The aplyronines are a family of structurally complex marine macrolides, isolated from the sea hare <i>Aplysia kurodai</i>, 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. We aim to design and synthesise novel and simplified hybrid structures based on the aplyronines and reidispongiolides. Routes to these function-orientated analogues should be more streamlined and efficient due to judicious structural editing, whilst functionality and potency are retained.<br/><br/>Guided by structure−activity relationship (SAR) studies and our total syntheses of the aplyronines, a highly convergent route towards these analogues has been designed. Analogue 1 contains three main structural simplifications that have been incorporated into advanced synthetic fragments on multi- gram scale. A flexible coupling strategy has been employed and material advanced to the macrocyclic core. Ongoing late stage manipulations have revealed an analogue for initial biological evaluation. Further synthetic studies towards suitable linker strategies and biological testing of various analogues will guide their development as cytotoxic payloads for future incorporation into antibody−drug conjugates.

Designed analogues of the aplyronines for next-generation antibody−drug conjugates

2019 Spring National Meeting

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