3-Hydroxyflavones vs. 3-hydroxyquinolinones: structure–activity relationships and stability studies on RuII(arene) anticancer complexes with biologically active ligands
Summary (2 min read)
- Ruthenium complexes represent a promising class of metal-based 20 chemotherapeutics.
- In the course of ruthenium anticancer drug development programmes, organometallic and especially half-sandwich RuII(η6-arene) complexes have more and more demonstrated their 35 potential.
- 4,14-16 Tethering ethacrynic acid to the arene ligand of RAPTA led to a compound capable of overcoming the glutathione transferase drug resistance mechanism of tumour cells and triggered several biological 55 pathways involving either endonuclease G, caspases or c-Jun Nterminal kinase.
- More recently, the authors have demonstrated that RuII(cym) (cym = η6-p-cymene) complexes of 3-hydroxyflavones are potent tumour cell growth inhibitors.
- These properties are compared with those of structurally related 3-hydroxyquinolinone complexes featuring a 15 nitrogen atom in the heterocyclic ligand.
- -derived b, the hydrolysis of , Supporting corresponding complex 2 were investigated and stability and dissociation constants were studied.
- Therefore, the pKa value spectra of the ligand species (HL, L on the basis of deconvoluted spect λmax values of both the protonated and the deprotonated forms of 90 ligand b are identical to those of the unsubstituted 3 hydroxyflavone a.25.
- Its p due to the electron withdrawing effect of the fluoro substituent.
- The appearance of the two emission bands indicates t pathways for deactivation of the excited state.
Solution equilibria of [RuII(cym)X3]
- This was studied in 20% (w/w) DMSO/H2O by UVvis spectrophotometric titrations .
- Similar but not identical speciation was found in pure aqueous solution.
- 65 Based on the increased proton dissociation constants of ligand b and maltol (see above), higher stability constants of [RuII(cym)(L)X]n+ are expected in 20% (w/w) DMSO/H2O than in pure aqueous solution.
- As also found for the maltolato complex, partial hydrolysis and dissociation of 2 are probable at 15 physiological pH.
Reactivity towards biomolecules
- For 12’ a reaction with Cys was observed but the compound also decomposed partly within 24 h.
- Two minutes after addition only traces of coordinated glycine (two doublets at approximately δ = 3.1 ppm)11 were observed in 12’ and only after 18 h in 13’, indicating again higher stability of the 3-hydroxyquinolinone 65 complexes concerning reactions with amino acids.
- In vitro anticancer activity The cytotoxic activity of the RuII complexes was determined in the human cancer cell lines CH1 (ovarian 80 carcinoma), SW480 (colon carcinoma) and A549 (non-small cell lung carcinoma) by means of the colorimetric MTT assay (Table 1).
- The latter compound class showed a strong dependence of 10 cytotoxicity on the coordinated arene.
- The authors have extended the series of compounds by varying the arene and halido ligands to learn about their influence on the biological activity, as well as compared the 3-hydroxyflavone complexes to quinolinone analogues in terms of cytotoxicity and reactivity towards 45 biomolecules.
- Considering stability data and in vitro anticancer activity, 3- hydroxyflavones seem to be a well-suited ligand system for anticancer RuII(cym) complexes and those represent a 70 promising compound class for further drug design.
- The authors thank the 75 University of Vienna, the Austrian Science Fund (FWF), the Johanna Mahlke geb.
- Obermann Foundation, and COST D39 for financial support.
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Q1. What have the authors contributed in "3-hydroxyflavones vs. 3-hydroxyquinolinones: structure-activity relationships and stability studies on ru(arene) anticancer complexes with biologically active ligands" ?
The authors have shown recently that Ru ( η-p-cymene ) complexes with 3hydroxyflavone ligands exhibit very high in vitro cytotoxic activities correlating with a strong inhibition of topoisomerase IIα.