3-Hydroxyflavones vs. 3-hydroxyquinolinones: structure–activity relationships and stability studies on RuII(arene) anticancer complexes with biologically active ligands
TL;DR: To expand knowledge about the structure-activity relationships and to determine the impact of lipophilicity of the arene ligand and of the hydrolysis rate on anticancer activity, a series of novel 3-hydroxyflavone derived Ru(II)(η(6)-arene) complexes were synthesised.
Abstract: RuII(η6-arene) complexes, especially with bioactive ligands, are considered to be very promising compounds for anticancer drug design. We have shown recently that RuII(η6-p-cymene) complexes with 3-hydroxyflavone ligands exhibit very high in vitro cytotoxic activities correlating with a strong inhibition of topoisomerase IIα. In order to expand our knowledge about the structure–activity relationships and to determine the impact of lipophilicity of the arene ligand and of the hydrolysis rate on anticancer activity, a series of novel 3-hydroxyflavone derived RuII(η6-arene) complexes were synthesised. Furthermore, the impact of the heteroatom in the bioactive ligand backbone was studied by comparing the cytotoxic activity of RuII(η6-p-cymene) complexes of 3-hydroxyquinolinone ligands with that of their 3-hydroxyflavone analogues. To better understand the behaviour of these RuII complexes in aqueous solution, the stability constants and pKa values for complexes and the corresponding ligands were determined. Furthermore, the interaction with the DNA model 5′-GMP and with a series of amino acids was studied in order to identify potential biological target structures.
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.
Did you find this useful? Give us your feedback
Related Papers (5)
Frequently Asked Questions (1)
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.