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

Author(s):

Wanderson Costa Souza, Lucas Danilo Dias, Jaqueline Evangelista de Queiroz, Hérika Danielle Almeida Vidal, Vinícius Barreto da Silva, Andréia Machado Leopoldino, Carlos Henrique Tomich de Paula da Silva, Giuliana Muniz Vila Verde and Gilberto Lucio Benedito Aquino*   Pages 1 - 10 ( 10 )

Abstract:


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.

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-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.

Keywords:

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

Affiliation:

Faculdade de Farmácia, Unidade de Ciências Exatas e Tecnológicas, Universidade Estadual de Goiás, Br 153, 75132400, Anápolis, Goiás, Coimbra Chemistry Centre (CQC), Departamento de Química da Universidade de Coimbra, Rua Larga, 3004-535 Coimbra, Laboratório de Pesquisa em Bioprodutos e Síntese (LPbioS), Universidade Estadual de Goiás, Br 153, 75132400, Anápolis, Goiás, Laboratório de Pesquisa em Bioprodutos e Síntese (LPbioS), Universidade Estadual de Goiás, Br 153, 75132400, Anápolis, Goiás, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da PUC, Rua 232, Setor Leste Universitário, 74605140, Goiânia, Goiás, Departamento de Ciências Farmacêuticas da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Departamento de Ciências Farmacêuticas da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Laboratório de Pesquisa em Bioprodutos e Síntese (LPbioS), Universidade Estadual de Goiás, Br 153, 75132400, Anápolis, Goiás, Coimbra Chemistry Centre (CQC), Departamento de Química da Universidade de Coimbra, Rua Larga, 3004-535 Coimbra



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