Exploring macrocycles as potential anticancer drug leads

This thesis describes the development of two anticancer drug leads from macrocyclic peptide-based natural products: Urukthapelstatin A (Ustat A) and Sansalvamide A (San A). Ustat A possesses a unique scaffold containing directly-linked two oxazoles, two thiazoles and one phenyl oxazole. It shows an average growth inhibition of 15.5 nM against 39 cancer cell lines, yet its mechanism of action remains unknown. My first project describes an efficient and viable synthetic approach of Ustat A either through solution or solid phase methodology, which includes the synthesis of the linear precursor and macrocycle. Chapter 2 describes the complete synthesis of heterocyclic fragments and a linear precursor, and discusses several strategies for cyclisation of Ustat A via solution phase synthesis. In addition, using solid phase approach, the complete synthesis of a flexible linear peptide and three oxazoles containing Ustat A is also described. Lastly, the biological activity of multi-heterocyclic containing fragments is compared against the cancer cell line, HCT-116. San A and its derivatives are heat shock protein 90 (HSP90) inhibitors that exhibit anti-cancer potency, with low micromolar cytotoxicity against multiple cancer cell lines. SM145, the lead HSP90 inhibitor, has limited potential as a drug candidate due to its poor solubility and low yield. Chapter 3 describes structure–activity relationship studies of SM145 analogues, which were developed to eliminate these issues. D-phenyl alanine and D-thiazolyl alanine were incorporated into SM145’s backbone to improve its solubility. Lysine was incorporated to determine its protein target. The resulting analogue, SM253, was synthesised in greater yield and also showed enhanced solubility when compared to the parent compound, SM145. SM253TII displayed anti-cancer activity and was shown to bind to HSP90 by western blot. My final project focuses on improving SM145’s efficacy using drug-delivery nanoparticles. Chapter 4 describes the synthesis of a cross-linked star polymer as a drug-delivery vehicle, via reversible addition−fragmentation chain transfer (RAFT) polymerisation and conjugating this to SM145 to generate the pH-dependent drug nanoparticle (14 nm). This improved SM145’s efficiency by 5-fold as verified by fluorescence microscopy and cytotoxicity assays. Furthermore, released SM145 from the star polymer induced apoptosis by a caspase 3-dependent pathway