Design, synthesis and biological evaluation of retinoid and non-retinoid mimetics of fenretinide as chemotherapeutic agents

Fenretinide is a potent chemotherapeutic and chemopreventive against a range of cancer tumour cell lines, namely Ewing’s Sarcoma Family of Tumours (ESFT) which is an aggressive malignant tumour primarily affecting children and young adults. The mechanism of action of the drug is not known. The major disadvantage to fenretinide as a treatment for cancer is its poor in vivo efficacy due to poor oral bioavailability, requiring the patient to take many tablets per day regularly in order to achieve an adequate plasma concentration. By use of computational drug design and medicinal chemistry-led design, we have identified both novel retinoid and non-retinoid mimetics of fenretinide, which demonstrate comparable in vitro activity to fenretinide against ESFT cell types. This research has investigated the molecular features of fenretinide which contribute to its inhibition of cell growth in order to establish structure-activity relationships (SAR). We have also investigated the mechanism of cell death for a number of compounds and have identified molecules which appear to induce cell death via a similar mechanism to fenretinide as well as those which function via an alternative mechanism. Additional studies aimed at understanding the mechanism of action of fenretinide through affinity chromatography studies, have implicated several proteins as potential binding partners for further investigation. The outcomes of the current project may aid the design of future retinoid or non-retinoid analogues of fenretinide with improved efficacy, whilst retaining the minimal toxicity profile of fenretinide as well as to better understand the mechanism of the chemotherapeutic induction of the cell death process in ESFT cells.