of drawbacks, which include toxic side effects and cellular resistance. Resistance occurs through processes such as repair of damaged DNA and inactivation of cisPt present in the cell. To overcome these challenges, the aim of this thesis work was to synthesize and investigate compounds that coordinate to different sites from those targeted by cisPt, including sites found in RNA. In this highly collaborative dissertation project, amino acid-linked platinum(II) compounds were synthesized and studied as alternatives to cisPt. The reactivity preferences of these compounds towards DNA/RNA nucleosides and oligonucleotides were determined through pseudo-first-order kinetics. The products formed by the reactions of amino acid-linked platinum(II) compounds with DNA and RNA were studied by electrospray ionization mass spectrometry (ESI-MS) to determine the type of adducts formed by the compounds. NMR spectroscopy was used to determine the non-canonical adducts formed by the compounds that include platination of the N1, N3, or N7 positions of RNA adenosine (Ado) residues. Features of amino acid-linked platinum(II) compounds that impact the glycosidic bond stability of Ado residues were explored by using tandem mass spectrometry in collaboration with the Rodgers laboratory. Furthermore, cytotoxicity assays and inductively coupled plasma mass spectrometry (ICP-MS) were used to determine the potency and accumulation of the compounds in cancer cells. Altogether, the unique characteristics of the amino acid-linked compounds such as altered reactivity preferences, formation of adducts at non-canonical residues, destabilization of glycosidic bonds, selective potency, and higher accumulation in cancer cells are important features that could circumvent drug resistance faced by the currently available platinum-based drugs.
Kimutai, Bett, "Non-Canonical Targets, Reaction Kinetics, And Cellular Potency Of Amino Acid-Linked Platinum(ii) Compounds" (2020). Wayne State University Dissertations. 2360.