The overarching objective of this project is the improvement of treatment outcomes for cancer patients who require chemotherapy. An important class of chemotherapeutic agents is that of platinum-containing antineoplastic drugs. The treatment is typically associated with numerous side effects and the risk of malignancies that develop drug resistance. Here the synthesis of new ligands for platinum complexes derived from amino acids is described. The complexes are designed to facilitate DNA-bending upon base crosslinking. The DNA-platinum adducts will be characterized to gain insight into the mechanisms of DNA-related cytotoxicity of these platinum compounds and to conduct cell-imaging studies. The new ligands are obtained from amino acids through a synthetic pathway involving N-protection, amidation, deprotection and reduction steps leading to substituted ethylenediamine ligands. Variation of the amino acid side chains are designed to modify the lipophilicity of ligands and to contribute some steric hindrance. The side chains can be functionalized to attach reporter groups to determine the position of adducts on the DNA strand as well as the location in the cell. Synthetic methodologies, procedures for the separation of enantiomeric products and analyses of platinum compounds are presented.

Synthesis of ligands for platinum drugs

2019 Spring National Meeting

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