Synthesis of tumour cell migration inhibitors

Abstract

Chapter one and two of this thesis describe the synthesis of novel migrastatin derivatives. Migrastatin is a fourteen-membered macrocycle isolated by Japanese researchers from the Streptomyces platensis. It has been shown to inhibit tumour cell migration. The total synthesis of migrastatin and a number of analogues have previously been described. However it has been found that analogues of the migrastatin core are up to one thousand times more active than migrastatin itself. As a result, current work focuses on the synthesis of new analogues of the migrastatin core. Much of the previous research has focused on closed macrocycles. However recent work suggests that the acyclic ring-closing metathesis pre-cursors also display activity. In this thesis, the synthesis of acyclic ester analogues of migrastatin will be described. Previous efforts have focused on relatively flexible structures. However in this study, the analogues synthesised incorporate aromatic rings such as 2, and sugars such as 3, and can be considered to be more rigid structures. Efforts towards the ring-closing metathesis of these acyclic compounds are also described. Chapter three seeks to investigate the conformations of a number of migrastatin analogues. It focuses on trying to rationalise on difficulties in obtaining ring closed products from more constrained substrates. This chapter also includes a study as to whether the structures of the macrolactone core of migrastatin, obtained from modelling using Macromodel¿, are supported experimentally by examining NMR data for the macrolactone. It seeks to investigate how well the modelling can predict the structure of the macrocycle. Chapter four describes the synthesis of a number of dimeric compounds. These are dimers of allylated aromatic compounds prepared by cross metathesis reactions. A vast number of stilbenoid natural products exist within the literature. However di-aryl compounds with a four-carbon inter-aryl bridge incorporating an alkene such as 4 and 5 are much less investigated. Chapter four contains a description of research on the synthesis of such dimers. Previously synthesised compounds appear to show that the two aryl rings must be in close proximity to one another for activity and as a result trans stilbenoids have shown little activity. It appears that it is the proximity of the aromatic rings to one another rather than the stereochemistry of bridging atoms which is of most importance for biological activity. It is hoped that, although the inter-aryl bridge is longer, that the increased flexibility this affords will allow both the cis and trans compounds to show activity.