The development of novel immunosuppressant drugs: the synthesis of thiazole analogues of 2-acetyl-1', 2', 3', 4' - tetrahydroxybutylimidazole

This thesis presents the synthesis of several structural analogues of the immunosuppressant compound THI. A number of the synthesised analogues were found to have higher levels of biological activity of the same type as THI. Chapter 1 presents an introduction and summary of some of the fundamental principles behind immunosuppression and the modes of action of a range of known commercial immunosuppressants. This chapter also looks at the role of immunosuppression in modern medicine and presents some potential new immunosuppressants yet to reach the commercial market. The final part of the chapter provides an introduction to, and background of THI, which leads into the aims of the project. Chapter 2 presents the synthesis of five-carbon side chain, 5-thiazole analogues of THI, with the aim of determining the effect of increasing the length of the pendant side-chain. The promising biological screening data generated for these compounds is presented towards the end of the chapter. Chapter 3 investigates the consequences of reversing the orientation of the thiazole heterocycle. This synthesis proceeds via a lithium-bromide exchange reaction to overcome the lower reactivity of the 4-thiazole position (compared to the 5-position). Chapter 4 provides a logical extension of the successful increase in side chain length from 4 to 5 carbons, by further extending this functionality out to 6 carbons. This Chapter also includes a more detailed study of metal hydride reductions and the stereochemical factors associated with these reactions. In order to determine the role of the absolute configuration of the polyhydroxyl side chain, Chapter 5 presents the synthesis of another range of 6-carbon side chain analogues with different absolute configurations. A brief summary of the work is presented in Chapter 6, along with some general observations brought about by the results of the project