Bio-orthogonal association of Janus-face fluorocyclohexyl rings for PET tumour imaging and delivery of drugs to cancer cells

The project will involve a collaboration between Professor David O'Hagan's laboratory and the pre-clinical imaging centres at the University hospitals in Aberdeen led by Dr Sergio Dall'Angelo and in Edinburgh led by Dr Adriana Tavares. The project will explore a fundamentally new concept in molecular recognition and apply it to cancer diagnosis and treatments. If successful it could be applied more widely to any targeted disease cell type. The project builds on the recent discovery that cyclohexane rings which have fluorines on one face of the ring, and hydrogens on the other face have extraordinarily polar properties [1]. These have been termed 'Janus face' rings. The polarised faces of the rings strongly self-associate and have no counterpart in Nature and thus they constitute a novel molecular motif that is 'orthogonal' to biochemistry. Chemistry that is orthogonal to biochemistry is of wide current interest for controlling molecular precision within cells in chemical biology. Organic bound fluorine forms only very weak hydrogen bonds, so it is anticipated that these rings will not hydrogen bond to proteins and other cellular components, and that self-association will be stronger than other interactions in the cellular environment [2]. We wish to explore this concept by preparing radiolabelled molecules of this class for positron emission tomography (PET) and cancer cell imaging. To facilitate this, collaborations are established with the pre-clinical imaging centres at Aberdeen and Edinburgh University hospitals, where they have ready access to the radio-isotope 18F-fluoride and to xenograft mouse models.
The project will synthesise Janus ring tagged RGD peptides and tagged 5'-chlorodeoxyadenosine for [18F]-radiolabelling with a C-F bond forming enzyme (fluorinase) [3]. Cyclic RGD peptides bind to specific protein motifs (epitopes) that are abundant on the surface of breast cancer cells, and therefore they are used to target such cells. The chloro-adenosine construct will then be radiolabelled with [18F]-fluoride using the enzyme. With the chemistry and radiochemistry in place small animal studies will be investigated in PET imaging experiments using xenograft mice models in Edinburgh.