Rational Design, Synthesis & Biological Evaluation of Febuxostat-based HDAC Inhibitors as Antitumor and Anti-hyperuricemic Agents

Cancer is a severe illness caused by abnormal cell growth. It can be treated with surgery, radiotherapy, and chemotherapy. Epigenetic modifications, including histone acetylation, play a significant role in cancer progression. Histone deacetylases (HDACs) are a potential target for the regulation of epigenetic aberrance and are well-evidenced to be associated with many oncogenes and tumor suppressors. In this thesis, our efforts to develop structural models with anti-tumor properties that also prevent drug-induced hyperuricemia have led us to create hydroxamic acids and anilides based on xanthine oxidase inhibitors. The design approach focused on integrating febuxostat, a xanthine oxidase inhibitor, as a surface recognition component of the HDAC inhibitor pharmacophore model. The febuxostat-based HDAC inhibitors were synthesized from commercially available chemicals following a multistep protocol. The compounds were further evaluated biologically using an MTT assay, an enzyme inhibition assay, Acridine orange staining, and Western blot analysis. The research findings demonstrated that hydroxamic acid 4 exhibited notable antileukemic effects by targeting HDAC isoforms. The adduct possessed xanthine oxidase inhibitory activity, which was a delightful discovery. Interestingly, further analysis revealed that its cell growth inhibitory effects were not primarily attributed to xanthine oxidase inhibition, indicating the presence of an alternative underlying mechanism. Compound 4 significantly effectively reduced high uric acid levels in an In vivo animal model induced with hyperuricemia and showed promising antitumor activity in a cell line HL-60 (IC50 = 0.706 ± 0.12 µM) xenograft mouse model. To minimize its toxicity toward normal cells, compound 4 was linked with poly (ethylene glycol) poly (aspartic acid) block copolymer to create polymeric nanoparticles (NPs) that respond to changes in pH. The scanning electron microscopy (SEM) analysis showed that the nanoparticles (NPs) had consistent size distributions, while transmission electron microscopy (TEM) analysis confirmed the NPs' spherical shape, indicating their potential for self-assembly.