Design of photoactivatable metallodrugs: Selective and rapid light-induced ligand dissociation from half-sandwich [Ru([9]aneS3)(N–N′)(py)]2+ complexes

TLDR: In this paper, the inert Ru(II) half-sandwich coordination compounds, [Ru([9]aneS3)(bpy)(py)][PF6]2, were reported along with the X-ray crystal structure of 1.

About: This article is published in Inorganica Chimica Acta.The article was published on 2012-12-01 and is currently open access. It has received 26 citations till now. The article focuses on the topics: Aquation & Coordination complex.

Figures

Fig. 4. Aromatic region of the 1 H-NMR spectrum of 1 and GSH in PBS (1:1 mixture, pH 7.2) recorded at different irradiation times; py(f) indicates free pyridine, 1-GS indicates [Ru([9]aneS3)(bpy)(GS)] 2+ .

Table 2. Extent (%) of light-induced (λex = 420 nm, 20mW/cm 2 ) aquation and 9-EtG binding for complexes 1–3.

Fig. 7. Selected Electron Density Difference Maps (EDDMs) of the four lowest energy triplet excited states of 1. Magenta indicates a decrease in electron density, while purple indicates an increase.

Fig. 3. Aromatic region of the 1 H-NMR spectrum of [Ru([9]aneS3)(bpy)(py)][PF6]2 (1) and 9-EtG in D2O (1:1 mixture, PBS buffer, pH 7.2) recorded after various irradiation times (λex = 420 nm, 20 mW/cm 2 ); py(f) indicates free pyridine and H8(1-G) is the resonance of the H8 proton of the coordinated 9-EtG in [Ru([9]aneS3)(bpy)(9-EtG)] 2+ .

Fig. 6. Experimental absorption spectrum (black line) and calculated singlet excited state transitions (magenta vertical bars) of 1 in H2O. The vertical bar height is the oscillator strength. Selected Electron Density Difference Maps (EDDMs) of singlet excited state transitions of 1 are reported on the top of the box. Yellow indicates a decrease in electron density, while orange indicates an increase.

Fig. 2. (A) UV-Vis spectra of [Ru([9]aneS3)(bpy)(py)][PF6]2 (1) in aqueous solution recorded at different irradiation times (λex = 420 nm, 7mW/cm 2 ); (B) 1 H-NMR spectra of 1 in D2O at t = 0 min and after 20 min of irradiation (λex = 420 nm, 20 mW/cm 2 ); 1a is the aqua species [Ru([9]aneS3)(bpy)(H2O)] 2+ , py(f) indicates free pyridine.

Frequently asked questions

Q1. What are the contributions in "Design of photoactivatable metallodrugs: selective and rapid light-induced ligand dissociation from half-" ?

The synthesis of the inert Ru ( II ) half-sandwich coordination compounds, [ Ru ( [ 9 ] aneS3 ) ( bpy ) ( py ) ] [ PF6 ] 2 ( 1, [ 9 ] aneS3 = 1,4,7-trithiacyclononane ), [ Ru ( [ 9 ] aneS3 ) ( en ) ( py ) ] [ PF6 ] 2 ( 2, en = 1,2-diaminoethane ), and [ Ru ( [ 9 ] aneN3 ) ( en ) ( dmsoS ) ] [ PF6 ] 2 ( 3, [ 9 ] aneN3 = 1,4,7-triazacyclononane ), is reported along with the X-ray crystal structure of 1. The authors investigated whether these complexes have photochemical properties which might make them suitable for use as pro-drugs in photochemotherapy. 2+. Density functional theory ( DFT ) calculations and time-dependent DFT reproduced the major features of the absorption spectra and suggested that the lowest-lying triplet state with 3 MLCT character, which is readily accessible via intersystem crossing, might be responsible for the 

Q2. What have the authors stated for future works in "Design of photoactivatable metallodrugs: selective and rapid light-induced ligand dissociation from half-" ?

The aim of this work was to study the photochemistry of some Ru ( II ) half-sandwich coordination compounds, structurally similar to the inert organometallic compounds of general formula [ ( η 6 -arene ) Ru ( N, N ) ( L ) ] These interesting properties of 1 prompted us to extend their studies on this compound. In the future the authors plan to perform in vitro antiproliferative tests on compounds 1 and 2, and their analogues, both in the dark and upon photo-irradiation, in order to assess if the photoactivation and reactivity observed in the test-tube leads to cytotoxicity towards cancer cells. 2+ developed in recent years by Sadler and coworkers, that can be activated by photo-induced dissociation of the monodentate ligand upon irradiation with visible light. 

Q3. How much of the complex was formed?

After 180 min under light excitation (when 100% py dissociation had occurred), 2-G accounted for ca. 56% of the total complex in solution, while with 135 min of irradiation and incubation at 37 °C overnight only a small fraction of 3-G (ca. 7%) was formed. 

Q4. What is the advantage of irradiating the tumor site with light?

The irradiation of the tumor site with a light source would lead to the release of active metal fragments directly into cancer cells [3]. 

Q5. What was the use of a light source?

As light source, a broadband visible light lamp (16 tubes, model LZC420; Luzchem research inc., Ottawa, Canada), operating with a maximum output at 420 nm and a maximum power of ca. 20 mW/cm 2 was used. 

Q6. What is the effect of the ligand on the photoactivation rate?

Also the nature of the chelating ligand has a strong impact on the photoactivation rate (cf. 1 with 2), possibly because there is a marked increase in the absorbance at the irradiation wavelength when the bpy aromatic system replaces 1,2- diaminoethane. 

Q7. How did the complexes react with the corresponding nucleobase?

In the presence of 9-EtG both complexes were stable in the dark at 37 °C (overnight), and underwent photoreaction to give the corresponding aqua derivatives and subsequent coordination of the nucleobase. 

Q8. What software was used to record UV-vis absorption spectra?

Spectra were recorded at 310 K in deionized water from 200 to 800 nm and were processed using Cary WinUV software for Windows XP and OriginPro8.1.HPLC 

Q9. What is the likely binding site for guanine?

As demonstrated by the 9-EtG binding experiment, it is likely that 1a binds first at the single guanine residue, as the N7 of guanine is usually the preferred DNA site for transition metal ions [20]. 

Q10. What is the advantage of a selective activation strategy?

Provided that activation occurs selectively, this strategy would have the clear advantage of limiting the undesired effects of the drug, thus increasing its therapeutic index. 

Q11. What is the nature of the triplet excited states?

triplet states are generally involved in the photochemistry of ruthenium complexes since they become efficiently populated after intersystem crossing (ISC). 

Q12. What was the intensity of the dmso ligand?

A singlet at = 2.72 corresponding to freedmso progressively increased in intensity, while the peak of the coordinated dmso-S at = 3.33 decreased in intensity, indicating the formation of [Ru([9]aneN3)(en)(H2O)] 

Q13. What is the significance of the interaction between GSH and 1?

Given the relevance of glutathione (γ-L-Glu-L-Cys-Gly, GSH) – the abundant intracellular tripeptide – as metal detoxification agent [19], its interaction with 1 was studied by 1 H-NMR spectroscopy (PBS, pH 7.2) both in the dark and under light irradiation (Fig. 4). 

Q14. How much free dmso did the irradiation produce?

The concentration of free dmso increased during the first two hours of irradiation, eventually reaching a plateau corresponding to the formation of ca. 23% 3a. 

Q15. What is the effect of the d–d ligand field states on the pyr?

In the case of 1, DFT calculations show that, dissociative 3 MC (d–d ligand field) states are accessible and can promote specific photodissociation of the pyridine ligand. 

Q16. What was the final concentration of d(ATACATGCTACATA)?

Compound 1 was dissolved in water and mixed with the oligonucleotide d(ATACATGCTACATA) in a 1:1 mol ratio (final concentration of 250 µM). 

Q17. What is the MLCT character of the band in the experimental spectrum?

In the experimental spectrum, the lowest-energy band is centered at 399 nm (ε = 3286 M –1 cm –1 ) and has a MLCT character as shown by the electron density difference map (EDDM) S1. 

Q18. What is the reverse binding of pyridine to 1a?

1 H-NMR shows that in the photolyzed solution the reverse binding of pyridine to 1a is very slow and not quantitative (see below). 

Q19. What is the MC character of the LUMO+4 orbitals?

there are weak transitions in the 350nm region (calculated) that have a dissociative MC character because of significant contributions from the σ-antibonding orbitals LUMO+4 and LUMO+5 (e. g. S4, Table S1).