Synthesis of Phosphine Glycoconjugates for Radiochemical Applications

  • Rachel A Lamb

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Several examples of phosphine glycoconjugate ligands, whereby a carbohydrate is covalently bonded to a phosphine moiety, have previously been reported but they have been used exclusively for catalytic applications. In this thesis, the synthesis of phosphine glycoconjugates has been investigated with a view to their use in medical imaging applications. Incorporation of a carbohydrate was explored to target cancerous cells, which exhibit increased glucose avidity compared with normal cells.
A variety of methods for the synthesis of monophosphine glycoconjugates with alkyl linkers have been investigated: Lewis acid catalysed glycosylation chemistry, hydrophosphination chemistry, lithium phosphide chemistry, quaternisation chemistry and amide coupling chemistry. Generally, these methods were incompatible with the phosphine moiety. However, we have demonstrated that amide coupling is a promising method by synthesising phosphine glycoconjugate 2.21, where D-glucose is conjugated to a PPh₂ moiety via an alkyl linker (Figure I). The Re coordination chemistry of 2.20 (the peracetylated analogue of 2.21) was investigated and this informed the subsequent ⁹⁹ᵐTc radiolabelling study. High quality results for the ⁹⁹ᵐTc radiolabelling of 2.21 was observed. However, poor serum stability of the ⁹⁹ᵐTc complex of 2.21 precluded in vivo testing.
In 1999, Beller et al. reported a method to prepare ligands 3.1 and 3.7 (Figure I), where D-glucose and D-galactose, respectively, were conjugated to a PPh₂ moiety via an aryl linker, and their use in biphasic catalysis was investigated. Using this method, a small library of related monophosphine glycoconjugates was synthesised. The phosphine moiety (PR₂ = PPh₂, P(o-tol)₂, P(p-tol)₂, PCy₂) and carbohydrate moiety (Glc, Gal, Lac) were varied and the Re coordination chemistry of these ligands was investigated. All examples, except where PR2 = P(o-tol)₂, formed a Re(I) complex and consequently, the ⁹⁹ᵐTc radiolabelling of these ligands was studied; these results reflect those of the Re(I) coordination study. Additionally, Re(I) uptake studies (in HeLa, HDF and EA.hy926) were performed for several of the complexes. Key findings include: (i) the introduction of a carbohydrate led to greater uptake in cells, compared with incorporation of a non-glycoconjugate phosphine ligand and (ii) cell lines could distinguish between Gal and Glc moieties.
The final Chapter presents the routes towards diphosphine glycoconjugate ligands that have been explored. Attempts to synthesise a bidentate glycoconjugate containing Ndiphosphinomethyl groups (4.29, Figure I) have been shown to be promising, but its purity was insufficient to justify radiolabelling. A 1,1-diphosphine moiety was conjugated to Dglucose via amide coupling to give ligand 4.36 (Figure I) and consequently, the Re(V) coordination studies were performed. However, ⁹⁹ᵐTc radiolabelling of 4.36 was unsuccessful.
Date of Award25 Jan 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorM C Galan (Supervisor), Paul G Pringle (Supervisor) & Michelle Ma (Supervisor)

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