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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

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Research Article

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

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*

Volume 16, Issue 4, 2020

Page: [432 - 441] Pages: 10

DOI: 10.2174/1573407215666190131121059

Price: $65

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.

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.

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

Graphical Abstract

[1]
Qiu, J.; Chen, S.; Su, L.; Liu, J.; Xiao, N.; Ou, T.M.; Tan, J.H.; Gu, L.Q.; Huang, Z.S.; Li, D. Cellular nucleic acid binding protein suppresses tumor cell metastasis and induces tumor cell death by downregulating heterogeneous ribonucleoprotein K in fibrosarcoma cells. Biochim. Biophys. Acta, 2014, 1840(7), 2244-2252.
[http://dx.doi.org/10.1016/j.bbagen.2014.02.025] [PMID: 24594223]
[2]
Kim, H.J.; Lee, J.J.; Cho, J.H.; Jeong, J.; Park, A.Y.; Kang, W.; Lee, K.J. Heterogeneous nuclear ribonucleoprotein K inhibits heat shock-induced transcriptional activity of heat shock factor 1. J. Biol. Chem., 2017, 292(31), 12801-12812.
[http://dx.doi.org/10.1074/jbc.M117.774992] [PMID: 28592492]
[3]
Leal, G.; Comprido, D.; de Luca, P.; Morais, E.; Rodrigues, L.; Mele, M.; Santos, A.R.; Costa, R.O.; Pinto, M.J.; Patil, S.; Berentsen, B.; Afonso, P.; Carreto, L.; Li, K.W.; Pinheiro, P.; Almeida, R.D.; Santos, M.A.S.; Bramham, C.R.; Duarte, C.B. The RNA-binding protein hnRNP K mediates the effect of BDNF on dendritic mRNA metabolism and regulates synaptic NMDA receptors in hippocampal neurons. eNeuro, 2017, 4(6), 1-23.
[http://dx.doi.org/10.1523/ENEURO.0268-17.2017] [PMID: 29255796]
[4]
Dinh, P.X.; Das, A.; Franco, R.; Pattnaik, A.K. Heterogeneous nuclear ribonucleoprotein K supports vesicular stomatitis virus replication by regulating cell survival and cellular gene expression. J. Virol., 2013, 87(18), 10059-10069.
[http://dx.doi.org/10.1128/JVI.01257-13] [PMID: 23843646]
[5]
Barboro, P.; Repaci, E.; Rubagotti, A.; Salvi, S.; Boccardo, S.; Spina, B.; Truini, M.; Introini, C.; Puppo, P.; Ferrari, N.; Carmignani, G.; Boccardo, F.; Balbi, C. Heterogeneous nuclear ribonucleoprotein K: altered pattern of expression associated with diagnosis and prognosis of prostate cancer. Br. J. Cancer, 2009, 100(10), 1608-1616.
[http://dx.doi.org/10.1038/sj.bjc.6605057] [PMID: 19401687]
[6]
Bomsztyk, K.; Denisenko, O.; Ostrowski, J. hnRNP K: One protein multiple processes. BioEssays, 2004, 26(6), 629-638.
[http://dx.doi.org/10.1002/bies.20048] [PMID: 15170860]
[7]
Zhang, Z.; Zhou, C.; Chang, Y.; Zhang, Z.; Hu, Y.; Zhang, F.; Lu, Y.; Zheng, L.; Zhang, W.; Li, X.; Li, X. Long non-coding RNA CASC11 interacts with hnRNP-K and activates the WNT/β-catenin pathway to promote growth and metastasis in colorectal cancer. Cancer Lett., 2016, 376(1), 62-73.
[http://dx.doi.org/10.1016/j.canlet.2016.03.022] [PMID: 27012187]
[8]
Ziv-Av, A.; Giladi, N.D.; Lee, H.K.; Cazacu, S.; Finniss, S.; Xiang, C.; Pauker, M.H.; Barda-Saad, M.; Poisson, L.; Brodie, C. RTVP-1 regulates glioma cell migration and invasion via interaction with N-WASP and hnRNPK. Oncotarget, 2015, 6(23), 19826-19840.
[http://dx.doi.org/10.18632/oncotarget.4471] [PMID: 26305187]
[9]
Hatakeyama, H.; Kondo, T.; Fujii, K.; Nakanishi, Y.; Kato, H.; Fukuda, S.; Hirohashi, S. Protein clusters associated with carcinogenesis, histological differentiation and nodal metastasis in esophageal cancer. Proteomics, 2006, 6(23), 6300-6316.
[http://dx.doi.org/10.1002/pmic.200600488] [PMID: 17133371]
[10]
Klimek-Tomczak, K.; Mikula, M.; Dzwonek, A.; Paziewska, A.; Karczmarski, J.; Hennig, E.; Bujnicki, J.M.; Bragoszewski, P.; Denisenko, O.; Bomsztyk, K.; Ostrowski, J. Editing of hnRNP K protein mRNA in colorectal adenocarcinoma and surrounding mucosa. Br. J. Cancer, 2006, 94(4), 586-592.
[http://dx.doi.org/10.1038/sj.bjc.6602938] [PMID: 16404425]
[11]
Ostrowski, J.; Bomsztyk, K. Nuclear shift of hnRNP K protein in neoplasms and other states of enhanced cell proliferation. Br. J. Cancer, 2003, 89(8), 1493-1501.
[http://dx.doi.org/10.1038/sj.bjc.6601250] [PMID: 14562022]
[12]
Paziewska, A.; Wyrwicz, L.S.; Bujnicki, J.M.; Bomsztyk, K.; Ostrowski, J. Cooperative binding of the hnRNP K three KH domains to mRNA targets. FEBS Lett., 2004, 577(1-2), 134-140.
[http://dx.doi.org/10.1016/j.febslet.2004.08.086] [PMID: 15527774]
[13]
Cardoso, L.N.F.; Nogueira, T.C.M.; Rodrigues, F.A.R.; Oliveira, A.C.A.; Luciano, M.C.S.; Pessoa, C.; Souza, M.V.N. N-acylhydrazones containing thiophene nucleus: A new anticancer class. Med. Chem. Res., 2017, 26(8), 1605-1608.
[http://dx.doi.org/10.1007/s00044-017-1832-y]
[14]
Leopoldino, A.M.; Carregaro, F.; Silva, C.H.T.P.; Feitosa, O.; Mancini, U.M.; Freitas, J.M.; Tajara, E.H. Sequence and transcriptional study of HNRPK pseudogenes, and expression and molecular modeling analysis of hnRNP K isoforms. Genome, 2007, 50(5), 451-462.
[http://dx.doi.org/10.1139/G07-016] [PMID: 17612614]
[15]
Oliveira, M.G.; Figueredo, A.S.; Aquino, G.L.B.; Leopoldino, A.M.; Silva, V.B.; Taft, C.A.; Silva, C.H.T.P. In Silico design of phenylbenzamide derivatives coupled to pyrimidines as novel hnRNP K ligands against cancer. Curr. Bioact. Compd., 2014, 10(3), 158-162.
[http://dx.doi.org/10.2174/157340721003141013142614]
[16]
Meira, C.S.; Dos Santos Filho, J.M.; Sousa, C.C.; Anjos, P.S.; Cerqueira, J.V.; Dias Neto, H.A.; da Silveira, R.G.; Russo, H.M.; Wolfender, J.L.; Queiroz, E.F.; Moreira, D.R.M.; Soares, M.B.P. Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents. Bioorg. Med. Chem., 2018, 26(8), 1971-1985.
[http://dx.doi.org/10.1016/j.bmc.2018.02.047] [PMID: 29523468]
[17]
Lannes, A.C. Cepas bacterianas: suscetibilidade a derivados da classe acilhidrazona em amostras do Hospital Universitário Antônio, PhD Thesis, Universidade Federal Fluminense (UFF): Niterói. 2010.
[18]
Charret, K.S.; Rodrigues, R.F.; Bernardino, A.M.R.; Gomes, A.O.; Carvalho, A.V.; Canto-Cavalheiro, M.M.; Leon, L.; Amaral, V.F. Effect of oral treatment with pyrazole carbohydrazide derivatives against murine infection by Leishmania amazonensis. Am. J. Trop. Med. Hyg., 2009, 80(4), 568-573.
[http://dx.doi.org/10.4269/ajtmh.2009.80.568] [PMID: 19346377]
[19]
Thota, S.; Rodrigues, D.A.; Pinheiro, P.S.M.; Lima, L.M.; Fraga, C.A.M.; Barreiro, E.J. N-Acylhydrazones as drugs. Bioorg. Med. Chem. Lett., 2018, 28(17), 2797-2806.
[http://dx.doi.org/10.1016/j.bmcl.2018.07.015] [PMID: 30006065]
[20]
Barreiro, E.J. Molecular simplification strategy in rational drug planning: The discovery of a new cardioactive agent. Quim. Nova, 2002, 25(6b), 1172-1180.
[http://dx.doi.org/10.1590/S0100-40422002000700018]
[21]
Fernandes, G.F.S.; Moreno-Viguri, E.; Santivañez-Veliz, M.; Paucar, R.; Chin, C.M.; Pérez-Silanes, S.; Santosa, J.L. A Comparative study of conventional and microwave-assisted synthesis of quinoxaline 1,4-di-N-oxide N-acylhydrazones derivatives designed a antitubercular drug candidates. J. Heterocycl. Chem., 2017, 54(4), 2380.
[http://dx.doi.org/10.1002/jhet.2830]
[22]
Santos Filho, J.M.; Pinheiro, S.M. Stereoselective, solvent free, highly efficient synthesis of aldo- and keto-N-acylhydrazones applying grindstone chemistry. Green Chem., 2017, 19, 2212-2224.
[http://dx.doi.org/10.1039/C7GC00730B]
[23]
Pineiro, M.; Dias, L.D.; Damas, L.; Aquino, G.L.B.; Calvete, M.J.F.; Pereira, M.M. Microwave irradiation as a sustainable tool for catalytic carbonylation reactions. Inorg. Chim. Acta, 2017, 455(2), 364-377.
[http://dx.doi.org/10.1016/j.ica.2016.06.043]
[24]
Henriques, C.A.; Pinto, S.M.A.; Aquino, G.L.B.; Pineiro, M.; Calvete, M.J.F.; Pereira, M.M. Ecofriendly porphyrin synthesis by using water under microwave irradiation. ChemSusChem, 2014, 7(10), 2821-2824.
[http://dx.doi.org/10.1002/cssc.201402464] [PMID: 25111181]
[25]
Vila Verde, G.M.; Barros, D.A.; Oliveira, M.S.; Aquino, G.L.B.; Santos, D.M.; de Paula, J.R.; Dias, L.D.; Piñeiro, M.; Pereira, M.M. A Green protocol for microwave-assisted extraction of volatile oil terpenes from Pterodon emarginatus Vogel. (Fabaceae). Molecules, 2018, 23(3), 651.
[http://dx.doi.org/10.3390/molecules23030651] [PMID: 29534046]
[26]
Dias, L.D.; Gonçalves, K.H.E.; Queiroz, J.E.; Vila Verde, G.M.; Aquino, G.L.B. An eco-friendly and alternative method of forced degradation of fluoroquinolone drugs by microwave irradiation: a new application for analytical eco-scale. J. Microwave Power EE, in press
[http://dx.doi.org/10.1080/08327823.2018.1494470]
[27]
de la Hoz, A.; Díaz-Ortiz, A.; Moreno, A. Microwaves in organic synthesis. Thermal and non-thermal microwave effects. Chem. Soc. Rev., 2005, 34(2), 164-178.
[http://dx.doi.org/10.1039/B411438H] [PMID: 15672180]
[28]
Anastas, P.T.; Warner, J.C. Green chemistry: theory and practice, 1st ed; Oxford University Press: New York, 1998.
[29]
Verdonk, M.L.; Cole, J.C.; Hartshorn, M.J.; Murray, C.W.; Taylor, R.D. Improved protein-ligand docking using GOLD. Proteins, 2003, 52(4), 609-623.
[http://dx.doi.org/10.1002/prot.10465] [PMID: 12910460]
[30]
Lin, C.J.; Barbosa, A.S. Techniques for analysis of gene transcription regulation and its applications in molecular endocrinology. Arq. Bras. Endocrinol. Metabol, 2002, 46(4), 330-340.
[http://dx.doi.org/10.1590/S0004-27302002000400004]
[31]
Backe, P.H.; Messias, A.C.; Ravelli, R.B.G.; Sattler, M.; Cusack, S. X-ray crystallographic and NMR studies of the third KH domain of hnRNP K in complex with single-stranded nucleic acids. Structure, 2005, 13(7), 1055-1067.
[http://dx.doi.org/10.1016/j.str.2005.04.008] [PMID: 16004877]
[32]
Braddock, D.T.; Baber, J.L.; Levens, D.; Clore, G.M. Molecular basis of sequence-specific single-stranded DNA recognition by KH domains: solution structure of a complex between hnRNP K KH3 and single-stranded DNA. EMBO J., 2002, 21(13), 3476-3485.
[http://dx.doi.org/10.1093/emboj/cdf352] [PMID: 12093748]
[33]
Guimarães, C.R.W. The multiple contributions to protein-linker complexation: Consequences in drug design the multiple contributions to protein-linker complexation: Consequences in drug design. Rev. Virtual. Quim., 2012, 4(4), 348-364.

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