Development of synthetic routes towards bis (macrocyclic) compounds for imaging and therapy of cancer

Welch, Chris J.

Abstract

Porphyrin molecules are efficient generators of singlet oxygen and are used as photosensitisers in PDT. They are also known to accumulate in tumour tissue due to the hyperpermeability of tumour vasculature and poor lymphatic drainage, thus exhibiting a passive tumour targeting property. Functionalised tetraazamacrocycles based around the cyclam and cyclen structures form thermodynamically stable and kinetically inert complexes with metal ions such as copper(II) and gadolinium(III), and are used in vivo for both imaging and radiotherapy (MRI, PET, radiotherapy).

Three convergent synthetic routes have been used to successfully synthesise novel molecules which combine these two elements, and therefore open up the possibility of combining imaging and therapy (PET-PDT and MRI-PDT) or dual therapy (radiotherapy-PDT) in one tumour avid compound. A series of novel macrocyclic chelators based around the cyclen framework have been successfully synthesised, each containing a functional handle for further elaboration of the structure. The amino bearing derivatives have been successfully coupled to a porphyrin compound via reductive amination and Buchwald-Hartwig coupling reactions, giving four new examples of porphyrin-cyclen conjugates.

A Suzuki coupling methodology has been used to synthesise a porphyrin-cyclen conjugate with an aryl-aryl linkage which exhibits enhanced stability towards acidic conditions.

The compounds have been characterised by NMR, mass spectrometry and UV/vis spectroscopy.

Citation

Welch, C. J. Development of synthetic routes towards bis (macrocyclic) compounds for imaging and therapy of cancer. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4208906

• Thesis Type: Thesis
• Deposit Date: Aug 15, 2011
• Publicly Available Date: Feb 22, 2023
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4208906
• Additional Information: Department of Chemistry, The University of Hull
• Award Date: Jan 1, 2008