Collected papers

• Main Author: Waigh, Roger David
• Format: Dissertation
• Language: English
• Published: University of Bath 2002

The work which is described in these papers is presented in chronological order, in each of five connected areas. The overall theme is the discovery of new drug molecules and an understanding of how they work. In section (1), the primary focus is on the development of new methods for the synthesis of isoquinolines, developing towards the synthesis of natural product analogues which have anticancer activity. This led directly to much of the work in section (3). In section (2), the chemical synthesis of isoquinolines is developed in the specialist area of neuromuscular blocking agents. These culminate in the synthesis of atracurium, which is widely used as a surgical muscle relaxant. In section (3) a variety of ideas are explored in the general context of drug discovery, many associated with isoquinolines. This section includes antimalarials and antileukaemics (for example benzo[c]phenanthridines) with biological activity mediated via DNA, as well as the development of new assay methods for DNA binding. The most recent work is focused on the discovery of new DNA-binding compounds, analogues of natural products, with potential anticancer and antiparasitic activity Section (4) is concerned with the isolation and structure elucidation of a variety of natural products. This section cross-relates to sections (1), (2) and (3) in the isolation and identification of the benzo[c]phenanthridine alkaloid nitidine, which is a potent antimalarial. The fmal section is concerned with the mechanisms of action and solution behaviour of drug molecules. A major theme in this group is the use of NMR, which reflects the methodology used in most of the other work.