Fudger, Alexander (2022) Chemical synthesis of a library of natural product-like molecules, based on pinnaic acid, and initial evaluation of their anti-cancer activity. (PhD thesis), Kingston University, .
Abstract
Halichlorine and pinnaic acid are natural products that were isolated from the marine sponge Halichondria Okadai and the bivalve Pinna Muricata. These natural products have been shown to be potent inhibitors of the inflammatory enzymes VCAM-1 and cPLA2 respectively and have also demonstrated some anti-cancer activity. Halichlorine and pinnaic acid possess an almost identical azaspirocyclic core consisting of a unique 3-dimensional geometry with five stereo centres, making them compounds of interest for further study not only synthetically but also to reveal any bioactivity not yet discovered. The azaspirocyclic core of halichlorine and pinnaic acid was synthesised via an established protocol, from which synthetic routes were designed to chemically manipulate the azaspirocyclic core. Successful reactions involved sequential reductions, oxidations, and chemoselective acylations and sulfonylations along with the introduction of a number of substituents to the azaspirocyclic core via cross metathesis, all of which resulted in the successful synthesis of twenty nine novel analogues. These analogues were then tested for anti-cancer activity against two cancer cell lines, HeLa and CaCo-2. Twelve compounds displayed anti-cancer activity with eleven selective for CaCo-2 and only one compound displaying toxicity when tested against non-cancerous keratinocyte cells.
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