Unusual mode of protein binding by a cytotoxic π-arene ruthenium(<scp>ii</scp>) piano-stool compound containing an O,S-chelating ligand

Hildebrandt, Jana; Görls, Helmar; Häfner, Norman; Ferraro, Giarita; Runnebaum, Ingo B.; Weigand, Wolfgang; Merlino, Antonello

doi:10.1039/c6dt02380k

Cited by 33 publications

(42 citation statements)

References 39 publications

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“…Recently, a novel mixed platinum(II) complex with an O , S -chelating ligand and the general formula [Pt(PPh 3 ) 2 (L- O , S )]PF 6 (L- O , S = N , N -morpholine- N ′-benzoylthiourea) has been synthetized and tested, and proves to be active against tumor cells. The choice of the β-hydroxydithiocinnamic acid ester as the ligand system is based on our described promising results for ruthenium(II) and osmium(II) complexes also bearing this O , S -bidendate ligand [ 49 , 50 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

Hildebrandt

Häfner

Görls

et al. 2022

IJMS

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(1) Background: Since the discovery of cisplatin’s cytotoxic properties, platinum(II) compounds have attracted much interest in the field of anticancer drug development. Over the last few years, classical structure–activity relationships (SAR) have been broken by some promising new compounds based on platinum or other metals. We focus on the synthesis and characterization of 17 different complexes with β-hydroxydithiocinnamic acid esters as O,S bidendate ligands for nickel(II), palladium(II), and platinum(II) complexes. (2) Methods: The bidendate compounds were synthesized and characterized using classical methods including NMR spectroscopy, MS spectrometry, elemental analysis, and X-ray crystallography, and their cytotoxic potential was assessed using in vitro cell culture assays. Data were compared with other recently reported platinum(II), ruthenium(II), and osmium(II) complexes based on the same main ligand system. (3) Results: SAR analyses regarding the metal ion (M), and the alkyl-chain position (P) and length (L), revealed the following order of the effect strength for in vitro activity: M > P > L. The highest activities have Pd complexes and ortho-substituted compounds. Specific palladium(II) complexes show lower IC50 values compared to cisplatin, are able to elude cisplatin resistance mechanisms, and show a higher cancer cell specificity. (4) Conclusion: A promising new palladium(II) candidate (Pd3) should be evaluated in further studies using in vivo model systems, and the identified SARs may help to target platinum-resistant tumors.

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Section: Introductionmentioning

confidence: 99%

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

Hildebrandt

Häfner

Görls

et al. 2022

IJMS

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“… 36 It has been recently pointed out that several therapies based on small molecules or oligonucleotides present the general aim of targeting RNA biology. 37 RNase A has been also frequently used as a model protein in metalation studies, and structures with several metallodrugs, 38 , 39 including cisplatin, carboplatin, oxaliplatin, 40 and Ru-, 41 Rh-, 42 Pd-, 43 Ir-, 44 and Au-based drugs, 45 are known. Recently, the metalation of arsenoplatin-1, a dual pharmacophore anticancer agent, has been presented.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A

et al. 2021

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The structure, stability, and enzymatic activity of the adduct formed upon the reaction of the V–picolinato (pic) complex [V IV O(pic) 2 (H 2 O)], with an octahedral geometry and the water ligand in cis to the V=O group, with the bovine pancreatic ribonuclease (RNase A) were studied. While electrospray ionization-mass spectrometry, circular dichroism, and ultraviolet–visible absorption spectroscopy substantiate the interaction between the metal moiety and RNase A, electron paramagnetic resonance (EPR) allows us to determine that a carboxylate group, stemming from Asp or Glu residues, and imidazole nitrogen from His residues are involved in the V binding at acidic and physiological pH, respectively. Crystallographic data demonstrate that the V IV O(pic) 2 moiety coordinates the side chain of Glu111 of RNase A, by substituting the equatorial water molecule at acidic pH. Computational methods confirm that Glu111 is the most affine residue and interacts favorably with the OC -6-23-Δ enantiomer establishing an extended network of hydrogen bonds and van der Waals stabilizations. By increasing the pH around neutrality, with the deprotonation of histidine side chains, the binding of the V complex to His105 and His119 could occur, with that to His105 which should be preferred when compared to that to the catalytically important His119. The binding of the V compound affects the enzymatic activity of RNase A, but it does not alter its overall structure and stability.

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“…Over the last two decades, Ru-arene complexes have become a focus of interest due to their anticancer properties [6][7][8][9]. These kind of metal complexes with monodentate or bidentate ligands showing different modes of action [10] such as apoptosis induction via DNA damage and anti-angiogenic properties [11], protein kinase inhibitors [12] protein RNase A [13] or a multi-target concept inhibit human topoisomerase IIα and covalently bind to DNA [14].…”

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confidence: 99%

Anti-Proliferative and Anti-Migration Activity of Arene–Ruthenium(II) Complexes with Azole Therapeutic Agents

et al. 2018

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The efficacy of organoruthenium complexes containing ergosterol biosynthesis inhibitors (CTZ: clotrimazole, KTZ: ketoconazole and FCZ: fluconazole) against tumor cells, and their interaction with important macro-biomolecules such as human serum albumin and DNA have been investigated here. Our experimental results indicated that these ruthenium(II) complexes present spontaneous electrostatic interactions with albumin, and act as minor groove binders with the DNA. The ability of these Ru(II)-azole complexes to inhibit the proliferation of selected human tumor and non-tumor cell lines was determined by MTT assay. Complexes [RuCl(CTZ)(η 6 -p-cymene)(PPh 3 )]PF 6 (3) and [RuCl(KTZ)(η 6 -p-cymene)(PPh 3 )]PF 6 (4) were shown to be between 3-and 40-fold more cytotoxic than the free ligands and the positive control cisplatin. Complex 3 was selected to continue studies on the triple negative breast tumor cell line MDA-MB-231, inducing morphological changes, loss of adhesion, inhibition of colony formation, and migration through Boyden chambers, cell cycle arrest in the sub-G1 phase, and a mechanism of cell death by apoptosis. All these interesting results show the potential of this class of organometallic Ru(II) complexes as an antiproliferative agent.

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Unusual mode of protein binding by a cytotoxic π-arene ruthenium(ii) piano-stool compound containing an O,S-chelating ligand

Cited by 33 publications

References 39 publications

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A

Anti-Proliferative and Anti-Migration Activity of Arene–Ruthenium(II) Complexes with Azole Therapeutic Agents

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Unusual mode of protein binding by a cytotoxic π-arene ruthenium(ii) piano-stool compound containing an O,S-chelating ligand

Cited by 33 publications

References 39 publications

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the VIVO–Picolinato Complex with RNase A

Anti-Proliferative and Anti-Migration Activity of Arene–Ruthenium(II) Complexes with Azole Therapeutic Agents

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Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A