Design and synthesis of biologically active Largazole derivatives, including development of improved syntheses of Largazole analogs
Date
2018
Authors
Dunne, Christine E., author
Williams, Robert M., advisor
Shi, Yian, committee member
Prieto, Amy, committee member
Thamm, Douglas, committee member
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Abstract
Natural product histone deacetylase inhibitor, Largazole, has been developed into a streamlined synthetic pathway for the development of a complex library of analogs. The library developed within the Williams laboratory encompasses an array of derivatives, including but not limited to: thiazole modification and macrocycle substitutions. The cap group of Largazole, portion of the molecule extending outside of the enzyme binding pocket, was successfully modified to install new chemical handles for biologic and dual therapeutic conjugation. Biological conjugates of Largazole, as well as its derivatives, aid in increasing selectivity and potency of the compound. Largazole has been conjugated to both biotin and folic acid for further studies. Additionally, a streamlined synthesis towards Wnt inhibitor 3289-5066 and a developed path for conjugation have been explored. Modified procedures were developed to aid in scale up and improvement of synthetic pathways. Scale up is crucial for development of sufficient material for biological testing and further development of conjugative therapeutics. One main impediment in the synthesis of Largazole peptide isostere is towards the southern fragment, specifically the Grubbs olefin metathesis. Multiple routes were explored to combat this low yielding step. Further exploration of these synthetic routes are underway.
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Subject
cancer
histone deacetylase
therapeutic
drug development
biological conjugates
Largazole