Synthesis and In silico Studies of N-acylhydrazone Derivatives as hnRNP K Ligands with Potential Anti-cancer Activity

Background: A green and efficient synthetic methodology for a wide family of Nacylhydrazones (yields: 42-76%) using microwave irradiation is described, as well as their full characterization. Their potential antineoplastic activity was evaluated in vitro via EMSA by testing protein- DNA interactions. Among the 11 compounds tested, N-acylhydrazone derivative 5 bearing a hydroxyl group, showed the highest affinity to bind and inhibit the hnRNP K KH3 domain. Docking simulations of compound 5 showed three possible modes of interaction between the KH3 domain of hnRNP K protein and compound predict. : The N-acylhydrazones are knows as powerful chemical entities for Medicinal Chemistry, since it has been identified in a huge number of hit and lead compounds that act on various types of molecular targets, including in tumorigenesis processes. Objective: We evaluated their potential ability to inhibit the KH3 domain of the hnRNP K protein binding to single stranded DNA (ssDNA). Furthermore, a docking simulation was performed for the newly synthetized compounds to evaluate their interactions between proteins and N-acylhydrazine derivative. Methods: The N-acylhydrazone derivatives were synthetized through three reaction steps, from a simple and commercial substrate, using microwave irradiation as a green energy source. The N-acylhydrazone derivatives ability to bind with the hnRNP K protein was evaluated via EMSA by testing protein-DNA interactions. The docking simulations were performed in a Gold 5.2.2 software using 100 conformers, 10.000 operations, 95 mutations and 95 crossovers. Results: Eleven new N-acylhydrazone derivatives were synthetized using microwave showing yields between 42% and 76%. Among the eleven compounds tested, compound 5 was shown to be most capable to prevent the natural binding of hnRNP K protein to the oligonucleotide. Regarding the docking simulation, compound 5 can bind to the main binding residues of KH3 domain and compete with the natural ligand ssDNA of this protein. Conclusion: A green and efficient synthetic methodology for a wide family of N-acylhydrazones (yields: 42-76%) using microwave irradiation is described, as well as their full characterization. Their potential antineoplastic activity was evaluated in vitro via EMSA by testing protein-DNA interactions. Among the 11 compounds tested, N-acylhydrazone derivative 5 bearing a hydroxyl group, showed the highest affinity to bind and inhibit the hnRNP K KH3 domain. Docking simulations of compound 5 showed three possible modes of interaction between the KH3 domain of hnRNP K protein and compound predict.