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oai:riubu.ubu.es:10259/47982026-02-06T12:54:15Zcom_10259_4365com_10259_5086com_10259_2604com_10259_4883col_10259_4366col_10259_4884

Pérez Arnáiz, Cristina Leal, Jorge . Busto Vázquez, Natalia Carrión, María C. . Rubio Antolin, Ana Rosa Ortiz, Imanol . Barone, Giampaolo Díaz de Greñu Puertas, Borja Santolaya, Javier Leal Villalba, José María Vaquero Gutiérrez, Mónica Jalón Sotés, Félix Ángel Manzano, Blanca R. . García Ruiz, Begoña Given the potent anticancer properties of cisdiamminedichloroplatinum( II) and knowing its mode of action, we synthesized four new cis-[PtCl2(N^N)] organoplatinum complexes, two with N-substituted pbi ligands (pbiR = 1-R-2-(2-pyridyl)benzimidazole) (namely, 1 and 2) and two more with 4,4′-disubstituted bpy ligands (bpy = 2,2′-bipyridine) (namely, 3 and 4). We explored their cytotoxicity and ability to bind to deoxyguanosine monophosphate (dGMP), DNA, and albumin models. By 1H NMR and UV−vis spectroscopies, circular dichroism, agarose gel electrophoresis, differential scanning calorimetry measurements, and density functional theory calculations, we verified that only 3 can form aquacomplex species after dimethyl sulfoxide solvation; surprisingly, 1, 2, and 3 can bind covalently to DNA, whereas 4 can form a noncovalent complex. Interestingly, only complexes 1 and 4 exhibit good cytotoxicity against human ovarian carcinoma (HeLa) cell line, whereas 2 and 3 are inactive. Although lung carcinoma (A549) cells are more resistant to the four platinum complexes than HeLa cells, when the protein concentration in the extracellular media is lower, the cytotoxicity becomes substantially enhanced. By native electrophoresis of bovine seroalbumin (BSA) and inductively coupled plasma mass spectrometry uptake studies we bear out, on one hand, that 2 and 3 can interact strongly with BSA and its cellular uptake is negligible and, on the other hand, that 1 and 4 can interact with BSA only weakly, its cellular uptake being higher by several orders. These results point up the important role of the protein binding features on their biological activity and cellular uptake of cis-“PtCl2” derivatives. Our results are valuable in the future rational design of new platinum complexes with improved biological properties, as they expose the importance not only of their DNA binding abilities but also of additional factors such as protein binding. 2018-05-21 2019-05-21 2018-05-21 info:eu-repo/semantics/article 0020-1669 http://hdl.handle.net/10259/4798 10.1021/acs.inorgchem.8b00713 eng Inorganic chemistry, 2018, V. 57, n 10, p. 6124-6134 http://dx.doi.org/10.1021/acs.inorgchem.8b00713 info:eu-repo/grantAgreement/MINECO/CTQ2014-58812-C2-2-R info:eu-repo/grantAgreement/MINECO/CTQ2014-58812-C2-1-R, info:eu-repo/grantAgreement/MINECO/CTQ2015-70371-REDT info:eu-repo/grantAgreement/JCyL/BU042U16 info:eu-repo/grantAgreement/FundaciónLaCaixa/LCF/PR/PR12/11070003) info:eu-repo/semantics/openAccess American Chemical Society