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A library of eight novel gymnastatin analogues has been prepared. The compounds consist of an unsaturated side chain linked to a tyrosine unit using an amide bond. The compounds have various chain lengths and degrees of conjugation. Additional functionality was added to the tyrosine unit by methylation of the acid side group to prepare methyl ester derivatives. While gymnastatins have shown promising cytotoxic activity, their mode of action is not fully understood. The prepared compounds were evaluated against the A549 cancer cell line. A selection of the compounds were further evaluated for inhibition against POLO like kinase (Plk1). The methyl ester derivatives showed more activity than compounds containing the acid side group. It was also observed that increasing the chain length resulted in increased activity against the cancer cells. The presence of an additional alkene did not significantly improve the activity. Furthermore, preliminary results of the activity of compounds using an ELISA assay showed that the compounds containing the methyl ester side group inhibited Plk1, while compounds with the acid side group showed no inhibition.
An introduction to gymnastatins is presented in Chapter 1 of this thesis. Chapter 2 contains a review of iron oxide nanoparticles, their synthesis and applications in targeted delivery. Due to time constraints, this part of the proposed study was not carried out synthetically. The synthesis and biological evaluation of gymnastatin analogues are presented in Chapter 3 and 4 respectively. The conclusions and future work are presented in Chapter 5. Finally, Chapter 6 details the experimental procedures employed in this work.
Mutuma, F. (2017) Synthesis and biological evaluation of gymnastatin analogues. Doctoral thesis, DIT, 2017.