Da Silva Sil Dos Santos, B; (2013) Zinc Ejectors – Synthesis of Epi-3,6-dithio-2,5-diketopiperazines as therapeutically active agents. Doctoral thesis , UCL (University College London).

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Abstract

This present thesis focuses on compounds related to the epidithiodiketopiperazine (ETP) family of natural products, their synthesis and biological effects. The domain of natural products has long been recognized as an invaluable source of lead structures for the discovery and development of novel therapeutic agents, with the motif being one example that has long been recognized for its potent biological effects which are directly related to the disulfide bridge at the central core. The first chapter provides a detailed analysis of the ETP family of natural products with both the monomeric and dimeric family members being described to provide an overview of this diverse family of compounds and their corresponding biological effects. The second section in this chapter highlights the various synthetic strategies adopted by a number of different research groups and attempts to classify these into the varying approaches towards the central core. Finally the section closes with a description of dimeric natural products and their biological effects in relation to the potent activity observed from the dimeric ETP congeners. The results of our own approach towards the ETP core are described in the third chapter which commences with the synthesis of disubstituted ETPs and expands towards our efforts in synthesizing their tri and tetrasubstituted counterparts. Efforts to extend this chemistry towards dimeric ETPs are also described and our successful routes towards these complex compounds are discussed. The following section of this chapter outlines the successful biological evaluation of the ETP compounds that were synthesised with relevance to their effects in a surrogate model of tuberculosis, cancer cells via inhibition of the hypoxia pathway and activity against the feline immunodeficiency virus. The final chapter provides a formal description of the experimental results and procedures with full characterisation of the data for each compound.

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