Tsoukala, Georgia; (2009) Design and synthesis of glycosides as potential anticancer agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Despite carbohydrates being abundant in Nature, there are surprisingly few carbohydrate-based compounds used in medicine. This thesis describes two investigations into carbohydrate derivatives with potential in the treatment of cancer. The ipomoeassins, which were isolated from the leaves of Ipomoea squamosa, a member of the morning glory family, exhibit highly potent cytotoxic activity against human ovarian cancer cell lines (IC50 35 nM) and thus constitute an interesting target for further investigation. They are polyacylated macrocyclic glycoresins, each incorporating a β-D-glucopyranosyl-(1β2)-β-D-fucopyranose glycoside and cyclised via a macrolactone with the glucose primary hydroxyl. Our initial synthetic approach involved the successful formation of the protected disaccharide using a glucosyl trichloroacetimidate donor and a suitably-derivatised fucose glycoside. However, all attempts at macrolactonisation proved fruitless, although several different routes to the precursors were identified. The potential of the glycolipid assembly was demonstrated by the synthesis of a novel non-macrocyclic glycoresin 212, similar to those found in several Ipomoea species. An alternative synthesis involved formation of the macrolactone ring via ring closing metathesis (RCM). For that purpose a glucose thioglycoside donor bearing a hept-6-enoate ester and a suitable hex-5-enyl fucoside acceptor were successfully synthesised. Unfortunately, assembly of the disaccharide was hampered by unpredictable side-reactions and unexpected protecting group migration. Glycoresins 212 and 227 are currently being evaluated for anticancer and antibacterial activity and for their potential as efflux pump inhibitors. Polysialic acid (PSA), a homopolymer of sialic acid, plays an important role during development and neural regeneration, but by adulthood is essentially non-existent. Significantly, it has been identified on the surface of a growing number of tumours and is associated with cancer progression and metastasis. PSA is synthesised by two polysialyltransferases, PST and STX, which act synergistically. The polysialyltransferases are exciting potential novel targets for cancer therapy since their inhibition will result in prevention of PSA synthesis and might therefore reduce metastatic potential. The aim of this project was the design and synthesis of a library of molecule inhibitors of PST and STX. A series of L-rhamnose-based compounds was successfully synthesised and characterised.

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