Design and synthesis of putative inhibitors of Granzyme b and Liver Receptor Homolog-1 and Increasing the bioavailability of Fulvestrant in the treatment of breast cancer

This thesis describes the work conducted on three projects towards the development of putative inhibitors of various targets involved in cancer development. Granzyme B (Grb) inhibitors: GrB is an interesting target for the treatment of leukaemia, as once inhibited it could simultaneously prevent Graft-Versus-Host disease and promote Graft-Versus-Leukaemia. Following the design of putative inhibitors of GrB using computational modelling, the synthesis of six analogues was carried out. Although these compounds could not be assessed in our biological assay due to lack of solubility, interesting synthetic routes have been developed in order to access these novel molecules. Liver receptor homolog-1 (LRH-1) inhibitors: LRH-1 has recently been demonstrated as being an interesting target in the treatment of breast cancer, potentially overcoming the resistance and side effects associated with currently widely used anti-oestrogen therapies, such as Tamoxifen. Following the identification of resorcylate compounds as a new class of inhibitors of LRH-1, work has been conducted in the design and the synthesis of novel analogues. As such, dehydroxylated resorcylates, N-heterocyclic resorcylates or steroidal hybrids were synthesised and tested in cell-based assays. Although no improvement of biological activity was achieved, they represent interesting compounds for targeting other members of the nuclear receptor family. Fulvestrant analogue: Fulvestrant is an approved drug in the treatment of breast cancer, however it requires intravenous administration due to its poor oral bioavailability. Recent development within our laboratory identified a triaminohydroxy side chain as greatly improving the bioavailability of inhibitors of CDK-7. As such, an analogue of Fulvestrant bearing a triaminohydroxy side chain was designed and the synthesis was initiated. After a failed initial synthetic route, the synthesis of an interesting novel intermediate was achieved, which could be used towards the synthesis of the desired analogue.Open Acces