Pradet, Charlotte; (2004) Studies towards the synthesis and mode of action of epidithio-3, 6-diketo-2, 5-piperazines. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The present thesis is concerned with two differing but equally important aspects of the chemistry of the epi-3,6-dithio-2,5-diketopiperazine family of natural products. The first of these is related to studies involving new and existing synthetic methodologies for the construction of the disulfide bridge whilst the second is concerned with probing a possible mode of action for these compounds both through in vitro and in vivo experiments. The thesis is divided into three sections. The first chapter provides a detailed introductory review and is organised into four sections. The first of these highlights both the structural diversity and wide range of biological activities found in this class whilst a second section outlines the biosynthetic studies which have been performed. The synthetic strategies adopted by various groups are then described and in a final section the spectral and physical properties which provide some insight into the unusual nature of the disulfide bridge are then examined. The results of our own studies are then presented in the second chapter which opens with the synthesis of 2,5-diketopiperazines and then leads on to an examination of the scope and limitations of the classical methodologies which have been developed to date for introduction of the disulfide bridge from these cyclic dipeptides. Although a number of simple epi-3,6-dithio-2,5-diketopiperazines were prepared, the tolerance of selectively protected derivatives proved problematic. Efforts to develop a xanthate based elimination-readdition strategy from either N-hydroxy- or C-hydroxy-2,5-diketopiperazines were also studied but no evidence for formation of the desired carbon sulfur bond was obtained. In similar vein, obtention of an unsaturated N-oxide derivative for further elaboration was unsuccessful. Efforts were then made to probe the idea that a thiyl radical produced from the opened form of the disulfide would be sufficiently reactive to abstract the hydrogen atom of a tetrahydrofuran based DNA model. Two polarity reversal catalysed based reactions were examined and it was demonstrated that whilst thiyl radicals derived from a cis-3,6-dithiol-2,5-diketopiperazine were not sufficiently reactive in the key reaction, they could function as catalysts for hydrosilylation of an enol lactone. Finally the reactivity of some epi-3,6-dithio-2,5-diketopiperazines was investigated with plasmid DNA under anaerobic conditions. The third chapter provides a formal description of the experimental results and procedures.

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