Synthesis and biological evaluation of polyamine DNA-intercalator conjugates and synthesis of N-hydroxyamide containing peptides

In the first chapter of the thesis, the synthesis of a series of derivatives is described along with their respective biological activities (i.e. topoisomerase II inhibition and IC50 values derived with L1210 murine leukemia cells). The derivatives are comprised of a spermine fragment covalently tethered via an aliphatic chain either to an acridine, anthracene or quinoline nucleus. Several conjugates (8, 9, 12, 13) have shown virtually complete inhibition of human DNA topoisomerase II (TOPO II) activity at JO µM, while the separate components (9-aminoacridine and 9-(N-butyl)aminoacridine at 20 µM) were not as effective as the intact conjugates (8, 9). The investigation of these derivatives strongly suggest that the appended spermine is a "value-added" fragment, which imparts enhanced biological activity to DNA binding ligands like anthracene and acridine. In the second chapter, earlier work in N-(benzoyloxy)arnine chemistry is extended into peptide synthesis. Peptide synthesis serves medicine in the study of peptide hormones and other peptides, which have important roles in the regulation of life processes. This technology allows for the introduction of one or more N-hydroxyarnide linkages into a peptide chain. A practical synthetic strategy was developed and racemization issues were addressed using diastereomeric Val-Leu peptide derivatives.