Synthesis of novel inhibitors of CDK 4 / Cyclin D1 based on the natural marine sponge pigment fascaplysin

This thesis describes an investigation into the design and synthesis of novel inhibitors of the cell-cycle regulatory enzyme CDK4/Cyclin D1 utilising the structure of the natural product fascaplysin as a lead compound. The structure activity relationship of fascaplysin (i) has been investigated and its structure simplified and rationalised to give novel inhibitor pharmacophores based on structures (ii) and (iii). Inhibitors of structure (ii) were found to possess activity against CDK4/Cyclin D1 of IC50 51-176 μM and to be approximately 15-20 fold selective over CDK2/Cyclin A. The second generation compounds of structure (iii) were synthesised to explore a suspected π-stacking pocket in the active site of CDK4 around the Phe93 residue. These compounds were active against CDK4/Cyclin D1 with IC50 values in the range 7-50 μM and to be 20-100 fold selective over CDK2/Cyclin A. New methodology towards the synthesis of un-natural products bearing a carbohydrate subunit connected via the anomeric 1-position and the 2- and 3- positions of the sugar was also explored. Indole was successfully glycosylated with a glucose subunit at the anomeric position (v) using the anhydrosugar (iv) and indoline was glycosylated with a glucose sugar derivative at the 3-position (viii) using the manno-epoxide (vi).EThOS - Electronic Theses Online ServiceGBUnited Kingdo