Synthetic studies towards natural products as potential treatment for liver fibrosis

Abstract

Whether your liver is infected with a virus, injured by chemicals or under attack from your own immune system, the damage to your liver is likely to progress in a similar way. In the early stages of liver disease, your liver becomes inflamed. If left untreated, the inflamed liver will start to scar. As excess scar tissue grows, it replaces the healthy liver tissues. This process is called fibrosis. MBP039-06, a natural product isolated and patented by Mitsubishi Pharmaceuticals, and dithiosilvatin a member of the epipolydithiodiketopiperazine alkoliod family, have evidence to indicate them as potential treatments for liver fibrosis. We report the total synthesis ofMBP039-06 and its absolute configuration, utilising the Lacey-Dieckmann condensation. Both enantiomers were prepared, and comparison of CD spectra with those of the naturally isolated material have enabled its absolute configuration to be established. In addition we report the synthesis of a small library of tetramic acid analogues. In our investigation we have shown MBP039-06 to be an effective inhibitor of HIF proyl hydroxylase. Inhibitors of this kind offer potential new therapies in ischaemicl hypoxic disease. In the second part of the thesis we report our work completed towards the total synthesis of dithiosilvatin, concentrating on an unnatural amino acid approach to the synthesis. We have established routes to a range of bis protected dithiodiketopiperazines, an important intermediate III the synthesis of the epipolydithiodiketopiperazine core. In addition we have discovered and disclose the structure of two novel potent inhibitors ofLys9-specific histone methyltransferase G9a. Methyltransferases are misregulated in tumors and are involved in neurodegenerative diseases such as Alzheimer's.

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