Synthesis of β-lactone, γ-lactam 20S proteasome inhibitors

Goodyear, Ross (2019) Synthesis of β-lactone, γ-lactam 20S proteasome inhibitors. Doctoral thesis, University of East Anglia.

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The 20S proteasome is a large protein complex, primarily responsible for the breakdown of ubiquitinated proteins. It is therefore a vital component in the ubiquitin proteasome pathway, disruptions of which can induce cell death. Such an effect could be targeted for cancer therapeutics. Some β-lactone γ-lactam scaffolds, such as the natural product omuralide (the biologically active form of lactacystin) have been found to inhibit the 20S proteasome.

The discovery of several new natural 20S proteasome inhibitors such as the salinosporamides and cinnabaramides, have shown potential for the development of new inhibitors with increased potency and specificity. Development of synthetic routes to produce these targets and their analogues is key to developing new proteasome inhibitors with greater potency and reduced side effects.

[Figure 1. Several natural products with 20S proteasome inhibitory activity]

Our methodology involves the incorporation of amino acids into the γ-lactam core. Leucine and serine have been used to produce a new formal synthesis of 9-deoxy omuralide and omuralide respectively. Key steps include a diastereoselective acylation with Mander’s reagent and desulfurization. This methodology offers a flexible route allowing rapid generation of omuralide analogues in order to produce known and novel 20S proteasome inhibitors for biological testing.

[Figure 2. An overview of our methodology]

In addition to our work incorporating amino acids into γ-lactam cores, we have also developed a new route to synthesize either diastereomer of hydroxy leucine. We hope that this valuable intermediate could be incorporated into the γ-lactam using our devised methodology quickly forming an advanced intermediate of omuralide.

[See PDF for figures]

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Chemistry
Depositing User: Jennifer Whitaker
Date Deposited: 10 Jun 2019 13:17
Last Modified: 10 Jun 2019 13:17


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