Design and development of novel isoflavonoid anti-inflammatory and anticancer agents

Cancer and chronic inflammatory diseases are leading causes of death and disease burden worldwide. Cancer is the second leading cause of death globally, accounting for nearly 10 million deaths in 2020 alone. Inflammation plays a central role in disease onset, progression, and resistance, and has been implicated in over 50% of all deaths, including approximately 20% of cancers. Persistent mortality and treatment resistance underscore the urgent need to understand and develop novel treatment options targeting the key drivers of these diseases. The aim of this thesis was to develop anticancer and anti-inflammatory agents derived from isoflavonoid and related scaffolds to target key oncogenic and inflammatory signalling pathways such as TBK1/STING, CDK7/MYC and ERα/ERβ. Computational modelling was utilised for compound design, screening and optimisation. In silico studies led to a focus on C6 and C7 modifications of the isoflavene idronoxil (IDX). C6 modification resulted in anti- inflammatory leads with potent TBK1 inhibitory potency (IC50 = 0.13 µM). The mechanism of the lead compounds was confirmed with multiple biological assays, and the viability of the lead as an anticancer agent was also evaluated through synergistic cytotoxicity studies. A further series of C6 modifications resulted in promising compounds with cytotoxic potency in acute myeloid leukemia. Similar modifications were also compared on other heterocyclic scaffolds but showed inferior activity to isoflavene analogues. Isoflavene leads were shown in biological assays to inhibit the superoncogenic target MYC by suppressing CDK7 activity. Structure-based design was further employed to attempt to modulate the estrogenic properties of isoflavonoids for the treatment of estrogen positive cancers. In this respect, two anticancer leads were obtained with low micromolar cytotoxicity against breast cancer cell lines (IC50 = 1.5 µM in T-47-D). Mechanistic analysis was also investigated through enzymatic assays. In addition, various strategies for incorporating fused ring structures to the C6 and C7 positions of the IDX A ring were investigated, with the objective of further enhancing anticancer or anti-inflammatory properties. Compounds were screened across various cancers including neuroblastoma, prostate, and breast cancers. Put together, this work expands the therapeutic potential and SAR of isoflavonoids against cancer and inflammatory diseases.