Exploration of newly synthesized deferasirox derivatives as potential anti-cancer agents via in-vitro and in-silico approaches

Carbonic anhydrase IX (CA IX), upregulated by hypoxia-inducible factor (HIF), plays a crucial role in regulation of intracellular and extracellular pH, which is essential for the growth and spread of tumors. The overexpression of CA IX in breast cancer is linked to a low post-radiation patient survival rate. Under normoxic conditions, CA IX expression is relatively low, but hypoxia-inducible factors (HIFs) upregulate its expression when oxygen levels drop. This adaptation supports the tumor's acidic microenvironment, aiding processes like metastasis, immune evasion, and resistance to therapies. Due to these functions, CA IX is considered a promising target for cancer therapy, with inhibitors in development aimed at disrupting its activity and thus hindering tumor growth and survival. Thus, various derivatives of already reported anticancer drug i.e., deferasirox were synthesized and their effect on CA IX enzyme were assessed. Additionally, the binding affinities of deferasirox derivatives with three distinct receptor proteins i.e., Tumor Protein P53 (TP53), Nuclear factor kappa B (NF-kappa B) and caspase 3 (pdb: 3DCY, 1NFI, 3DEI) were also observed. Their anticancer effect was evaluated by using non-invasive human breast cancer cells i.e., MCF-7 and glioblastoma cells (U87). Among all derivatives, the four thioureas derivatives showed more anticancer potential. The 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)-N-((3,4-dimethoxyphenyl)carbamothioyl) benzamide (6) derivative exhibited maximum anticancer potential (0.33 +/- 0.02 mu M) with greater binding affinity at different protein receptors. The MTT results further confirmed the enzyme inhibition results of deferasirox derivatives. In conclusion, targeting hypoxia-induced CA IX expression in breast cancer through the use of deferasirox-derived thiourea derivatives presents a promising therapeutic approach.