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Title: Designed analogues of the aplyronines for use in antibody-drug conjugates
Author: Porter, Rachel Jayne
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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The aplyronines are a family of structurally complex marine macrolides, isolated from the sea hare Aplysia kurodai, that exhibit picomolar growth inhibitory activity in the NCI 60 cell line panel. An unprecedented heterotrimeric complex has been observed to form between aplyronine A and actin and tubulin together, resulting in disruption of cytoskeletal dynamics and subsequent cell death. This novel mode of action, coupled with their exquisite biological activity, renders the aplyronines compelling candidates for incorporation as payloads into antibody-drug conjugates provided the supply problem can be solved. Guided by structure-activity relationship (SAR) studies, a highly convergent route towards novel and simplified aplyronine structures has been designed. Routes to these function- oriented analogues should be more streamlined and efficient due to judicious structural editing, whilst functionality and potency are retained. Chapter 1 introduces marine natural products and illustrates their therapeutic potential alongside the challenges associated with these highly complex structures. The aplyronine family of natural products is introduced and a function-oriented approach towards analogue design is presented. The avenue of targeted therapies is discussed, with particular focus on the field of antibody-drug conjugates. Chapter 2 outlines the synthesis of our key simplified fragments. Significant optimisation efforts towards the synthesis of the side chain ketone are discussed, together with the synthesis of the northern fragment. Chapter 3 outlines two complementary fragment coupling strategies to access our designed analogues. Contrasting to the established sequence, an alternate approach is examined in which the southern and side chain fragments are first connected before the northern piece is appended. The strengths and shortcomings of each route are reviewed. Chapter 4 culminates in endgame manipulations to generate a range of simplified analogues and details their initial biological evaluation. Preliminary investigations into linker strategies using a quaternary amine approach are investigated. Chapter 5 summarises this work and presents suggestions for future directions of this research for the purpose of developing antibody-drug conjugates.
Supervisor: Paterson, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: antibody drug conjugates ; total synthesis ; natural products