Research Project
7189804
[unreadable] DESCRIPTION (provided by applicant): The objective of this proposal is to investigate how the size and shape of the amine ligands of platinum diamine complexes will affect both the type of protein adducts that form and the rate of formation of these adducts. An understanding of the factors influencing the binding of platinum to proteins has relevance to platinum complexes that are used as anticancer drugs. Preliminary studies have suggested that bulky diamine ligands prevent coordination of two methionine residues to a platinum atom and also greatly affect the rate of formation of the products. In contrast, reaction with guanine is significantly less affected by bulk. Thus, a primary advantage that may result from additional bulk may be a kinetic preference for platinum-DNA complexes over platinum-protein complexes; the former are responsible for the anticancer activity. The first aim is to use NMR spectroscopy and other techniques to characterize products formed by reaction of bulky platinum complexes with methionine and other amino acids. Adducts formed with peptides containing methionine residues will also be characterized to see if reaction occurs at sites other than methionine. The next aim will be to determine the effects of bulk on the rate of reaction with peptide and oligonucleotide complexes; it is hypothesized that bulk may favor reaction with the latter over reaction with the former. HPLC and/or NMR spectroscopy will be used to monitor the rates of reaction. Finally, inductively coupled plasma-atomic emission spectroscopy (ICP-AES) will be utilized to study the factors that affect the binding of platinum to intact proteins or DNA sequences. The effects of bulk, leaving ligand, pH, and other factors will be determined. This project will study how the size and shape of a platinum anticancer drug affects the reactions with key biological targets. Model systems will be used to study the reactions in order to determine whether larger platinum compounds may have advantages in terms of target selection. [unreadable] [unreadable] [unreadable]
