Cytotoxic (cis,cis-1,3,5-triaminocyclohexane)ruthenium(<scp>ii</scp>)-diphosphine complexes; evidence for covalent binding and intercalation with DNA

Wise, Dan; Gamble, Aimee J.; Arkawazi, Sham; Walton, Paul H.; Galan, M. Carmen; O’Hagan, Michael; Hogg, Karen; Marrison, Joanne; O’Toole, Peter; Sparkes, Hazel A.; Lynam, Jason M.; Pringle, Paul G.

doi:10.1039/d0dt02612c

Cited by 4 publications

(2 citation statements)

References 71 publications

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“…This confirms published data pointing to a DNA-independent mode of action for ruthenium compounds [41,71,104]. However, other data show an interaction of ruthenium complexes with DNA [33,43,99,105,106]. These contrary observations may relate to experimental conditions or specific ligands.…”

Section: Biological Behaviorsupporting

confidence: 88%

Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms

Hildebrandt

Häfner

Kritsch

et al. 2022

IJMS

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(1) Background: Ruthenium and osmium complexes attract increasing interest as next generation anticancer drugs. Focusing on structure-activity-relationships of this class of compounds, we report on 17 different ruthenium(II) complexes and four promising osmium(II) analogues with cinnamic acid derivatives as O,S bidentate ligands. The aim of this study was to determine the anticancer activity and the ability to evade platin resistance mechanisms for these compounds. (2) Methods: Structural characterizations and stability determinations have been carried out with standard techniques, including NMR spectroscopy and X-ray crystallography. All complexes and single ligands have been tested for cytotoxic activity on two ovarian cancer cell lines (A2780, SKOV3) and their cisplatin-resistant isogenic cell cultures, a lung carcinoma cell line (A549) as well as selected compounds on three non-cancerous cell cultures in vitro. FACS analyses and histone γH2AX staining were carried out for cell cycle distribution and cell death or DNA damage analyses, respectively. (3) Results: IC50 values show promising results, specifically a high cancer selective cytotoxicity and evasion of resistance mechanisms for Ru(II) and Os(II) compounds. Histone γH2AX foci and FACS experiments validated the high cytotoxicity but revealed diminished DNA damage-inducing activity and an absence of cell cycle disturbance thus pointing to another mode of action. (4) Conclusion: Ru(II) and Os(II) compounds with O,S-bidentate ligands show high cytotoxicity without strong effects on DNA damage and cell cycle, and this seems to be the basis to circumvent resistance mechanisms and for the high cancer cell specificity.

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Section: Biological Behaviorsupporting

confidence: 88%

Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms

Hildebrandt

Häfner

Kritsch

et al. 2022

IJMS

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“…KP1339 is a ruthenium(III) complex that has undergone clinical trials against various solid tumors, including nonsmall cell lung carcinoma and neuroendocrine tumors . TLD-1433 is the first ruthenium complex that has entered clinical trials, as a photodynamic therapy agent against BCG refractory/intolerant nonmuscle invasive bladder cancer. , Controlled multistep synthesis helps to incorporate various ligands of interest to render optimized ruthenium complexes with efficient antitumor activity. ,,,− …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, and Cytotoxicity of Morpholine-Containing Ruthenium(II) p-Cymene Complexes

et al. 2021

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Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a metal complex, six bidentate N,O-donor ligands with or without a pendant morpholine unit and their corresponding ruthenium(II) p-cymene complexes (1–6) are synthesized, purified, and structurally characterized by various analytical methods including X-ray diffraction. Complexes 2–4 crystallized in the P21/c space group, whereas 5 and 6 crystallized in the P1̅ space group. The solution stability studies using 1H NMR support instantaneous hydrolysis of the native complexes to form monoaquated species in a solution of 3:7 (v/v) dimethyl sulfoxide-d 6 and 20 mM phosphate buffer (pH* 7.4, containing 4 mM NaCl). The monoaquated complexes are stable for at least up to 24 h. The complexes display excellent in vitro antiproliferative activity (IC50 ca. 1–14 μM) in various cancer cell lines, viz., MDA-MB-231, MiaPaCa2, and Hep-G2. The presence of the pendant morpholine does not improve the dose efficacy, but rather, with 2-[[(2,6-dimethylphenyl)imino]methyl]phenol (HL1) and its pendant morpholine analogue (HL3) giving complexes 1 and 3, respectively, the antiproliferative activity was poorer with 3. MDA-MB-231 cells treated with the complexes show that the acidic vesicles remain acidic, but the population of acidic vesicles increases or decreases with time of exposure, as observed from the dispersed red puncta, depending on the complex used. The presence of the 2,6-disubstituted aniline and the naphthyl group seems to improve the antiproliferative dose. The complex treated MDA-MB-231 cells show that cathepsin D, which is otherwise present in the cytosolic lysosomes, translocates to the nucleus as a result of exposure to the complexes. Irrespective of the presence of a morpholine motif, the complexes do not activate caspase-3 to induce apoptosis and seem to favor the necrotic pathway of cell killing.

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Photoinduced Synthesis of Bisphosphinated Quinoxalines via Radical Cyclization ofo‐Diisocyanoarenes with Diphosphines

Yamamoto

2023

Chemistry An Asian Journal

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The cycloaddition reaction of o-diisocyanoarenes with interelement compounds under light is a very important reaction system to clarify whether this reaction proceeds by radical cyclization or by aza-Bergman cyclization. In this study, a series of diphosphines with phosphorus-phosphorus single bonds were selected as interelement compounds, and their cycloaddition reactions with o-diisocyanoarenes under light were investigated in detail to achieve a novel photo-induced synthesis of bisphosphinated quinoxalines via the radical cyclization pathway. In addition, the photoinduced reaction of diphosphines with isocyanides having o-functional groups such as cyano and ethenyl groups allowed us to elucidate the reaction pathway and product selectivity of this bisphosphination. Furthermore, the one-pot synthesis of Pd II -quinoxaline complex was successfully achieved by applying the developed reaction.

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Cytotoxic (cis,cis-1,3,5-triaminocyclohexane)ruthenium(ii)-diphosphine complexes; evidence for covalent binding and intercalation with DNA

Abstract: We report cytotoxic ruthenium(II) complexes of the general formula [RuCl(cis-tach)(diphosphine)]+ (cis-tach = cis-cis-1,3,5-triaminocyclohexane) that have been characterised by 1H, 13C and 31P{1H} NMR spectroscopy, mass spectrometry, X-ray crystallography and elemental...

Cited by 4 publications

References 71 publications

Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms

Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms

Synthesis, Characterization, and Cytotoxicity of Morpholine-Containing Ruthenium(II) p-Cymene Complexes

Photoinduced Synthesis of Bisphosphinated Quinoxalines via Radical Cyclization ofo‐Diisocyanoarenes with Diphosphines

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