Submit Manuscript  

Article Details


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

[ Vol. 16 , Issue. 4 ]

Author(s):

Wanderson C. Souza, Lucas D. Dias, Jaqueline E. de Queiroz, Hérika D. A. Vidal, Vinícius B. da Silva, Andréia M. Leopoldino, Carlos H. T. de Paula da Silva, Giuliana M. V. Verde and Gilberto L. B. Aquino*   Pages 432 - 441 ( 10 )

Abstract:


Background: 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 charac-terization. Their potential antineoplastic activity was evaluated in vitrovia 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 pro-tein 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 tar-gets, including in tumorigenesis processes.

Objective: We evaluated their potential ability toinhibit the KH3 domain of the hnRNP K protein bind-ing 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

Method: 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-acylhydrazonederivatives 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 dock-ing simulation, compound5 can bind to the main binding residues of KH3 domain and compete with the natural ligand ssDNA of this protein.

Conclusion: 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 vitrovia 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 5showed three possible modes of interaction between the KH3 domain of hnRNP K protein and compound predict.

Keywords:

Protein hnRNP K, KH3 domain, N-acylhydrazones, docking, cancer, antineoplastic activity

Affiliation:

Faculty of Pharmacy, Unit of Exact and Technological Sciences, State University of Goiás, Br 153, 75132400, Anápolis, Goiás, Coimbra Chemistry Center (CQC), Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Laboratory on Bioproducts and Synthesis Research (LPbioS), Universidade State of Goiás, Br 153, 75132400, Anápolis, Goiás, Laboratory on Bioproducts and Synthesis Research (LPbioS), Universidade State of Goiás, Br 153, 75132400, Anápolis, Goiás, School of Medical, Pharmaceutical Sciences and Biomedical at PUC, Rua 232, Setor Leste Universitário, 74605140, Goiânia, Goiás, Science Department Pharmacists of the Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Black, Sao Paulo, Science Department Pharmacists of the Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Black, Sao Paulo, Laboratory on Bioproducts and Synthesis Research (LPbioS), Universidade State of Goiás, Br 153, 75132400, Anápolis, Goiás, Coimbra Chemistry Center (CQC), Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra



Read Full-Text article