The design and synthesis of duocarmycin-based conjugates for targeted delivery to tumours

Cartwright, Oliver (2018) The design and synthesis of duocarmycin-based conjugates for targeted delivery to tumours. Doctoral thesis, University of East Anglia.

Preview

PDF Download (8MB) | Preview

Abstract

The CC-1065 and duocarmycin family of compounds are ultrapotent antitumour antibiotics which demonstrate activity in the picomolar range. These agents exert their biological effect through a sequence selective alkylation at the N3 position of adenine resulting in apoptosis. Despite the potential of this family to exert themselves as successful chemotherapeutic agents, a lack of clinical success has been observed for these compounds. This has been attributed to a lack of selectivity resulting in off-target side effects and toxicity. For this reason, research now focuses on ways in which these alkylating agents could realise their potential using tumour specific, targeted delivery strategies.

Herein, we investigate the use of a duocarmycin SA analogue, functionalised for solid phasesynthesis, in the design of conjugates for targeted delivery to cancerous tissue via the Thomsen-Friedenreich antigen (T-antigen). This antigen is overexpressed in 90% of primary human carcinomas, yet is cryptic in healthy cells, therefore presenting itself as an ideal moiety for the delivery of duocarmycin agents to cancerous tissue.

The research presented in this thesis will begin with detailing the synthesis of the Fmoc-duocarmycin SA analogue along with attempted modifications to the synthetic route to try and achieve greater efficiency. Additionally, this chapter will detail investigations into alternative protecting group removal strategies to improve the effectiveness of this analogues use in solid phase synthesis. The chapters subsequent to this will detail the design, synthesis and biological evaluation of a series of duocarmycin-based conjugates for targeted delivery to the T-antigen. These conjugates involve the use of T-antigen specific lectins and peptides. Furthermore, the development of a gold nanoparticle delivery system involving duocarmycin and a T-antigen specific lectin will be detailed. The investigations presented herein provide scope for future investigations into the design of clinically successful duocarmycin-based conjugates.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Users 11011 not found.
Date Deposited:	17 Oct 2019 11:51
Last Modified:	25 Sep 2021 00:39
URI:	https://ueaeprints.uea.ac.uk/id/eprint/72641
DOI:

Downloads

Actions (login required)

View Item