Cytotoxicity of Ru(II) piano–stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA

Colina‐Vegas, Legna; Villarreal, Wilmer; Navarro, Maribel; Oliveira, César R. de; Graminha, Angélica E.; Maia, Pedro Ivo da Silva; Deflon, Victor M.; Ferreira, Antônio G.; Cominetti, Márcia Regina; Batista, Alzir A.

doi:10.1016/j.jinorgbio.2015.07.016

Cited by 59 publications

(44 citation statements)

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“…For ad erivativec ontaining as econdary amino group (ArNH(nPr)) that is comparable to 3bBF 4 ,aRu1ÀN2 distance of 2.108 and aN 1-C5-C6-N2 dihedral angle of 3.48 were found. [9] The RuÀNd istances for compound 3gPF 6 ,w hich crystallizes with two crystallographicallyi ndependent molecules in the unit cell, were reported to be in the range of 2.087-2.101 ; [15] this is in agreement with the Ru1ÀN1 distances found in our study.T he dihedrala ngle N1-C5-C6-N2 of 3gPF 6 is closet o0 8.T ogether with previously published solid-state structures, [9] the structurald ata of the new ruthenium(II) complexes clearly prove the pronounced influence of the substituent attached in the 2-position of the 2-(pyrimidin-4-yl)pyridinetype ligand on the Ru1ÀN2 distance and, in particular, on the dihedrala ngle N1-C5-C6-N2. While the distances between the ruthenium(II) site Ru1 and the pyridine nitrogena tom N1 differ only slightly in all ruthenium complexes, there is clearly ab road variation in the Ru1ÀN2 distances.…”

Section: Molecular Structuressupporting

confidence: 88%

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Mechanistic Studies on Ruthenium(II)‐Catalyzed Base‐Free Transfer Hydrogenation Triggered by Roll‐Over Cyclometalation

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The synthesis of 2‐substituted pyridine–pyrimidine ligands and their complexation with arene ruthenium(II) chloride moieties is reported. Depending on the electronic and steric influences of the ligand, the catalysts undergo CH activation by roll‐over cyclometalation. This process opens up the route to the catalytic transfer hydrogenation of ketones with isopropanol as the hydrogen source under base‐free and mild conditions. Barriers related to the roll‐over cyclometalation process can be determined experimentally by collision‐induced dissociation ESI mass spectrometry. They are supported by DFT calculations and allow the classification of the ligands according to their electronic and steric properties, which is also in accordance with critical bond parameters derived from X‐ray structure data. DFT calculations furthermore reveal that the formation of a ruthenium(II) hydrido species is plausible through β‐hydride elimination from isopropanol.

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Section: Molecular Structuressupporting

confidence: 88%

“…To complete the investigations into transfer hydrogenations with AC, the amount of substrate and the solventv olume were optimized (Table 3, entries [15][16][17]. Thef inally found optimized conditions are described in Ta ble 3, entry 17.…”

Section: Cid Eis-msmeasurementsmentioning

confidence: 99%

Mechanistic Studies on Ruthenium(II)‐Catalyzed Base‐Free Transfer Hydrogenation Triggered by Roll‐Over Cyclometalation

et al. 2016

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“…The interaction between the complexes and BSA is found to be are predominantly hydrophobic character, characterized by an intermediate DG value since both the enthalpic and entropic terms are positive and it is likely that it occurs in the proximity of Trp-212. The magnitude of the BSA-binding constant of SCAR 4 and 5, compared with other ruthenium(II) complexes reported recently (Colina-Vegas et al 2015;Camargo et al 2016) suggests a relatively moderate interaction with the BSA molecule, while SCAR 6 shows a stronger interaction with the protein.…”

Section: Viscositymentioning

confidence: 47%

Human topoisomerase inhibition and DNA/BSA binding of Ru(II)–SCAR complexes as potential anticancer candidates for oral application

et al. 2017

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Three ruthenium(II) phosphine/diimine/picolinate complexes were selected aimed at investigating anticancer activity against several cancer cell lines and the capacity of inhibiting the supercoiled DNA relaxation mediated by human topoisomerase IB (Top 1). The structure-lipophilicity relationship in membrane permeability using the Caco-2 cells have also been evaluated in this study. SCAR 5 was found to present 45 times more cytotoxicity against breast cancer cell when compared to cisplatin. SCAR 4 and 5 were both found to be capable of inhibiting the supercoiled DNA relaxation mediated by Top 1. Interaction studies showed that SCAR 4 and 5 can bind to DNA through electrostatic interactions while SCAR 6 is able to bind covalently to DNA. The complexes SCAR were found to interact differently with bovine serum albumin (BSA) suggesting hydrophobic interactions with albumin. The permeability of all complexes was seen to be dependent on their lipophilicity. SCAR 4 and 5 exhibited high membrane permeability (P > 10 × 10 cm·s) in the presence of BSA. The complexes may pass through Caco-2 monolayer via passive diffusion mechanism and our results suggest that lipophilicity and interaction with BSA may influence the complexes permeation. In conclusion, we demonstrated that complexes have powerful pharmacological activity, with different results for each complex depending on the combination of their ligands.

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“…Ruthenium arene “piano-stool” complexes are very prominent anticancer agents, and some studies have reported a dual-binding mode in which ruthenation occurs through a leaving group while the p -cymene group intercalates between nearby bases [67]. Recent examples include a series of complexes incorporating 1,3-Dimethyl-4-acylpyrazolon-5-ato ligands, of which the lead compound, [Ru( p -cymene)(1,3-dimethyl-4-(1-naphthoyl)-pyrazolon-5-ate)Cl] ( Ru8 , Figure 10), demonstrated potent activity against several cell lines [67], and a chloroquine-tethered complex with submicromolar activity against A549 and MCF-7 cells ( Ru9 , Figure 10) [68]. …”

Section: Rutheniummentioning

confidence: 99%

Transition Metal Intercalators as Anticancer Agents—Recent Advances

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et al. 2016

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The diverse anticancer utility of cisplatin has stimulated significant interest in the development of additional platinum-based therapies, resulting in several analogues receiving clinical approval worldwide. However, due to structural and mechanistic similarities, the effectiveness of platinum-based therapies is countered by severe side-effects, narrow spectrum of activity and the development of resistance. Nonetheless, metal complexes offer unique characteristics and exceptional versatility, with the ability to alter their pharmacology through facile modifications of geometry and coordination number. This has prompted the search for metal-based complexes with distinctly different structural motifs and non-covalent modes of binding with a primary aim of circumventing current clinical limitations. This review discusses recent advances in platinum and other transition metal-based complexes with mechanisms of action involving intercalation. This mode of DNA binding is distinct from cisplatin and its derivatives. The metals focused on in this review include Pt, Ru and Cu along with examples of Au, Ni, Zn and Fe complexes; these complexes are capable of DNA intercalation and are highly biologically active.

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Cytotoxicity of Ru(II) piano–stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA

Cited by 59 publications

References 49 publications

Mechanistic Studies on Ruthenium(II)‐Catalyzed Base‐Free Transfer Hydrogenation Triggered by Roll‐Over Cyclometalation

Mechanistic Studies on Ruthenium(II)‐Catalyzed Base‐Free Transfer Hydrogenation Triggered by Roll‐Over Cyclometalation

Human topoisomerase inhibition and DNA/BSA binding of Ru(II)–SCAR complexes as potential anticancer candidates for oral application

Transition Metal Intercalators as Anticancer Agents—Recent Advances

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