Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

On the Cytotoxicity of Chiral Ruthenium Complexes Containing Sulfur Amino Acids against Breast Tumor Cells (MDA-231 and MCF-7)

Author(s): Celisnolia M. Leite*, João Honorato de Araujo-Neto, Rodrigo S. Corrêa, Legna Colina-Vegas, Diego Martínez-Otero, Paulo R. Martins, Cristiane G. Silva and Alzir A. Batista*

Volume 21, Issue 9, 2021

Published on: 24 August, 2020

Page: [1172 - 1182] Pages: 11

DOI: 10.2174/1871520620666200824114816

Price: $65

Abstract

Background: Breast cancer is one of the most common types among women. Its incidence progressively increases with age, especially after age 50. Platinum compounds are not efficient in the treatment of breast cancer, highlighting the use of other metals for the development of new chemotherapeutic agents.

Objective: This paper aims to obtain three new ruthenium compounds that incorporate sulfur amino acids in their structures and to investigate their cytotoxic activity in breast tumor cell lines.

Methods: Complexes with general formula [Ru(AA)(dppb)(bipy)] (complexes 1 and 2) or [Ru(AA)(dppb) (bipy)]PF6 (complex 3), where AA = L-cysteinate (1), D-penicillaminate (2), and L-deoxyalliinate (3), dppb = 1,4-bis(diphenylphosphino)butane and 2,2´-bipyridine, were obtained from the cis-[RuCl2(dppb)(bipy)] precursor. The cytotoxicity of the complexes on MDA-MB-231 (triple negative human breast cancer); MCF-7 (double positive human breast cancer) and V79 (hamster lung fibroblast) was performed by the MTT (4,5- dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) method. The control agent was the cisplatin, which is a commercially available drug for cancer treatment.

Results: In complexes (1) and (2), the ligands are coordinated to the metal center by nitrogen and sulfur atoms, while in complex (3), coordination is through the oxygen and nitrogen atoms. These suggestions are based on the infrared and 31P{1H} NMR data. For complexes (1) and (2), their X-ray structures were determined confirming this suggestion. The three complexes are stable in a mixture of DMSO (80%) and biological medium (20%) for at least 48h and presented cytotoxicity against the MDA-MB-231 and MCF-7 tumor cells with reasonable selectivity indexes.

Conclusion: Our work demonstrated that ruthenium complexes containing sulfur amino acids, bipyridines and bisphosphines showed cytotoxicity against the MDA-MB-231 and MCF-7 cancer cell lines, in vitro, and that they interact weakly with the DNA (Deoxyribonucleic Acid) and the HSA (Human Serum Albumin) biomolecules.

Keywords: Ru(II)/amino acid complexes, diastereoisomers, breast cancer cells (MDA-MB-231 and MCF-7), cytotoxicity, DNA and HSA interaction, DNA docking.

« Previous Next »
Graphical Abstract

[1]
Hanna, N.; Einhorn, L.H. Testicular cancer: a reflection on 50 years of discovery. J. Clin. Oncol., 2014, 32(28), 3085-3092.
[http://dx.doi.org/10.1200/JCO.2014.56.0896] [PMID: 25024068]
[2]
Hu, Z.; Yu, J.; Gui, G.; Chen, Y.; Huang, R.; Jiang, L.; Kwong, J.S.W.; Li, Y.; Zhang, L. Cisplatin for testicular germ cell tumors: A rapid review. J. Evid. Based Med., 2016, 9(3), 144-151.
[http://dx.doi.org/10.1111/jebm.12210] [PMID: 27376482]
[3]
Qi, L.; Luo, Q.; Zhang, Y.; Jia, F.; Zhao, Y.; Wang, F. Advances in toxicological research of the anticancer drug cisplatin. Chem. Res. Toxicol., 2019, 32(8), 1469-1486.
[http://dx.doi.org/10.1021/acs.chemrestox.9b00204] [PMID: 31353895]
[4]
Zeng, L.; Gupta, P.; Chen, Y.; Wang, E.; Ji, L.; Chao, H.; Chen, Z-S. The development of anticancer ruthenium(ii) complexes: From single molecule compounds to nanomaterials. Chem. Soc. Rev., 2017, 46(19), 5771-5804.
[http://dx.doi.org/10.1039/C7CS00195A] [PMID: 28654103]
[5]
Cao, W.; Zheng, W.; Chen, T. Ruthenium polypyridyl complex inhibits growth and metastasis of breast cancer cells by suppressing FAK signaling with enhancement of TRAIL-induced apoptosis. Sci. Rep., 2015, 5, 9157.
[http://dx.doi.org/10.1038/srep09157] [PMID: 25778692]
[6]
Kenny, R.G.; Marmion, C.J. Toward multi-targeted platinum and ruthenium drugs-a new paradigm in cancer drug treatment regimens? Chem. Rev., 2019, 119(2), 1058-1137.
[http://dx.doi.org/10.1021/acs.chemrev.8b00271] [PMID: 30640441]
[7]
de Sousa, I.H.; Campos, V.N.S.; Vale, A.A.M.; Maciel-Silva, V.L.; Leite, C.M.; Lopes, A.J.O.; Mourão, P.S.; Lima, F.C.A.; Batista, A.A.; dos Santos, A.P.S.A.; Almeida, M.A.P.; Pereira, S.R.F. Ruthenium(II) complexes with N, O-chelating proline and threonine ligands cause selective cytotoxicity by the induction of genomic instability, cell cycle arrest and apoptosis in breast and prostate tumor cells. Toxicol. In Vitro, 2020, 62, 104679.
[8]
Vettore, L.; Westbrook, R.L.; Tennant, D.A. New aspects of amino acid metabolism in cancer. Br. J. Cancer, 2020, 122(2), 150-156.
[http://dx.doi.org/10.1038/s41416-019-0620-5] [PMID: 31819187]
[9]
Melvik, J.E.; Pettersen, E.O. Reduction of cis-dichloro diammineplatinum-induced cell inactivation by methionine. Inorg. Chim. Acta, 1987, 137, 115-118.
[http://dx.doi.org/10.1016/S0020-1693(00)87128-5]
[10]
Alden, W.W.; Repta, A.J. Exacerbation of cisplatin-induced nephrotoxicity by methionine. Chem. Biol. Interact., 1984, 48(1), 121-124.
[http://dx.doi.org/10.1016/0009-2797(84)90012-7] [PMID: 6537905]
[11]
Chauhan, M.; Banerjee, K.; Arjmand, F. DNA binding studies of novel Copper(II) complexes containing L-tryptophan as chiral auxiliary: In vitro antitumor activity of Cu-Sn2 complex in human neuroblastoma cells. Inorg. Chem., 2007, 46(8), 3072-3082.
[http://dx.doi.org/10.1021/ic061753a] [PMID: 17378549]
[12]
Yu, Q.; Liu, Y.; Wang, C.; Sun, D.; Yang, X.; Liu, Y.; Liu, J. Chiral ruthenium(II) polypyridyl complexes: Stabilization of g-quadruplex DNA, inhibition of telomerase activity and cellular uptake. PLoS One, 2012, 7(12), e50902.
[http://dx.doi.org/10.1371/journal.pone.0050902] [PMID: 23236402]
[13]
Sharma, S.; Chauhan, M.; Jamsheera, A.; Tabassum, S.; Arjmand, F. Chiral transition metal complexes: Synthetic approach and biological applications. Inorg. Chim. Acta, 2017, 458, 8-27.
[http://dx.doi.org/10.1016/j.ica.2016.12.011]
[14]
Wang, Y.; Huang, H.; Zhang, Q.; Zhang, P. Chirality in metal-based anticancer agents. Dalton Trans., 2018, 47(12), 4017-4026.
[http://dx.doi.org/10.1039/C8DT00089A] [PMID: 29479608]
[15]
Wu, Q.; Zhang, S-Y.; Liao, S-Y.; Cao, J-Q.; Zheng, W-J.; Li, L.; Mei, W.J. Chiral Ru(II) complexes act as a potential non-viral gene carrier for directional transportation to the nucleus and cytoplasm. Metallomics, 2020, 12(4), 504-513.
[http://dx.doi.org/10.1039/C9MT00192A] [PMID: 32051986]
[16]
Reymer, A.; Nordén, B. Enantiospecific kinking of DNA by a partially intercalating metal complex. Chem. Commun. (Camb.), 2012, 48(41), 4941-4943.
[http://dx.doi.org/10.1039/c2cc31176c] [PMID: 22476247]
[17]
Almeida, M.A.P.; do Nascimento, F.B.; Graminha, A.E.; Ferreira, A.G.; Ellena, J.; Mello, F.M.S.; de Lima, A.P.; Silveira-Lacerda, E.P.; Batista, A.A. Structural features and cytotoxic activities of [Ru(AA-H)(dppb)(bipy)]PF, complexes. Polyhedron, 2014, 81, 735-742.
[http://dx.doi.org/10.1016/j.poly.2014.07.024]
[18]
Queiroz, S.L.; Batista, A.A.; Oliva, G.; Gambardella, M.T.P.; Santos, R.H.A.S.; MacFarlane, K.S.; Rettig, S.J.; James, B.R. The reactivity of five-coordinate Ru(II) (1,4-bis(diphenylphosphino) butane) complexes with the N-donor ligands: ammonia, pyridine, 4-substituted pyridines, 2,2′-bipyridine, bis(o-pyridyl)amine, 1,10-phenanthroline, 4,7-diphenylphenanthroline and ethylenediamine. Inorg. Chim. Acta, 1998, 267(2), 209-221.
[http://dx.doi.org/10.1016/S0020-1693(97)05615-6]
[19]
Sheldrick, G.M. A short history of SHELX. Acta Crystallogr. A, 2008, 64(Pt 1), 112-122.
[http://dx.doi.org/10.1107/S0108767307043930] [PMID: 18156677]
[20]
Macrae, C.F.; Bruno, I.J.; Chisholm, J.A.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P.A. Mercury CSD 2.0 - new features for the visualization and investigation of crystal structures. J. Appl. Cryst., 2008, 41, 466.
[http://dx.doi.org/10.1107/S0021889807067908]
[21]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[22]
Gratton, E.; Silva, N.; Mei, G.; Rosato, N.; Savini, I. Finazzi- Agro, A. Fluorescence lifetime distribution of folded and unfolded proteins. Int. J. Quantum Chem., 1992, 42, 1479-1489.
[http://dx.doi.org/10.1002/qua.560420522]
[23]
da Silva, M.M.; de Camargo, M.S.; Correa, R.S.; Castelli, S.; De Grandis, R.A.; Takarada, J.E.; Varanda, E.A.; Castellano, E.E.; Deflon, V.M.; Cominetti, M.R.; Desideri, A.; Batista, A.A. Non-mutagenic Ru(II) complexes: Cytotoxicity, topoisomerase IB inhibition, DNA and HSA binding. Dalton Trans., 2019, 48(39), 14885-14897.
[http://dx.doi.org/10.1039/C9DT01905G] [PMID: 31555783]
[24]
Correa, R.S.; Bomfim, L.M.; Oliveira, K.M.; Moreira, D.R.M.; Soares, M.B.P.; Ellena, J.; Bezerra, D.P.; Batista, A.A. Ru(II) complexes containing uracil nucleobase analogs with cytotoxicity against tumor cells. J. Inorg. Biochem., 2019, 198, 110751.
[http://dx.doi.org/10.1016/j.jinorgbio.2019.110751] [PMID: 31220757]
[25]
dos Santos, E.R.; Corrêa, R.S.; Pozzi, L.V.; Graminha, A.E.; Selistre-de-Araujo, H.S.; Pavan, F.R.; Batista, A.A. Antitumor and anti-Mycobacterium tuberculosis agents based on cationic ruthenium complexes with amino acids. Inorg. Chim. Acta, 2017, 463, 1-6.
[http://dx.doi.org/10.1016/j.ica.2017.04.012]
[26]
Dos Santos, E.R.; Corrêa, R.S.; Ribeiro, J.U.; Graminha, A.E.; Ellena, J.; Selistre-de-Araujo, H.S.; Batista, A.A. Ru(II)/bisphosphine/diimine/amino acid complexes: diastereoisomerism, cytotoxicity, and inhibition of tumor cell adhesion to collagen type I. J. Coord. Chem., 2016, 69(23), 3518-3530.
[http://dx.doi.org/10.1080/00958972.2016.1244334]
[27]
Nakamoto, K. Infrared and Raman Spectra of Inorganic and Coordination Compounds; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2008.
[28]
Lever, A.B.P. Electrochemical parametrization of metal complex redox potentials, using the Ruthenium(III)/Ruthenium(II) couple to generaTe a ligand electrochemical series. Inorg. Chem., 1990, 29(6), 1271-1285.
[http://dx.doi.org/10.1021/ic00331a030]
[29]
Carvalho, D.E.L.; Oliveira, K.M.; Bomfim, L.M.; Soares, M.B.P.; Bezerra, D.P.; Batista, A.A.; Correa, R.S. Nucleobase derivatives as building blocks to form Ru(II)-based complexes with high cytotoxicity. ACS Omega, 2020, 5(1), 122-130.
[http://dx.doi.org/10.1021/acsomega.9b01921] [PMID: 31956759]
[30]
Dos Santos, E.R.; Graminha, A.E.; Schultz, M.S.; Correia, I.; Selistre-de-Araújo, H.S.; Corrêa, R.S.; Ellena, J.; Lacerda, E.P.S.; Pessoa, J.C.; Batista, A.A. Cytotoxic activity and structural features of Ru(II)/phosphine/amino acid complexes. J. Inorg. Biochem., 2018, 182, 48-60.
[http://dx.doi.org/10.1016/j.jinorgbio.2017.12.010] [PMID: 29433005]
[31]
Adeniyi, A.A.; Ajibade, P.A. Exploring the ruthenium-ligands bond and their relative properties at different computational methods. J. Chem., 2016, 2016, Article ID 3672062.
[http://dx.doi.org/10.1155/2016/3672062]]
[32]
Ghazaryan, V.V.; Minkov, V.S.; Boldyreva, E.V.; Petrosyan, A.M. Cysteine halogenides: A new family of salts with an -cystein - cysteinium dimeric cation. J. Mol. Struct., 2016, 1121, 60-69.
[http://dx.doi.org/10.1016/j.molstruc.2016.05.049]
[33]
Sáez, R.; Lorenzo, J.; Prieto, M.J.; Font-Bardia, M.; Calvet, T.; Omeñaca, N.; Vilaseca, M.; Moreno, V. Influence of PPh3 moiety in the anticancer activity of new organometallic ruthenium complexes. J. Inorg. Biochem., 2014, 136, 1-12.
[http://dx.doi.org/10.1016/j.jinorgbio.2014.03.002] [PMID: 24690555]
[34]
Correa, R.S.; de Oliveira, K.M.; Delolo, F.G.; Alvarez, A.; Mocelo, R.; Plutin, A.M.; Cominetti, M.R.; Castellano, E.E.; Batista, A.A. Ru(II)-based complexes with N-(acyl)-N′,N′-(disubstituted)thiourea ligands: Synthesis, characterization, BSA- and DNA-binding studies of new cytotoxic agents against lung and prostate tumour cells. J. Inorg. Biochem., 2015, 150, 63-71.
[http://dx.doi.org/10.1016/j.jinorgbio.2015.04.008] [PMID: 26160296]
[35]
Živec, P.; Perdih, F.; Turel, I.; Giester, G.; Psomas, G. Different types of copper complexes with the quinolone antimicrobial drugs ofloxacin and norfloxacin: Structure, DNA- and albumin-binding. J. Inorg. Biochem., 2012, 117, 35-47.
[http://dx.doi.org/10.1016/j.jinorgbio.2012.08.008] [PMID: 23078773]
[36]
Saeed, A.; Larik, F.A.; Jabeen, F.; Mehfooz, H.; Ghumro, S.A.; El-Seedi, H.R.; Ashraf, H. Synthesis, antibacterial and antileishmanial activity, cytotoxicity, and molecular docking of new heteroleptic Copper(I) complexes with thiourea ligands and triphenylphosphine. Russ. J. Gen. Chem., 2018, 88(3), 541-550.
[http://dx.doi.org/10.1134/S1070363218030246]
[37]
Sarwar, T.; Husain, M.A.; Rehman, S.U.; Ishqi, H.M.; Tabish, M. Multi-spectroscopic and molecular modelling studies on the interaction of esculetin with calf thymus DNA. Mol. Biosyst., 2015, 11(2), 522-531.
[http://dx.doi.org/10.1039/C4MB00636D] [PMID: 25424306]
[38]
Tang, B.; Shen, F.; Wan, D.; Guo, B.H.; Wang, Y.J.; Yi, Q.Y.; Liu, Y.J. DNA-binding, molecular docking studies and biological activity studies of ruthenium(II) polypyridyl complexes. RSC Advances, 2017, 7(56), 34945-34958.
[http://dx.doi.org/10.1039/C7RA05103D]
[39]
Honorato, J.; Colina-Vegas, L.; Correa, R.S.; Guedes, A.P.M.; Miyata, M.; Pavan, F.R.; Batista, A.A. Esterification of the free carboxylic group from the lutidinic acid ligand as a tool to improve the cytotoxicity of Ru(II) complexes. Inorg. Chem. Front., 2019, 6(2), 376-390.
[http://dx.doi.org/10.1039/C8QI00941D]
[40]
Xue, F.; Xie, C-Z.; Zhang, Y-W.; Qiao, Z.; Qiao, X.; Xu, J-Y.; Yan, S-P. Two new dicopper(II) complexes with oxamido-bridged ligand: synthesis, crystal structures, DNA binding/cleavage and BSA binding activity. J. Inorg. Biochem., 2012, 115, 78-86.
[http://dx.doi.org/10.1016/j.jinorgbio.2012.05.018] [PMID: 22926027]

Rights & Permissions Print Cite
Article Metrics
25
1
© 2024 Bentham Science Publishers | Privacy Policy