Design and Synthesis of Duocarmycin Analogues for the Treatment of Cancer

Cassidy, Lily Rebecca (2024) Design and Synthesis of Duocarmycin Analogues for the Treatment of Cancer. Doctoral thesis, University of East Anglia.

Preview

PDF Download (8MB) | Preview

Abstract

The duocarmycins are a family of natural compounds and their synthetic analogues that are highly potent DNA alkylating agents. The parent compounds are among the most potent cytotoxic compounds discovered in nature and therefore offer great potential for cancer treatment. However, high toxicity and low selectivity mean there has been limited progress towards the clinic as chemotherapeutic agents. Research into finding ways to achieve tumour selective cytotoxicity is of great importance. One approach is with antibody drug conjugates, or ADCs. Here the cytotoxic drug (the payload) is bound by a linker to the antibody and in doing this the payload can be targeted directly to the tumours. A duocarmycin-based ADC called SYD985 or trastuzumab duocarmazine has recently finished phase III clinical trials for the treatment of HER-2 metastatic breast cancer, for which approval is currently being sought.1 This shows an exciting new field to be explored and this project will look at preparing dimeric payloads that could potentially be used as a warhead for an ADC.

The duocarmycin family consists of different alkylating subunits, including the duocarmycin SA unit, DSA, one of the most potent subunits and of great interest in the design of analogues. This thesis gives a review over chemotherapeutic agents and the new focus of treatments shifting towards more targeted therapies. The project initially follows work previously done by Searcey et al. where the DSA alkylating unit was synthesised and will then go on to discuss an alternative route which is able to avoid some of the challenges from the initial synthesis. The synthesis of a set of novel dimers is then described, and the importance of stereochemistry is addressed. DNA stapling with the duocarmycins is something that has not previously been investigated, so opens this project to a new field of study. Finally, the ability for the compounds to alkylate DNA as well as their anti-proliferate activity was investigated and all the dimers synthesised were shown to be active against HL-60 cells, a human leukemia
cell line.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024)
Depositing User:	Chris White
Date Deposited:	05 Nov 2024 09:44
Last Modified:	05 Nov 2024 09:44
URI:	https://ueaeprints.uea.ac.uk/id/eprint/97495
DOI:

Downloads

Actions (login required)

View Item