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Impairment of the autophagy-related lysosomal degradation pathway by an anticancer rhenium(i) complex.

PMID: 30864598
Journal of Photochemistry and Photobiology 8 (2021) 100078 Contents lists available at ScienceDirect Journal of Photochemistry and Photobiology journal homepage: www.sciencedirect.com/journal/journal-of-photochemistry-and-photobiology Photophysical properties of a β-Carboline Rhenium (I) complex. Solvent effects on excited states and their redox reactivity Iván Maisuls a, b, Ezequiel Wolcan a, Pedro M. David-Gara c, Franco M. Cabrerizo b, Guillermo J. Ferraudi d, Gustavo T. Ruiz a, * a Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas (INIFTA, UNLP, CCT La Plata-CONICET), Diag. 113 y 64, Sucursal 4, C.C. 16, (B1906ZAA) La Plata, Argentina Instituto Tecnológico de Chascomús (INTECH, UNSAM, CONICET), Intendente Marino Km 8.2, CC 164 (B7130IWA), Chascomús, Argentina c Centro de Investigaciones Ópticas (CIOP, CONICET, CIC), Universidad Nacional de La Plata, CC.3, (1897), La Plata, Argentina d Radiation Research Building, University of Notre Dame, Notre Dame, IN 46556, United States b A R T I C L E I N F O A B S T R A C T Keywords: Rhenium tricarbonyl complexes Singlet oxygen generation Photophysics Photochemistry Norharmane – TD-DFT Pulse radiolysis The photochemical and photophysical properties of a Re(I) tricarbonyl complex, ClRe(CO)3(nHo)2, where nHo = 9H-pyrido[3,4-b] indole (norharmane), were investigated in solution phase by a combination of steady state emission spectroscopy, laser flash photolysis (LFP) and pulse radiolysis (PR) techniques. These results allowed us to identify and study the reactivity of the β-carboline (nHo) Rhenium(I) complex main excited states. The ab­ sorption spectrum as well as the steady-state and time-resolved luminescence of the complex exhibits a marked dependence with the solvent properties. These experimentally observed results were corroborated by quantum chemical calculations, TD-DFT. The most important electronic transitions present in the spectrum in all solvents are MLLCTRe(CO)3→nHo1, nHo2 along with a mixture of ILnHo and LLCTCl→nHo transitions. The relationship between the dipole moment and the polarity of the solvent was rationalized in terms of the electron density inside and outside the complex. While the luminescence of the complex is mainly attributed to the emitting 1ILnHo state, in LFP experiments a MLCT excited state was also detected. The species generated in either reductive or oxidative conditions in LFP experiments were compared with those obtained in PR. Also, the quenching rate constant (kq) of the excited state with MV+2 was calculated. The excited state of the complex can efficiently generate singlet oxygen in acetonitrile yielding a ΦΔ = 0.25 ± 0.02. Optoacoustic measurements showed that, after photonic excitation, almost all the absorbed energy by the complex is released to the medium as prompt heat. The investigated photophysical and photochemical properties of ClRe(CO)3(nHo)2 are of significant importance in relation to the use of this β-carboline Rhenium(I) complex in several biomedical fields, such as photodynamic therapy and photoactivated chemotherapy as well as new alternative therapies such as regional hyperthermia. 1. Introduction β-Carbolines (βCs) are a group of alkaloids widely spread in nature. Their presence has been suggested in several plant and animal species, displaying a pharmacological functions including antioxidants, anti­ tumor, antiviral and antimicrobial activities, among many others [1–10]. In addition, these biological activities can be enhanced or trig­ gered by light [11–17]. As it is widely known, the combination of light-sensitive bioactive ligands such as βCs with transition metals permits the design of inno­ vative compounds that can optimize or enhance the intrinsic photochemical, photophysical, or photobiological properties of the noncoordinated βC molecules [18–22]. Recent work from a few research groups has shown the potential anticancer properties of different β-carboline metal complexes [23]. The nature of metal core strongly modulates the multi-mechanistic anticancer activities as well as the se­ lective toxicity against different cancer cell lines. In addition, the type of transition metal bound to the βC derivative induce distinctive photo­ physical properties [24–28]. In particular, Rhenium (I) tricarbonyl complexes with different polypyridines as bidentate ligands, in addition to on βC moiety placed as an ancillary ligand, represent a set of metal complexes with quite promising photophysical and photobiological * Corresponding author. E-mail address: gruiz@inifta.unlp.edu.ar (G.T. Ruiz). https://doi.org/10.1016/j.jpap.2021.100078 Received 27 June 2021; Received in revised form 29 September 2021; Accepted 21 October 2021 Available online 28 October 2021 2666-4690/© 2021 The Authors. Published by Elsevier B.V. This is an open (http://creativecommons.org/licenses/by-nc-nd/4.0/). access article under the CC BY-NC-ND license I. Maisuls et al. Journal of Photochemistry and Photobiology 8 (2021) 100078 properties. We have shown, for example, the differential capabilities of this kind of complexes to induce (or photoinduce) DNA damage [29,30]. In general, Re(I) complexes offer numerous advantages over other metal coordination compounds such as thermal and photochemical stability and an exceptionally rich excited-state and thermal redox chemistry behavior, among others [29,31–35]. In addition, the accessible excited states of Re(I) tricarbonyl complexes, such as metal to ligand charge transfer (MLCTRe→L) and/or intraligand (IL) excited states, are generally long-lived and luminescent at room temperature [36–39]. These con­ ditions allow us to investigate the photophysical processes in which these excited states are involved as well as their redox reactivity [29, 40–43]. Besides, Re(I) complexes has been proposed, also, as promising candidates in anticancer treatments and as biological probes [44–50]. While there are scarcely reported Re(I) complexes with βCs as ligands present in the bibliography, in all the recorded complexes the photo­ physical properties of the compounds were commanded by the bidentate accompanying luminophore [25,26,51]. In those complexes, the βC derivative was acting only as a spectator ligand, with a minor photo­ physical role when compared with the other moieties. Therefore, in this work, we undertook a deep photophysical and photochemical study of a Re(I) complex with βCs as the only type of constitutive ligand, ClRe(CO)3(nHo)2 where nHo = norharmane, to avoid the influence of any additional ligands, (Scheme 1) [25]. Although we have recently shown that the most important electronic transitions present in the absorption spectrum of this complex are metal to ligand charge transfer (MLCTRe–>nHo) along with a mixture of intra­ ligand (ILnHo) and ligand to ligand charge transfer (LLCTCl–>nHo) tran­ sitions by TDDFT calculations [25], in this work we extend the studies on the experimental photophysical behavior of solutions of ClRe (CO)3(nHo)2 complex in solvents of different polarity. We also present their photoluminescence properties (such as excited state photo­ luminescence lifetimes, emission spectra, and quantum yields) in different solvents, and these experimental results were complemented through theoretical calculations. With the assistance of laser flash photolysis (LFP) and pulse radiolysis (PR) techniques, we performed a full analysis of the possible excited state species and/or radicals derived from the complex after a pulse of light or electrons. Furthermore, the excited state´s redox properties of the complex were examined by both reductive and oxidative quenching. Finally, the ability of the complex to generate singlet oxygen was evaluated as well as their skill to release heat through laser-induced optoacoustic spectroscopy (LIOAS) measurements. available from previous works [25,52]. Norharmane, 2-hydroxybenzo-­ phenone and phenalenone were purchased from Sigma Aldrich at the highest purity available and were used as received. Spectrograde and HPLC grade acetonitrile (ACN), dichloromethane (DCM), ethanol (EtOH), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), toluene (Tol), acetone (Ace) and triethylamine (TEA) were purchased to Sigma-Aldrich and used without further purification. Methanol (MeOH), benzene (BzH) and carbon tetrachloride (CCl4) were purchased to Merck and K2HPO4 to J.T. Baker. 2.2. Solutions with methyl-viologen Methanolic solutions of Re(nHo)2 with different concentrations of MV+2 were prepared by adding different volumes of MV+2 (10−4 M) to the complex solution, reaching a final volume of 10 ml. The concen­ tration of the complex (10−5 M) was kept constant in all experiments. 2.3. Photochemical and photophysical measurements UV−vis spectra were recorded on a Shimadzu UV-1800 spectro­ photometer. Emission spectra were obtained with a computer-interfaced Near-IR Fluorolog-3 Research Spectrofluorometer and were corrected for differences in spectral response and light scattering. Solutions were deaerated with O2-free N2 in a gas-tight cell before recording the spectra. Luminescence lifetime measurements were carry out using a nanoLED, λex = 341 nm, as excitation source. Photoluminescence quantum yields, ΦF, were calculated using eq. (1). ∅F = Aref IF n2F ∅ref AF Iref n2ref (1) where A is the absorbance of the sample, I is the intensity of the lumi­ nescence calculated as the integral under the entire emission spectra, Φref is the quantum yield of the reference and n is the refractive index of the solvent. For the experiments, nHo (Φref = 0.30 in MeOH) was used as reference [53–55]. 2.4. Flash photolysis and pulse radiolysis Absorbance changes, ΔA, occurring in a time scale longer than 10 ns were investigated with a flash photolysis apparatus described elsewhere [56,57]. In these experiments, 10 ns flashes of 351 nm light were generated with a Lambda Physik SLL −200 excimer laser. The energy of the laser flash was attenuated to values equal to or less than 20 mJ/pulse by absorbing some of the laser light in a filter solution of Ni(ClO4)2 having the desired optical transmittance, T = It /I0 where I0 and It are respectively the intensities of the light arriving to and transmitted from the filter solution. The transmittance, T = 10−A, was routinely calculated by using the spectrophotometrically measured absorbance, A, of the filter solution. A right-angle configuration was used for the pump and the probe beams. Concentrations of the photolytes were adjusted to provide homogeneous concentrations of photogenerated intermediates over the optical path, l = 1 cm, of the probe beam. To satisfy this optical condition, solutions were made with an absorbance equal to or less than 0.8 over the 0.2 cm optical path of the pump. Pulse radiolysis experiments were carried out with a model TB-8/ 16–1S electron linear accelerator, LINAC. The instrument and comput­ erized data collection for time-resolved UV–Vis spectroscopy and reac­ tion kinetics have been described elsewhere in the literature [58,59]. Thiocyanate dosimetry was carried out at the beginning of each exper­ imental session. The details of the dosimetry have been reported else­ where [60]. The procedure is based on the concentration of (SCN)2●̶ radicals generated by the electron pulse in a N2O saturated 10−2 M SCN¡ solution. In the procedure, the calculations were made with G = 6.13 and an extinction coefficient, ε = 7.58 × 103 M − 1 cm−1 at 472 nm, for the (SCN)2●̶ radicals [58,60]. In general, the experiments were carried 2. Methods and materials 2.1. General ClRe(CO)3(nHo)2 (Re(nHo)2) and Methyl-Viologen (MV+2) were Scheme 1. Structure of ClRe(CO)3(nHo)2 (Re(nHo)2). 2 I. Maisuls et al. Journal of Photochemistry and Photobiology 8 (2021) 100078 out with doses that in N2 saturated aqueous solutions resulted in (2.0 ± 0.1) × 10−6 M to (6.0 ± 0.3) × 10−6 M concentrations of e¡solv. In all the experiments, solutions in methanol were deaerated under vacuum in a gas-tight cell. In methanolic solutions, the radiolytic pulse yield e¡solv and C●H2OH radicals according to the following reactions scheme 2: Thereby, in pulse radiolysis of methanolic solutions under an N2 atmosphere, the main reducing species formed are e¡solv and C●H2OH [60]. As these species have large reduction potentials (−0.92 V for C●H2OH and −2.8 V for e¡solv, both against NHE [61]) they have been used for the study of both electron transfer and reduction reactions of different species like coordination complexes of different transition metals. The G-value of e¡solv in MeOH (G ≈ 1.2) is approximately one-third part of the yield in the radiolysis of H2O (G ≈ 2.8). When the e¡solv is scavenged with N2O, the C●H2OH radical is the predominant product (yield >90%) of the reaction between O●¡ and CH3OH. The reaction kinetics were investigated by following the absorbance change at given wavelengths of the spectrum and incorporating those changes in the dimensionless parameter ξ, according to eq. (2). ξ= ΔAinf − ΔAt ΔAinf − ΔA0 LIOAS signals, eq. (3) was used, which relates the peak to peak ampli­ tude of the first optoacoustic signal (H) with the fraction of the excita­ tion laser fluence (F) absorbed by the sample [66]. ) ( (3) H = K αF 1 − 10−A where K is the experimental constant that contains the thermo-elastic parameters of the solution as well as instrumental factors, A is the absorbance of the sample at λex and a is the fraction of the energy released to the medium as prompt heat within the time resolution of the experiment. 3. Results and discussion 3.1. UV–Vis spectroscopy Fig. 1 shows the solvent dependence of the spectral features of Re (nHo)2 in solvents of different polarities. As observed, the intense band centered at λmax ~ 240 nm is practically not affected by the solvent, as depicted also in Table 1. In contrast, the lower energy absorption band experiences a bathochromic shift and an intensity decrease as the dielectric constant (ε) drops. The latter fact was further explored with an additional group of solvents, showing a clear correlation between the wavelength of the lower energy band with the solvent dielectric constant (Figure S1a). Similar spectroscopic behavior observed previously in the non-coordinated nHo indicates a strong interaction of the solvent with the ligand [53,67] . A comparative analysis of the absorption spectra of the complex in methanolic solutions with those recorded for non-coordinated neutral (nHo) and protonated (nHoH+) norharmane (Fig. 1), clearly evidenced that, despite other electronic transitions, both nHo-like (probably to a greater extent) and nHoH+-like βC’s rings contribute, at least in part, to the overall absorption of Re(nHo)2 [25,53,67,68]. In addition, new charge transfer transitions must be present also at λ > 300 nm due to the coordination of the βC molecule to Re(I) metal. It should be noted that although the recorded spectra show that the highest energy band is rather insensitive to the polarity of the solvent while the band centered at ~310 nm experiences a bathochromic shift when the polarity of the solvent decreases, this effect is not seen with DMSO (Figure S1a). This fact pinpoints to a probable specific interaction between DMSO and the Re(I) complex which was not taken account in the theoretical calculations presented below. (2) where ΔA0, ΔAt and ΔAinf are the absorbance changes at the beginning of the reaction, at a given time t, and at the end of the reaction, respectively. 2.5. Singlet oxygen production and optoacoustic measurements The experimental details of this technique have been published previously [62]. Briefly, quantum yields of photosensitized singlet ox­ ygen production, ΦΔ, were obtained using the third harmonic of a Q-switched Nd-YAG laser as the excitation source (λex = 355 nm, Surelite II- Continuum), looking at the 1270 nm 1O2 phosphorescence with a Ge-photodiode (Applied Detector Corporation, resolution time of 1 μs). Measurements were performed in air-equilibrated solutions. The averages of signals generated by 64 laser shots were recorded to improve the signal-to-noise ratio. Single exponential analysis of emission decays was performed with the exclusion of the initial part of the signal. ΦΔ was determined by measuring its phosphorescence intensity using an opti­ cally matched solution of a reference sensitizer. In acetonitrile, the reference used was phenalenone (ΦΔ =0.975) [63]. Photoacoustic measurements were performed by using a set-up already described [62]. The resolution time in our experimental set-up, tR, was ca. 800 ns [62]. 2-hydroxybenzo-phenone was used as calorimetric reference (CR) compounds in ACN solutions [64,65]. Ex­ periments were performed under a controlled atmosphere, bubbling N2 or O2 in the solution, for 15 min. In principle, all the excited species with lifetimes t ≤ ⅕ tR release their heat content as prompt heat, whereas excited species with a lifetime of τ ≥ 5 tR function as heat storage within the time resolution of the LIOAS experiment. For the handling of the Fig. 1. Normalized UV–Vis spectra of Re(nHo)2 in different solvents (solid lines). For comparison, non-coordinated nHo and nHoH+ in neutral and acidic organic solvent (green and blue dotted lines, respectively) are also shown. Absorption coefficients are displayed in Figure S1b. Scheme 2. Generated MeOH-derived species after the radiolytic pulse. 3 I. Maisuls et al. Journal of Photochemistry and Photobiology 8 (2021) 100078 centered on nHo2 and nHo1, respectively. H-2 is very similar in shape to H-1. Therefore, all the electronic transitions in vacuo in this region of wavelengths are MLLCT(Re(CO)3→nHo1, nHo2). MO shapes in BzH are very similar to MO shapes in vacuo. In THF, however, H and H-1 have in addition significant contributions from nHo1 and nHo2, respectively. On the other hand, L and L + 1 have in THF even contributions from nHo1 and nHo2 and those MOs are widespread between both ligands. In DMSO, the charge density is widespread between Re, COs, nHo1, and nHo2 in H and H-1. The solvent effect on MOs charge density is responsible for a decrease of the percentage of charge-transfer transi­ tion, CT%, as polarity increases, from 48% in vacuo to nearly 32% in DMSO (see definition of CT% in Supporting Material and Table S6). The decrease in CT% as polarity increases also explains the bath­ ochromic shift of the calculated MLLCTRe(CO)3→nHo1, nHo2 wavelength (λcalc) as solvent polarity decreases. As the charge density over Re is lower in DMSO than in BzH, the energy of the MLLCTRe(CO)3→nHo1, nHo2 is higher in DMSO than in BzH and the charge transfer process becomes energetically less feasible. As observed in the previous figures, our cal­ culations are in agreement with the negative solvatochromism observed in less polar solvents. The direction of the solvent dependence is asso­ ciated with a reduced (and reversed) molecular dipole in their MLCT excited states, as stated in the bibliography [70]. As depicted in the Fig. 4, the molecular dipole moment, µ, increases with the increase on the dielectric constant, εr. Moreover, the vector of the dipole moment is directed between the two nHo ligands. The solvent effect on the dipole moment can be interpreted in terms of electron density plots (Figure S2). In vacuo, the electron density is more concentrated inside the “shape” of the molecule. However, when the polarity of the solvent increases, the electron density becomes more diffuse and it is enhanced outside the molecular limits. Therefore, µ increases. Table 1 λmax of Re(nHo)2 in different solvents and dipole moment (μ) and dielectric constant (ε) of the solvents [69]. Solvent λmax, nm λmax, nm μ, D (debye) ε at 25 ◦ C CH3CN CH3OH CH2Cl2 CCl4 239 241 241 — 305 307 309 315 3.53 (at 25 ◦ C) 2.87 (at 20 ◦ C) 1.14 0 35.94 32.66 8.93 2.23 3.2. Quantum chemistry of Re(nHo)2 To get a deeper understanding of the absorption spectrum of Re (nHo)2 and its dependence with the solvent described above, a system­ atic TD-DFT theoretical study is present herein. To this aim, spectra were simulated under 10 different solvents (i.e., PCM = DMSO, ACN, MeOH, EtOH, Ace, DCM, THF, Tol, BzH and CCl4) with different intensive properties. A set of MLCT, LLCT and IL electronic transitions was taken into account in the calculations. The calculations were carried out at the M06/6–311 G/6–311G*/LanL2TZ(f)/PCM level of theory. Fig. 2 depicts the UV–visible absorption spectra of Re(nHo)2 simu­ lated under both vacuo and the 10 different solvents mentioned above (Figure S1a). The calculated absorption spectra follow the experimental trend showing a clear bathochromic shift of the lowest energy absorp­ tion band as the polarity of the solvent decreases while the higher energy band experiences hardly any shift. In addition, the highest energy band in vacuo is only blue-shifted by 7 nm relative to the solvent media while the lowest energy band in vacuo is displaced by 20–40 nm to the red relative to its position under the PCM. Electronic transitions results calculated at the same level of theory in vacuo, BzH, and DMSO are summarized in Tables S1-S3. The most relevant MOs which are responsible for the electronic transitions in the absorption spectroscopy of Re(nHo)2 in the 230–500 nm wavelength range are: HOMO, LUMO, and the groups of MOs H-10 through H-1 and L + 1 through L + 6. The percentage compositions of those MOs were obtained from Mulliken population analysis with the aid of AOMIX program from contributions of five fragments: (i) Re atom, (ii) the three carbonyls, (iii) nHo-1 molecule, (iv) nHo-2 molecule, and (v) Cl atom. Tables S4-S5 show the calculated% compositions of all fragments at each MO for Re(nHo)2 in BzH and DMSO. In the 330–500 nm region, the most relevant electronic transitions are H→L, H→L + 1, H-1→L, H-2→L, and H-2→L + 1. Fig. 3 shows the spatial plots of a selection of those MOs of Re(nHo)2 in vacuo, BzH, THF, and DMSO, which give insight into the electronic transitions. Fig. 3 shows that in vacuo, H and H-1 are MOs mostly centered on the Re atom with contributions from the three CO while L and L + 1 are MOs 3.3. Photophysical and photochemical measurements of Re(nHo)2 3.3.1. Luminescence measurements The emission spectra of Re(nHo)2 were recorded in MeOH, ACN, and DCM (Fig. 5). For comparative purposes, spectra of non-coordinated nHo recorded under different solvent or pH conditions are also shown. Luminescence spectra of both Re(nHo)2 and non-coordinated nHo, showed a strong solvent dependence. Briefly, a set of three emission bands centered 370–400 nm, 400–480 nm, and 480–550 nm. While the lowest energy transition could be associated to MLCT transitions, the spectrum of non-coordinated nHo suggests a dominant contribution of ILnHo transition [25,67,72]. When Re(nHo)2 is dissolved in a non-protic solvent with a low polarity like ACN, the only evident emission band is the one attributed to an intraligand excited state, ILnHo, where the emission spectrum of the complex is quite similar to the emission spectrum of the non-coordinated nHo ligand, with no spectral contri­ butions at wavelength larger than 450 nm. On the contrary, emission spectrum of Re(nHo)2 recorded in methanolic solution (Fig. 5, left) shows two broad bands. The highest energy bands (λ ~ 360 – 390 nm) are attributed to the radiative decay of ILnHo electronic states [68,73, 74]. The emission centered at λ ~ 440 nm, has been previously attrib­ uted to an ILnHo excited state where the n electrons of the pyridinic N are compromised, as in the cationic form of nHo (nHoH+) [67,72]. In addition, a shoulder spans the 480 – 600 nm region of the spectra. As it was previously established, when an organic molecule is part of a transition metal complex, nonbonding electrons of the N atoms of the ligands, that contributed the nπ* excited state, is turned into a charge transfer (CT) excited state. Bearing this in mind we can assume that this effect could explain the similarities observed in the luminescence spectra in ACN and MeOH namely where interaction of solvent mole­ cules with the nonbonding electrons is strong [53]. Conversely in DCM, the emission spectrum of non-coordinated nHo does not resemble the spectra of the complex. While the nHo emission band (ILnHo excited state) is located at λmax = 380 nm, a band centered at λmax = 450 nm was Fig. 2. Simulation of the UV/Vis spectra of Re(nHo)2 in 10 different solvents and vacuo. Inset: Amplification of the band centered in λ~350 nm. 4 I. Maisuls et al. Journal of Photochemistry and Photobiology 8 (2021) 100078 Fig. 3. Spatial plots of most representative MOs of Re(nHo)2 (isovalue = 0.02). Photoluminescence quantum yields (ΦF), as well as the photo­ luminescence excited state lifetimes (τ) of Re(nHo)2, were measured in ACN, DCM, and MeOH, and the results are depicted in Table 2. Lumi­ nescence lifetime were recorded at different wavelengths, depending on the prominent emission bands of the complex. As shown in Table 2, both ΦF and τ also depend in a certain way on the solvent. From the obtained values of τ, two main points can be discussed. First, as depicted, there is a mild dependency on the presence of O2, as expected for this kind of compounds and their ability to interact with 3O2 to generate 1O2, (see below). Second, the obtained values for the two main ILnHo emission bands closely resemble the τ previously reported for the excited states of non-coordinated nHo molecule [53, 67]. This outcome suggests once more, that the main emitting excited states in Re(nHo)2 are mainly ILnHo. 3.3.2. Photochemical reactions induced by laser flash photolysis (LFP) LFP measurements were carried out using a XeF laser (λex = 351 nm). Fig. 6 shows the transient spectra obtained when either Re(nHo)2 or non-coordinated nHo solutions (10−5 M) were flash photolyzed in MeOH. As it can be observed, the main transient absorption band observed with Re(nHo)2 solution is centered at λmax ~ 555 nm (blue). However, the main absorption band with the nHo solution is centered at λmax ~ 500 nm (red). The latter spectral feature was previously attrib­ uted to an excited state of the nHo [68]. The spectra obtained are dis­ similar and, therefore, the transient of Re(nHo)2 should not be assigned to an intrinsic ILnHo excited state. Besides, the decay of the transient of the complex after the irradia­ tion adjusts perfectly to a monoexponential decay (τ = 75 ns), sug­ gesting that only one species is present. This lifetime is much longer than the luminescence lifetime of Re(nHo)2 (Table 2), and is markedly shorter than the reported (and also measured in this work) for the transient decay of non-coordinated nHo (τ = 2 μs), as it is shown in the supplementary information (Figure S3) [53,68,72]. These differences Fig. 4. Molecular dipole moment, μ, of Re(nHo)2 as a function of the dielectric constant, εr. observed to Re(nHo)2. Under acidic conditions, when the n electrons of the pyridinic N of the free nHo are compromised, as in nHoH+, a λmax of 450 nm is observed. This equivalence between the spectra of the nHoH+ and Re(nHo)2 in DCM suggests that in this solvent the complex exper­ iments a charge distribution where an electronic deficiency over the nHo is obtained and therefore the spectral features of an ILnHo electron-deficient excited state is observed. In this sense, the nature of the excited state responsible for the luminescence at λ ~ 450 nm could be attributed to a protonated-like ILnHo excited state [67]. The changes in the electronic density, along with the “heavy atom effect” caused by the Re atom can lead to an electronic distribution like the free nHoH+, giving as a result similar emission spectral features. 5 I. Maisuls et al. Journal of Photochemistry and Photobiology 8 (2021) 100078 Fig. 5. Left: normalized emission spectra of Re(nHo)2 (dash lines) and nHo (dotted lines) in ACN (red) and MeOH (black). Right: normalized emission spectra of Re (nHo)2, nHo in DCM and nHo in DCM + H+ (dotted line and dashed line, respectively) λex = 320 nm. Emission spectra of non-coordinated nHo are in agreement with that reported in the literature [53,68,71]. Table 2 Photoluminescence excited state lifetimes and emission quantum yields of Re(nHo)2in different solvents. Solvent ΦF τ Re(nHo)2 λem = 380 nm/air τ Re(nHo)2 λem = 380 nm/N2 τ Re(nHo)2 λem = 450 nm/air τ Re(nHo)2 λem = 450 nm/N2 ACN DCM 0.010 0.025 τ = 3.06 ± 0.02 τ = 2.56 ± 0.02 τ = 3.84 ± 0.02 τ = 2.71 ± 0.02 – – MeOH 0.018 τ = 3.77 ± 0.01 τ = 4.51 ± 0.02 equilibrated/ns equilibrated/ns equilibrated/ns τ1 = 1.25 ± 0.03 (93%) τ2 = 20.4 ± 0.3 (7%) τ1 = 3.65 ± 0.04 (76%) τ2 = 18.5 ± 0.1 (24%) equilibrated/ns τ1 = 1.41 ± 0.06 (81%) τ2 = 17.2 ± 0.2 (19%) τ1 = 4.36 ± 0.06 (72%) τ2 = 26.2 ± 0.1 (28%) flash irradiated in a neat MeOH solution (10−5 M) containing also 0.1 M TEA. The transient spectrum recorded is shown in Fig. 7. This transient spectrum is very similar to the one observed in the absence of TEA Fig. 6). In addition, the decay lifetime of the transient observed was longer lived (τ = 6.04 μs) than excited state decay. These results suggest that the similarity between the excited state and the transient in Fig. 7 spectral features is the result of the charge separation established in the complex when an excited state MLCTRe→nHo is popu­ lated (formally Re(II) and a ligand radical anion) and the net location of an electron in the ligand, i.e., forming the reduced radical generated by reaction of the MLCT with TEA, Eq. (4) and ((5). Fig. 6. LFP spectra for non-coordinated nHo (red) and Re(nHo)2 complex (blue) recorded in MeOH. are explained by assuming that some excited states in the Re(nHo)2 complex are different than those present in the non-coordinated nHo, as observed previously in different coordination complexes with nHo as ligand [29]. The ability of the excited states to participate in redox reactions it is well documented in the literature [29,56,75,76]. The electron transfer reactions between the excited states of Re(I) complexes with the sacri­ ficial electron donor triethylamine (TEA) as well as with the electron acceptor methyl viologen (MV+2) are often used to probe their redox reactivity. Reductive quenching with amines, in particular, it is used for the identification of MLCT excited states. They react generating a reduced radical of complex. In this work, the Re(nHo)2 complex was Fig. 7. LFP spectra of Re(nHo)2 with an excess of TEA in MeOH (λex = 351 nm). Inset: oscillographic trace recorded at λob = 550 nm showing the decay of the transient absorbance (ΔA), with a lifetime τ = 6.04 μs. 6 I. Maisuls et al. Journal of Photochemistry and Photobiology 8 (2021) 100078 [ ] hv [ ]∗ ClReI (CO)3 (nHo)2 → ClReII (CO)3 (nHo)(nHo•− ) (4) [ ]∗ +TEA [ ] ClReII (CO)3 (nHo)(nHo•− ) ̅̅̅̅→ ClReI (CO)3 (nHo)(nHo•− ) •+ (5) −TEA The quenching rate constant (kq) was calculated from the slope of the plot kd vs MV+2, yielding the value kq = 4.8 × 109 M − 1s−1 (Fig. 9). This value of kq is in within the order of magnitude of kq constants in the literature for structurally related complexes [29,77,78]. Furthermore, it is 2.3 to 34.3 times greater than those reported for the relative com­ plexes [(nHo)Re(CO)3(L)]+, where L = bidentate N,N´-ligands [29]. In sum, the excited state oxidation reaction of Re(nHo)2 occurs with greater ease than those complexes with bidentate ligands. Such a greater ease is probably due to steric effects that energetically optimize the re­ action path for monodentate ligands. Thus, contrasting what is observed in a non-coordinated nHo solu­ tion, an MLCT excited state is generated when a solution of Re(nHo)2 was flash photolyzed. 3.3.3. Pulse radiolysis (PR) The pulse radiolysis technique was used also to generate the reduced radical of Re(nHo)2 complex by reaction mainly with solvated electrons, e¡solv, (experimental conditions MeOH/N2, see 2.4 section). Fig. 8 shows that the spectrum for the reduced species of Re(nHo)2, (blue), consist of a narrow band at λ ~ 390 nm along with a broad band at λ ~ 550 nm, both bands nearly with the same intensity. The same spectral features are observed in the reduction of non-coordinated nHo (red). Hence, the complex is reduced by the thermal reaction with e−solv producing a radical, eq. (6). [ ] e−solv [ )] ClReI (CO)3 (nHo)2 → ClReI (CO)3 (nHo)(nHo•− 3.3.4. Singlet oxygen generation and optoacoustic measurements Singlet oxygen generation by the Re(nHo)2 complex in ACN solu­ tions was analyzed by time-resolved phosphorescence measurements (1270 nm). The phosphorescence showed clear evidence of singlet ox­ ygen formation. Linear correlations were obtained from the plots of the dependence of the singlet oxygen phosphorescence intensity emission at zero time, S(0), as a function of the laser energy for the complex and the reference. From these slopes (Figure S5) and the usual procedure described elsewhere [62,79], the determined quantum yield of singlet oxygen production was ΦΔ = 0.25 ± 0.02. This result is similar to values of ΦΔ of Re(I) complexes which have similar structures or with nHo as ligand [30,62,80]. As observed in Fig. 10, the photoacoustic signal of Re(nHo)2, as well as the reference in ACN solutions, showed the same behavior: no time shift or changes of shape, with respect to the calorimetric reference signal (inset of Fig. 10). Linear relationships in both solvents were ob­ tained between the amplitude of the first optoacoustic signal (H) and the excitation fluence (F) for samples and references at various A, in a flu­ ence range between 1 and 10 J/m2. The ratio between the slopes of these lines for sample and reference yielded the values of α for the samples. From these plots, considering that aR = 1 for CR, the a value = 0.89 ± 0.04 was obtained for Re(nHo)2 complex. Consequently, this complex released to the medium almost all the absorbed energy as prompt heat (integrated by the transducer) in processes faster than τR/5. These values, combined with the photochemical data, were satisfactorily adjusted to the energy balance [62,66], where the molar exciting energy from the laser photon (Eλ = 80.5 kcal/mol at 355 nm) provides the sum of the fraction of energy dissipated as prompt heat, plus the energy lost in rapid radiative processes, e.g. fluorescence, and the energy "stored" in long-lived transient species, such as a singlet oxygen. (6) The high spectral resemblance between the spectrum generated by PR and the spectrum recorded by LFP in the reductive quenching with TEA (Fig. 7), confirms the Re(nHo)2 role of electron acceptor in the photoinduced process in which the participation of a MLCTRe→nHo excited state must be required [29]. Oxidative quenching of Re(nHo)2 was investigated by the LFP gen­ eration of the excited states of the complex in the presence of MV+2. The latter species oxidize the excited state of the complex producing the radical MV●+. Such a radical exhibits a characteristic absorption at λ ~ 600 nm (Figure S4). The redox process must involve the photo­ generation of MLCT, eq. (4), followed by its reaction with MV+2, eq. (7). [ )]∗ ]+ [ ClReII (CO)3 (nHo)(nHo•− + MV+2 → ClReII (CO)3 (nHo)2 + MV•+ (7) Solutions of the complex with MV were flash irradiated at 351 nm. The rate constants of the quenching reactions were determined by varying the concentration of MV+2 while keeping the complex concen­ tration constant. The kinetics of the reactions was investigated under a pseudo-first-order regime in MV+2 concentration. A single exponential decay of the excited state with a rate constant (kd), eq. (8), corre­ sponding to a pseudo-first-order dependence on MV+2 concentration was obtained [29,76]. +2 −kd t ΔAt = ΔA0 e 4. Conclusions (8) The photophysical and photochemical properties of ClRe (CO)3(nHo)2 were studied in solution phase. These results allowed us to Fig. 8. Pulse radiolysis spectra of Re(nHo)2 (blue) and non-coordinated nHo (red) of N2 deaerated solutions (10−5 M, MeOH). Fig. 9. Plot of kd vs [MV+2]. kq is represented as the slope of the linear fit. 7 I. Maisuls et al. Journal of Photochemistry and Photobiology 8 (2021) 100078 112–2013–01–00236CO), ANPCyT (PICT 2018–03193 and PICT 2018–03341) and UNLP (11/X779 and 11/X679) Argentina. F.M.C, E. W. and G.T.R. are Research Members of CONICET (Argentina). P.D.G. is a Research Member of CICBA (Argentina). I.M. thanks ANPCyT, CONI­ CET and the Fulbright Program for research scholarships. Part of this work was also carried out in the Notre Dame Radiation Laboratory (NDRL). The NDRL is supported by the Division of Chemical Sciences, Geosciences and Biosciences, Basic Energy Sciences, Office of Science, United States Department of Energy through grant number DEFC02–04ER15533. This is contribution number NDRL 5320. 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The complex luminescence is mainly attributed to the emitting 1ILnHo state although overlapping emission from 3MLCT states in the low energy region cannot be ruled out. How­ ever, in flash photolysis experiments the MLCT excited states generated govern the photochemistry of the complex. The excited state of Re (nHo)2 complex can efficiently generate singlet oxygen as well as reduced radicals or oxidized species of Re(II) reactive against substrates present, for example, in cellular environments. These photophysical properties suggest the potential application of Re(nHo)2 complex in photodynamic therapy (PDT) or photoactivated chemotherapy (PACT), antioxidant activity, or photocytotoxicity. In this sense, the cellular uptake characteristics of the Re(nHo)2 in A549 cells as well as their cytotoxicity against these human carcinoma lung cells, acquire even more relevance [25]. Moreover, after photonic excitation, almost all the absorbed energy by the complex is released to the medium as prompt heat. This thermal feature could be of interest also for new alternative therapies such as regional hyperthermia that allows counteracting tumor growth and progression due to a localized increase of the tem­ perature inside of the cancer cell. The photophysical properties estab­ lished in the ClRe(CO)3(nHo)2 allow us to imagine some intracellular photobiological action that could be modulated by the difference in the polarity of the different cell compartments. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgments This work was supported in part by CONICET (PIP 8 Journal of Photochemistry and Photobiology 8 (2021) 100078 I. Maisuls et al. [19] V. Fernández-Moreira, M.L. Ortego, C.F. Williams, M.P. 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