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REGULAR ARTICLE

Photochemical and photocytotoxic evaluation of new Oxovanadium (IV) complexes in photodynamic application

BANDANA SANASAMa, MD KAUSAR RAZAb, DULAL MUSIBaand MITHUN ROYa,*

aDepartment of Chemistry, National Institute of Technology, Manipur, Langol, 795004 Imphal, Manipur, India

bDepartment of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India E-mail: mithunroy@nitmanipur.ac.in

MS received 25 October 2020; revised 13 January 2021; accepted 24 February 2021

Abstract. Four new ternary Oxovanadium(IV) complexes, [VO(L)(B1-4)](acac), where, L = (E)-2- (2- hydroxybenzylideneamino)-5-guanidinopentanoic acid (Argininesalisylidene) and B were 1H-imidazo-[4,5- f][1,10]-phenanthroline (B1) (1), 2-phenyl-1H-imidazo [4,5-f][1,10] phenanthroline (B2) (2), 2-(naphthalen-1- yl)-1H-imidazo [4,5-f][1,10] phenanthroline (B3) (3) or 1-(pyren-2-yl)-1H-imidazo[4,5-f][1,10] phenanthro- line (B4) (4) were synthesized, characterized and photocytotoxicity in A549 cell were studied in dark and visible light (400–700 nm, 10 J cm-2). Photochemistry of the complexes (1-4) related to the generation of singlet oxygen (1O2) was studied in detail. The presence of triplet excited state in the complexes was probed from perylene assay. Photo-activated generation of singlet oxygen from the complexes was probed by DPBF assay and the degree of photo-cytotoxicity of the complexes was related to their ability in photo-activated1O2

generation. Complexes4exhibited remarkable photocytotoxicity in A549 cells with photo index (PI)*16 in visible light (400–700 nm, 10 J cm-2) (IC50, 3.81lM), while complexes were almost less-toxic in dark (IC50, 59.7 lM). Intracellular ROS generation was studied from 20,70-dichlorofluorescein diacetate (DCFH-DA).

Annexin V-FITC/PI assay suggested apoptotic nature of cell death. Overall, the remarkable photocytotoxic efficacy of the new Oxovanadium(IV) complexes (1-4) making them the potential photochemotherapeutic agents in lieu of porphyrin-based PDT agents.

Keywords. Oxovanadium (IV) complexes; Singlet oxygen (1O2); Photo-cytotoxicity in A549 cells;

Intracellular ROS generation; Apoptosis.

1. Introduction

Photodynamic Therapy (PDT) emerged as the tumour specific and non-invasive treatment modality for can- cer around the 1980s, and it required a non-toxic photosensitizer, red lightand molecular oxygen.1–6 PDT is an effective treatment modality for cancer in which it targets the tumour cells selectively and leaving the unaffected healthy cells. In this therapy, the photosensitizer drug located in cancer affected cells is activated by radiations whose wavelength is within the PDT window (600-850 nm).7PhotofrinÒis the FDA approved the first generation PDT drug used for lung and oesophageal cancers. Photo-activation of PhotofrinÒ forms cytotoxic singlet oxygen (1O2),

responsible for tumor ablation. Porphyrin-based drugs showed hepatotoxicity due to the formation of biliru- bin on oxidative conversion. Skin photo-sensitivity was the other major drawback with porphyrin-based photo-sensitizers.8–15 Significant limitations of por- phyrin-based photosensitizers resulted in extensive research on exploring alternative nonporphyrin-based photochemotherapeutic drugs that are less toxic and photoreactive at longer wavelengths near the upper limit of ‘PDT therapeutic window’ of 600-850 nm.16–20

The wide range of oxidation states, coordination number and geometry; the ligand-induced tunability of optical, redox, thermodynamic and kinetic properties, have rendered the transition metal complexes as

*For correspondence

Supplementary Information: The online version contains supplementary material available athttps://doi.org/10.1007/s12039-021- 01896-4.

J. Chem. Sci. (2021) 133:42 ÓIndian Academy of Sciences https://doi.org/10.1007/s12039-021-01896-4Sadhana(0123456789().,-volV)FT3](0123456789().,-volV)

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successful candidates for medicinal applications.21–26 Photo-activate transition metal complexes exhibiting ligand exchange, ligand dissociation, isomerization reactions, electron transfer or redox reactions also have emerged as the viable alternative of current porphyrin or phthalocyanine-based PDT agents.27–32 The photo-activated states of the transition metal complexes releasing small molecules like CO or NO, generating hydroxyl or superoxide radicals through photo-redox chemistry, yielding singlet oxygen (1O2) through the process of photosensitization induced oxidative stress in the cancer cells promoting apopto- sis in cancer cells.33–36 The stable 3d transition metal complexes, soluble in the biologically relevant sol- vent, exhibiting chemical reactions by absorbing the light of lower energy are of paramount biological importance to develop metal-based photochemothera- peutic agents because of higher tissue penetration of longer wavelength light.37,38

There are several advantages in developing vana- dium-based photo-chemotherapeutic agents over other metal ions.39,40For example, (i) Vanadium (V), being a part of several metalloenzymes is considered as a bio-essential element and considered to be non-toxic;

(ii) The oxidation state of vanadium ranges from- 1 to ?5 and switch between the oxidation states ?5,

? 4 and ? 3 in the physiological medium; (iii) Vanadium often exhibit a broad spectrum of coordi- nation geometry; (iv) There is a unique structural resemblance of the tetrahedral anion vanadate(V) to the phosphate anion making vanadate able to interact with various physiological substrates and explain the antidiabetic potential of vanadium.41–43

Oxovanadium(IV) complexes with single d-electron often resemble the chemistry of copper(II) and exhibit broad d-d transition in the PDT window (600–800 nm). Most often, the redox potential was observed beyond the biological redox window preventing Oxovanadium(IV) reduction from cellular thiols. Such factors contributed to Oxovanadium complexes for potential candidates for photochemotherapeutic applications.44–48 Arignine is one of the most impor- tant essential amino acid in a biological system and involved in the synthesis of endogenous nitric oxide (NO) which is a powerful neurotransmitter controlling blood pressure.49 The clinical use of arginine in ang- ina, hypertension, erectile dysfunction, and anti-ageing effect of arginine prompted us to use 2-(2-hydroxy- benzylideneamino)-5-guanidinopentanoic acid (Argininesalisylidene) (L) as the tridentate ligand for coordinating to Oxovanadium (V=O).50,51 The p-acid character of 1H-imidazo-[4,5-f][1, 10]-phenanthroline and its derivatives, the photo-active properties of such

ligands, providing a unique platform to attach different chromophores were the key factors for considering the N,N-donor 1H-imidazo-[4,5-f][1, 10]-phenanthroline- based ligands for complexation with Oxovana- dium(IV).52,53 Therefore, the complexes were designed for photocytotoxicity in the PDT window without any unwanted toxicity associated with bio- compatible ligands and metal ions. Herein, we report the synthesis, characterization, photo-physical prop- erties, singlet oxygen generation ability, and cytotox- icity of four new ternary Oxovanadium(IV) complexes (1–4) with the generic molecular formula [VO(L) (B1-4)](acac), where acac denoted acetylacetonate, L was 2-(2-hydroxybenzylideneamino)-5-guanidinopen- tanoic acid (Argininesalisylidene) and B were 1H imidazo [4,5-f][1, 10] phenanthroline (B1) (1), 2-phe- nyl-1H-imidazo [4,5-f][1, 10] phenanthroline (B2) (2), 2-(naphthalen-1-yl)-1H-imidazo [4,5-f][1, 10] phenan- throline (B3) (3) or 1-(pyren-2-yl)-1H-imidazo[4,5- f][1, 10] phenanthroline (B4) (4).

2. Experimental

2.1 Materials and reagents

All reagents and chemicals were obtained from Sigma Aldrich (USA) or HiMedia (India) and used as received without further purification. The solvents used were purified by standard methods.54 Diphenylisobenzofuran (DPBF), 1,10-phenanthroline, formaldehyde, benzaldehyde, 1-napthaldehyde, pyr- ene-1-carbaxyldehyde and vanadyl acetylacetonate were procured from SRL and Alfa Aesar (USA). A reported synthetic procedure was used to synthesize 1,10-phenanthroline-5,6-dione, 1H-imidazo[4,5-f][1, 10] phenanthroline (B1), 2-phenyl-1H-imidazo [4,5- f][1, 10] phenanthroline (B2), 2-(napthalen-1-yl)-1H- imidazo [4,5,f][1, 10] phenanthroline (B3) and 1-(pyren-2-yl)-1H-imidazo [4,5- f][1, 10] phenan- throline (B4) and (E)—2- (2-hydroxybenzylide- neamino)-5-guanidinopentanoic acid (L) with minor modifications.53–57 The IR spectroscopy, UV-visible spectroscopy and photoluminescence spectroscopy were recorded on Perkin-Elmer UATR TWO FT-IR Spectrometer operating from 400 to 4000 cm-1, Per- kin-Elmer UV/VIS spectrometer and HITACHI F-7000 Fluorescence spectrophotometer respectively.

The molar conductivity measurements were done using a EUTECH INSTRUMENT CON 510 (India) conductivity meter. Q-TOF ESI Mass spectra (MS) were recorded in Bruker Esquire 3000 Plus spec- trophotometer (Bruker-Franzen Analytic GmbH

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Bremen, Germany). The absorbance reading of MTT assays was collected using a Molecular Devices Versa Max tunable microplate reader. Flow cytometric experiments were performed using fluorescence-acti- vated cell sorting (FACS) Verse instrument (BD Biosciences) fitted with a MoFLoXDP cell sorter and analyzer with three lasers (k= 488, 365, and 640 nm) and 10-color parameters. Electron Spin Resonance (ESR) spectra was done using JEOL, Model: JES- FA200 ESR-Spectrometer. All Theoretical calcula- tions (DFT) on all the complexes were carried out using Gaussian 09rev. A.02. The input files to Gaus- sian 09 were prepared with Gauss view 5.0.8. Sche- matic drawing of the compounds and IUPAC names of all the ligands (L and B1-4) were obtained by using Chem Draw Professional 15.

2.2 Synthesis and characterization

2.2a Synthesis of ligands L through B1-4: A reported protocol was cited to synthesize 1,10-phenanthroline- 5,6-dione, 1H-imidazo[4,5-f][1, 10] phenanthroline (B1), 2-phenyl-1H-imidazo-[4,5-f][1, 10]-phenanthroline (B2), 2-(napthalen-1-yl)-1H-imidazo [4,5,f][1, 10]

phenanthroline (B3) and 1-(pyren-2-yl)-1H-imidazo [4,5-f][1, 10] phenanthroline (B4) and 2- (2- hydroxybenzylideneamino)-5-guanidinopentanoic acid (L) with minor modifications and characterized by 1H,

13 C NMR spectra (Figure S1-S10, Supplementary Information).55–57

2.2b General procedure for the synthesis of complexes 1–4: Complexes 1–4 were synthesized by dissolving 0.75 mmol (0.199 g) VO(acac)2 in CH3OH (10 mL) followed by the addition of 4 mL methanolic solution of B1-4 (0.75 mmol) [B1(0.1651 g), B2(0.2222 g), B3(0.2597 g), or B4 (0.3153 g) and 0.75 mmol of L (0.21024 g) with constant stirring at room temperature. The mixtures were stirred for*2 h at room temperature, then stored in a refrigerator for one day. The dark-green colored precipitates were filtered, washed with cold ethanol (0–5 °C), and dried under vacuum. All of the complexes were obtained as microcrystalline solids with yields of 0.2540 g (1, 51 %), 0.1726 g (2, 56%), 0.3378 g (3, 57%), and 0.3176 g (4, 49%).

2.2.2a. b Analysis of complex 1 (C31H33N8O6-

V) Yield: 51% (0.38 mmol). Calculated: C, 56.02; H, 5.00; N, 16.86. Found: C, 55.92; H, 4.89; N, 16.77.

FT-IR (solid phase): br, broad; vs, very strong; s, strong; m, medium; w, weak. 1068s, cm-1 (VO, s);

1662s, cm-1(C=O, s); 1556s cm-1(C=N, s). Time-of- flight electrospray ionization mass spectrometry (Q- TOF ESI MS) in CH3CN: m/z 565.1219 [VO(L)(B1)]?. UV-visible spectroscopy in 10% v/v DMSO/H2O/HEPS buffer, pH 6.9,e(L mol-1cm-1) at kmax (nm): 595, L mol-1cm-1 (293 nm); 470 L mol-1cm-1(375 nm); 81 L mol-1cm-1(704 nm).KM

(S m2 mol-1) in 1:9 (v/v) DMSO/H2O: 92 at 298 K.

2.2.2b. b Analysis of complex 2 (C37H37N8O6- V) Yield: 56% (0.23 mmol). Calculated: C, 60.00; H, 5.04; N, 15.13. Found: C, 59.88; H, 4.97; N, 14.92.

FT-IR (KBr phase): 1065s cm-1(VO, s); 1678s cm-1 (C=O, s); 1529s cm-1 (C=N, s). Q-TOF ESI MS in CH3CN: m/z 641.1819 [VO(L)(B2)]?. UV-visible spectroscopy in 10% v/v DMSO/H2O/HEPS buffer, pH 6.9,e(L mol-1cm-1) atkmax(nm): 1099 L mol-1 cm-1 (261 nm); 123 L mol-1 cm-1 (416 nm); 35 L mol-1 cm-1(746 nm). KM(S m2mol-1) in 1:9 (v/v) DMSO/H2O: 78 at 298 K.

2.2.2c. b Analysis of complex 3 (C41H39N8O6- V) Yield: 57% (0.42 mmol). Calculated: C, 62.28; H, 4.97; N, 14.17. Found: C, 62.15; H, 4.82; N, 14.11.

FT-IR (KBr phase): 995s cm-1 (VO, s); 1682 cm-1 (C=O, s); 1547 cm-1 (C=N, s). Q-TOF ESI MS in CH3CN: m/z 691.1299 [VO(L)(B3)]?. UV-visible spectroscopy in 10% v/v DMSO/H2O/HEPS buffer, pH 6.9,e(L mol-1cm-1) atkmax(nm): 621 L mol-1cm-1 (254 nm); 305 L mol-1cm-1(427 nm); 248 L mol-1 cm-1(432 nm); 134 L mol-1cm-1(725 nm).KM(S m2 mol-1) in 1:9 (v/v) DMSO/H2O: 81 at 298 K.

2.2.2d. b Analysis of complex 4 (C47H41N8O6-

V) Yield: 49% (0.36 mmol). Calculated: C, 65.27; H, 4.78; N, 12.96. Found: C, 65.16; H, 4.71; N, 12.91.

FT-IR (KBr phase): 1012s cm-1(VO, s); 1645 s cm-1 (C=O, s); 1538 s cm-1 (C=N, s). Q-TOF ESI MS in CH3CN: m/z 765.6962 [VO(L)(B4)]?. UV-visible spectroscopy in 10% v/v DMSO/H2O/HEPS buffer, pH 6.9,e(L mol-1cm-1) atkmax(nm): 1618 L mol-1 cm-1 (310 nm); 257 L mol-1 cm-1 (420 nm); 62 L mol-1 cm-1(730 nm);KM(S m2 mol-1) in 1:9 (v/v) DMSO/H2O: 83 at 298 K.

2.3 Reactive oxygen species (ROS)58,59

We studied singlet oxygen (1O2) generation via UV- visible spectrophotometry using 50 lM 1,3- diphenylisobenzofuran (DPBF). DPBF is a fluorescent molecule that characteristically and specifically reacts with1O2to form an endoperoxide, which decomposes

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to give 1,2-dibenzoylbenzene. The UV-vis spectra of DPBF (kmax417 nm) were recorded in the presence of the complexes (50 lM) exposed to visible light (400–700 nm) for 200 s. A gradual decrease in absorbance by DPBF indicated the generation of 1O2. We measured DPBF absorbance over time to monitor the photoactivated generation of singlet oxygen.

2.4 Singlet oxygen (1O2) quantum yield determination60

The singlet oxygen (1O2) quantum yields of the complexes and ligands at ambient temperature in DMSO were determined using visible light (400–700 nm) for photosensitization. The 1O2 quantum yields were determined by monitoring the photooxidation of DPBF after sensitization by the complexes and a pyrene ligand. DPBF is a convenient acceptor because it absorbs in the region where the dye is transparent and rapidly scavenges singlet oxygen to generate colorless products. This reaction occurs with little or no physical quenching. The solutions contained dyes in low concentrations and had optical densities ranging from 0.12 to 016 to minimize the possibility of 1O2 quenching by the dyes. The photooxidation of DPBF was monitored from 20 s to 200 s. The 1O2 quantum yields were calculated relative to optically matched solutions and comparing the quantum yield of DPBF photooxidation after sensitization by the compound of interest to that of Rose Bengal (RB) (U[1O2] 0.76 in DMSO) as a reference compound according to Equation (1).

UDc ¼UDRBmc=mRBFRB=Fc ð1Þ where c denotes a complex and ligand, and RB denotes Rose Bengal. UD is the 1O2 quantum yield, and mis the slope of the plot of DPBF absorbance at 417 nm vs. irradiation time. F is the absorption cor- rection factor, which is given by Equation (2).

F ¼110OD ð2Þ

Where, OD is the optical density at the irradiation wavelength.

2.5 Computational details

Theoretical calculations on the complexes were per- formed by using Gaussian 09 version A.02 (Gaussian Inc., USA) and the Gaussian 09 input files were pre- pared by using GaussView 5.0.8. The geometric structures of the complexes and ligands in the ground

state were fully optimized at the B3LYP/GEN level using 6-31G(d,p) basis sets for H, C, N, O, and S atoms. A LANL2DZ basis set was used for V atoms in the gas-phase. Fractional contributions of various groups to each molecular orbital and the contributions (%) of the metal and ligands to the corresponding HOMOs and LUMOs were predicted from GaussSum.

2.6 Cellular studies

The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra- zolium bromide (MTT) assay was used to evaluate the photocytotoxicity of the complexes. Mitochondrial dehydrogenases in viable cells cleave the tetrazolium rings on MTT, resulting in the formation of insoluble, dark purple formazan crystals. The crystals are soluble in DMSO, so they can be quantified by performing spectral measurements. Approximately 8000 A549 cells were plated separately in two different 96-well culture plates. The cells were incubated with com- plexes 1–4 in concentrations ranging from 3.125 to 100 lM in Dulbecco’s modified Eagle medium (DMEM) containing 1% DMSO for 4 h in darkness.

The medium was removed after the incubation and replaced with Dulbecco’s phosphate-buffered saline (DPBS). The cells were exposed to visible light (400–700 nm, 10 J cm-2) for 1 h. A LZC-1 photore- actor (Luzchem, Ontario, Canada) fitted with eight white fluorescent tubes (Sylvania, USA) were used to irradiate one of the plates for 1 h, while the other was kept in darkness using standard protocols. After exposure to light, the DPBS was removed and replaced with a fresh medium, and the plates were incubated for another 19 h in darkness. The cells spent a total of 24 h in the plates. After the 24 h incubation period, 20lL of MTT (5 mg/mL) was added to each well. The 96-plates were incubated for an additional 4 h, after which all of the media was removed from the wells followed by DMSO (200lL) was added to each well, and spectra were collected at 570 nm using a micro- plate reader (TECAN, Switzerland).

The cytotoxicity of each complex was measured as the ratio of absorbance by the treated cells to absor- bance by the untreated controls. The IC50 values were obtained from nonlinear regression analysis GraphPad Prism 6. The data at each concentration were obtained from three independent sets of experiments performed in triplicate culture. The non-fluorescent dye 2,7- dichlorofluorescein diacetate (DCFDA) was used to detect cellular ROS generation. DCFDA is oxidized to 2,7-dichlorofluorescein (DCF), a fluorescent dye with a maximum emission wavelength of 528 nm. The

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amount of oxidized DCF generated from DCFDA is directly proportional to the fluorescence intensity, which was determined via flow cytometry analysis.

The most active complex (4, 5 lM) were incubated with A549 cells for * 4 h. The medium was then removed, and DPBS medium containing plate. The plate was photo-irradiated for 1 h, while an identical plate was maintained in darkness. The cells were removed via trypsinization and collected, and cell suspensions containing 1 9 106 cells per mL were prepared. The cells were treated with a 1lM DCFDA solution in DMSO in darkness for * 15 min at room temperature. The fluorescence intensity of DCFDA in cells treated with complex4was measured in the FL-1 channel during flow cytometry analysis.

An annexin V-FTIC assay was conducted to investigate apoptotic cell death. A549 cells (39 105) were plated in six-well plates and allowed to grow for

* 24 hours. Complex 4 (5 lM) was added, and the plates were incubated in darkness for 4 h. All of the media was removed from the plates. One was sub- jected to visible light irritation (400–700 nm, 10 J cm-2) for 1 h, and an identical plate was stored in the dark. At 19 h post-incubation, the cells were washed with DPBS and trypsinized in 400 lL of 1X binding buffer. Annexin V-FITC (1lL) and propidium iodide (PI, 0.5 lL) were added to each cell suspension, and the suspensions were incubated for* 10 min at room temperature in darkness.

3. Results and Discussion

3.1 Synthesis, Characterization and General Aspects

A reported protocol was cited to synthesize all the ligands (L, B1-B4) and characterized by1H,13C NMR spectra (Figure S1-S10, Supplementary Information).

Ternary Oxovanadium (IV) complexes 1–4 was obtained in reasonably good yields of 49–57%. All the dark-coloured complexes were isolated as microcrys- talline solid, and purified by washing with cold methanol. Initially, the formation of the complexes was confirmed by the UV-visible spectral measure- ments recorded in 10% v/v DMSO-H2O (Figure S11, Supplementary Information). All the four complexes were obtained in analytically pure form and charac- terized spectroscopically and analytically. Elemental analysis and High performance liquid chromatography (HPLC) confirmed the purity of the complexes (1-4) (Figures S12-S15, Supplementary Information). The geometry of the complexes (1-4) were confirmed by

EPR spectra (Figures S16-S19, Supplementary Infor- mation). The X-band EPR spectra of complexes 1-4 in DMSO at 298 K, showed an axially symmetrical sig- nal of tetravalent vanadium in solution, which further split into a number of hyperfine lines, originated from the d1 electron interaction with a nuclear spin I = 7/2 (Table S1, SI). The spectrum displays well-resolved V (I = 7/2) hyperfine lines. The g values of the com- plexes (1-4) are 1.979, 2.011, 2.021 and 2.002. This further established the geometry of the complexes (1-4). The V=Ostr stretching was observed at

* 995–1068 cm-1 along with the C=Ostr and C=Nstr

at 1645–1682 cm-1and 1529–1556 cm-1respectively (Figures S20-S23) in FT IR spectra complexes.61 The molecular ions for the general formula [VO(L?)B] (L was 2-(2-hydroxybenzylideneamino)-5-guanidinopen- tanoic acid and B were 1H imidazo [4,5-f][1, 10]

phenanthroline (B1) (1), 2-phenyl-1H-imidazo [4,5- f][1, 10] phenanthroline (B2) (2), 2-(naphthalen-1-yl)- 1H-imidazo [4,5-f][1, 10] phenanthroline (B3) (3) or 1-(pyren-2-yl)-1H-imidazo[4,5-f][1, 10] phenanthro- line (B4) (4)) along with other fragments of complexes were detected in the Q-TOF ESI mass spectra in CH3CN solutions. Isotopic distributions correlated with the proposed molecular formula of the complexes (Figures S24-S27). The molar conductivity of the complexes was determined in DMSO/H2O (10% v/v DMSO) and the molar conductance values were observed in the range from 78 to 92 S m2mol-1. This indicated a 1:1 electrolyte corresponding to a salt of the cationic [VO(L)(B)]? complexes and an acety- lacetonate (acac) anion (Table 1).

The room temperature magnetic moments of com- plexes 1–4 ranged from 1.68 to 1.72 Bohr magnetons (B. M.) indicating the presence of only one unpaired electron in the complexes. Overall, by analysing the FT-IR, Q-TOF ESI mass spectra, elemental analysis, magnetic measurements, and the molar conductance measurements the structure of the complexes were proposed as shown in Scheme 1, and the proposed structures of the complexes were energetically and structurally optimized by performing unrestricted B3LYP density functional theory calculations.62,63 The corresponding HOMO and LUMO stereographs of the complexes are shown in Figure S28.

3.2 Solubility and stability

Probing the solubility and stability of the complexes of photochemotherapeutic potential in biologically rele- vant solvents is very important for biological appli- cation. We observed that all the complexes (1–4) were

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Table1.SelectedPhysicochemicaldataofthecomplexes(1-4). Complexes1234 IRa :(V=O,C=O,C=N)/ cm-11068s,1662s,1556s1065s,1678s,1529s995s,1682,1547s1012s,1645s,1538s KMb :/Sm2 mol-1 92788183 Q-TOFESIMS(m/ z)c565.1219[VO(L)(B1 )]? 641.1819[VO(L)(B2 )]? 691.1299[VO(L)(B3 )]? 765.6962[VO(L)(B4 )]? Electronicd :MLCT/ LMCT/max/nm(/L mol-1 cm-1 )

293(595),375(470),704(81)261(1099),416(123),746(35)254(621),305(427),432(248),725(134)310(1618),420(257),730(62) Magneticvalues (B.M.)(298K)1.761.711.751.78 em/nm[kex=360nm]e 421486456 A(1 O2)f 0.150.220.310.52 a Solid-phaseIRspectra b MolarconductivitydataofthecomplexesinaqueousDMSO(10%v/vDMSO)at25C c Q-TOFESIMassspectraofthecomplexesrecordedinCH3CN d UV-visiblespectraofthecomplexesin10%v/vDMSO/H2O/HEPSbufferat25°C e Luminescencespectraofthecomplexesrecordedin10%v/vDMSO/H2O/HEPSbufferat25°C f Singletoxygen(1 O2)quantumyieldofthecomplexeswithDPBFandRoseBengalasstandardinDMSOat25°C.

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soluble in acetonitrile (CH3CN), methanol (CH3OH), dimethylsulfoxide (DMSO), dimethylformamide (DMF), aqueous DMF (10% v/v DMF/H2O), aqueous DMSO (10% v/v DMSO/H2O), and aqueous DMSO (10% v/v DMSO/H2O/HEPS buffer, pH 6.9). The stability of the complexes was probed in aqueous DMSO (10% v/v DMSO/H2O/HEPS buffer, pH 6.9) using UV-visible spectrophotometer. The UV-visible spectra of the complexes remained almost unchanged up to 48 h as determined from UV-visible spectral measurements during 0-48 h. (Figures S29-S32, Sup- plementary Information). Negligible changes in the UV-visible spectra traces during 48 hrs probed the stability of the complexes in a biologically relevant solvent. The stability of the complexes was not influ- enced by the visible light (400-700 nm, 10 Jcm-2) (Figures S33-S26).

3.3 Electronic properties

The electronic spectra of complexes 1–4 were recor- ded by using solutions in aqueous DMSO (10% v/v

DMSO/H2O/HEPS buffer, pH 6.9). The spectrum of all the complexes contained a broad and a very weak d-dband (Eg?T2g) in the range 630 and 780 nm, as well as an intense MLCT band near 350 nm (kmax).

Strong ligand-centred bands were observed near 280 nm (kmax), which were attributed to p–p* or n–p* electronic transitions (Figure 1).

Normalized emission spectra were recorded at room temperature using solutions of the complexes in aqueous DMSO (10% v/v DMSO/H2O/HEPS buffer, pH 6.9) with excitation (kex) at 360 nm. The lumi- nescent complexes (1–4) exhibited fluorescence at wavelengths ranging from 420 to 490 nm (Figure S37, Supplementary Information).

3.4 Triplet excited states of the complexes

We studied the presence of energetically low-lying triplet excited states of complexes (1–4), which could be accessible during photo-activation. Up-conversion viatriplet-triplet annihilation (TTA) generally requires a triplet photosensitizer, which could absorb energy, and a triplet acceptor (perylene) as well for up-con- verted emission.64,65 Energy is transferred from the photosensitizer to the acceptorviatriplet-triplet energy transfer (TTET). The electrons in the acceptor mole- cules are excited to their singlet excited state, and as a result, we observe the emission intensity increases.

The intensity of the emission by triplet perylene in CH3CN would have been increased with the duration of photo-exposure in the presence of each complex (1–

4). The up-converted emission spectrum was shown in Figure 2 and Figures S38–S40, Supplementary Infor- mation. We assumed that the photoactivated com- plexes quickly relaxed to the energetically low-lying Scheme 1. Schematic representation of the complexes of

generic molecular formula [VO(L)(B1-4)](acac), where acac denoted acetylacetonate, L was 2-(2-hydroxybenzylide- neamino)-5-guanidinopentanoic acid (Argininesalisylidene) and B were 1H imidazo [4,5-f][1, 10] phenanthroline (B1) (1), 2-phenyl-1H-imidazo [4,5-f][1, 10] phenanthroline (B2) (2), 2-(naphthalen-1-yl)-1H-imidazo [4,5-f][1, 10] phenan- throline (B3) (3) or 1-(pyren-2-yl)-1H-imidazo[4,5-f][1, 10]

phenanthroline (B4) (4).

Figure 1. UV-visible spectra of the complexes 1-4 in aqueous DMSO (10% v/v DMSO/H2O/HEPS buffer, pH 6.9) with the inset showing d-d bands of complexes.

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triplet excited states from their doublet excited states of the photo-activated complexes. The excited triplet states could be proposed as the oxidized NN-donor ligands (B). The exited triplet state of the complexes was quenched by singlet perylene and resulted in emission from triplet perylene. The upconverted emission spectra of perylene in the presence of the complexes (1-4) indicated the presence of the triplet excited states in the complexes which could be pop- ulated during photo-activation. No emission by per- ylene was observed in the presence of the complexes in dark.

3.5 Singlet oxygen generation

The photo-sensitized generation of singlet oxygen (1O2) by the complexes (1-4) was probed by using diphenylisobenzofuran (DPBF) as a reference com- pound.66 The reaction between DPBF and singlet oxygen (1O2) is very specific and forms an endoper- oxide which spontaneously decomposes to 1,2-diben- zoylbenzene at room temperature. The decrease in absorbance of DPBF at 417 nm (kmax) in presence of complex (1–4) suggests the photoactivated generation of singlet oxygen, which can be quantifiable with respect to a reference such as Rose Bengal. We observed a steady decrease in absorbance by DPBF (50lM) at 417 nm while photo-irradiated with visible light (400–700 nm, 10 J cm-2) in the presence of each complex (50 lM) in time-dependent manner. The amounts of 1O2 generated by the complexes was graphically represented by plotting the relative decrease in DPBF absorbance (A/A0) against photo-

irradiation time, t(s). Absorbance (A) by DPBF was measured at predetermined time intervals and com- pared to absorbance by DPBF att= 0 s, A0(Figures3 and S41-S43). We observed a nearly linear decrease in A/A0 over time, which indicated the photoinduced generation of 1O2 from 3O2 by the complexes. The absorbance plots for the complexes had different slopes and qualitatively indicated that the amount of singlet oxygen generated in the presence of complex4 was highest. We quantitatively analysed singlet oxy- gen generation by calculating the quantum yield (U) of

1O2 using Rose Bengal in DMSO as a reference at room temperature (Table1).60 The quantum yields of complexes 1–4 ranged from 0.15 to 0.52. The signif- icant quantum yield of complex4(0.52) suggested for potential PDT applications.

3.6 Photocytotoxicity assay

The in-vitro photodynamic anticancer activities of complexes (1–4) and their corresponding ligands (B1-4) were probed in A549 cells through a 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro- mide (MTT) assay (Table 2, Figures4 and S44, Sup- plementary Information). The assay is based on the ability of the mitochondrial dehydrogenase of the live cells to transform 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide into a cell impermeable formazan crystals which absorb at 570 nm in DMSO.

The relative intensity of the formazan in the drug- treated cells is the measure of cytotoxicity. The cells were treated with the complexes (1–4) and the ligands in a dose-dependent manner for 4 h followed by photo-

Figure 2. (a) Up-conversion emission spectra of the acceptor (Perylene) (30lM) in the presence of complex4(10lM) recorded against the exposure to the visible light in CH3CN. The upconverted emission spectra of triplet perylene indicated the presence of triplet excited state of complex 4, which could be populated during the photo-activation. (b) Proposed mechanism for TTET conversion of complex4 with perylene.

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irradiation for 1 hr. The IC50values for complexes and ligands under dark and visible light (400-700 nm, 10 J cm-2) were obtained from non-linear regression of the normalized dose-response curve and listed in Table2.

Complexes (1–4) in A549 cells caused significant photocytotoxicity with IC50 values ranging from 3.81 lM to 19.4lM under visible light (400–700 nm, 10 J cm-2) while the IC50 values in darkness were in the range 50–60 lM. The photo-index (PI) varied from 3

to 16 with the complex 4 exhibited remarkable pho- tocytotoxicity (PI = 15.66). The photocytotoxicity index of each complex was calculated by dividing its IC50 in darkness by its IC50 under light. PhotofrinÒ, which is an FDA approved drug for photodynamic therapy (PDT) exhibited a significantly higher PDT effect as compared to the present complexes (1-4).

Nevertheless, the non-porphyrin-based Oxovana- dium(IV) complexes (1-4) absorbing near-IR light, Figure 3. (a) UV-vis absorption spectra of 50lM diphenylisobenzofuran (DPBF) treated with complex4(50lM) upon exposure to visible light at wavelengths from 400 to 700 nm (10 J cm-2) recorded over 180 s. (b) Relative change in absorbance by DPBF at 417 nm (A/A0) with time (Sec.).

Table 2. Cytotoxicity data (IC50/lM) of the complexes in dark and on visible light exposure.

Complexes A549 Cell line IC50/lM

Darka R2value[d] Light[b] R2value Photo-index (PI)

1 63.2(±0.3) 0.991 19.4(±0.2) 0.993 3

2 55.2(±0.4) 0.989 12.6 (±0.4) 0.996 4.3

3 54.2(±0.4) 0.992 8.69 (±0.3) 0.994 6.23

4 59.7(±0.4) 0.996 3.81 (±0.2) 0.989 15.66

B1 [100 88.3 (±0.2) 0.992 ND

B2 [100 79.2 (±0.3) 0.994 ND

B3 [100 59.2 (±0.3) 0.989 ND

B4 ND ND ND

L [100 63.5 (±0.2) 0.996 ND

VO(acac)2 76.3±0.2 0.995 ND

PhotofrinÒ[c] 0.5 [50 [100

aIC50 values correspond to 24 h incubation in dark

bIC50values correspond to 4 h incubation in the dark followed by 1 h photo exposure to visible light 400–700 nm,10 J cm-2, post incubation 19 h

cReference 63, ND Not determined

dR2: Standard deviation

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remarkably efficacy in generating singlet oxygen (1O2) and exhibiting photocytotoxicity in visible light were potentially important as the viable alternative of por- phyrin-based PDT agents. Complex 4, which con- tained a photo-active pyrene-based chromophore, exhibited remarkable photocytotoxicity with an IC50

of 3.81(± 0.2)lM, while remaining almost non-toxic (IC50, 59.7 lM) in dark. Enhanced photo-cytotoxic efficacy of complexes 3 and 4 could be due to the photoactive nature and photo-sensitizing ability of pyrene or naphthalene-based chromophores. Ligands B1-4, L and VO(acac)2 alone were non-toxic to A549 cells in dark (IC50 [ 100 lM) and very less-toxic under visible light (IC50 * 59–89 lM). We also compared the photo-cytotoxicity of the other related N,N donar type oxo-vanadium complexes (Table S2, Scheme S1, Supplementary Information). The photo- cytotoxic efficacy of the complexes could be corre- lated with the extent of singlet oxygen generation on photo-activation. The oxovanadium could assist the oxidation of the NN-donor ligands in their metal- bound form when activated with visible light. The proposed short-lived transient state could be proposed

to the triplet excited state of the complexes, as the presence of triplet excited state in the complexes was already probed previously from perylene assay. The triplet excited state of the complex could transform molecular oxygen (3O2) into singlet oxygen (1O2), which could be responsible for phototoxicity.

3.7 In vitro reactive oxygen species (ROS) generation

The intracellular ROS generation was studied by flu- orescence assisted cell sorting using 2’,7’- dichlo- rofluorescin diacetate (DCFDA) assay. The 2’,7’- dichlorofluorescin diacetate (DCFDA) which is a non- fluorescent dye, hydrolyzed by intracellular esterase’s and further oxidized into green fluorescent 2’,7’- dichlorofluorescen (DCF). The fluorescence intensity of oxidized DCF is proportional to the amount or ROS generation. Therefore, the greater the shift in fluores- cence intensity, higher in the intracellular ROS gen- eration. The greater shift of fluorescence intensity in A549 cells treated with complex 4 upon exposure to Figure 4. MTT assay plot for the complexes (1-4) in A549 cells in presence of visible light (400-700 nm, 10 J cm-2) and dark

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the visible light probed for intracellular ROS genera- tion (Figure S45, Supplementary Information).

Although such a shift in A549 cells treated with the complex 4 in dark was negligible as compared to the untreated A549 cells.

3.8 Annexin V-FITC/PI assay

To characterize the mode of cell death, and annexin V-isothiocyanate (FITC)/propidium iodide (PI) fluo- rescence assay coupled with flow cytometry was per- formed to analyze the disruption of lysosomal membranes in A549 cells.67 Annexin V is an intra- cellular protein that typically binds to phos- phatidylserine, which is a glycerophospholipid component of cell membranes. Annexin V-FTIC emits at 535 nm, and the detection of annexin V on the external surfaces of plasma membranes is indicative of apoptosis. The most PDT-active complex (4, 5 lM) in vitro was used to quantify the percentage of A549 cells that underwent apoptosis under visible light (400–700 nm, 10 J cm-2). The flow cytometry data indicated that 10.53% of the treated A549 cells were in the early stage of apoptosis, 34.38% were in the late stage of apoptosis, and there was a population of 9.05% necrotic A549 cells. But in dark the flow cytometry data indicated that only 7.57% of the treated cells were in the early stage of apoptosis, and 2.91%

were in the late stage of apoptosis, and 5.76% under- went necrosis (Figure5). The results demonstrated that apoptosis was the predominant mode of cell (A549) death that took place due to the generation of 1O2by complex 4 on activation with visible light (400–700 nm, 10 J cm-2).

4. Conclusions

Here in the photocytotoxic efficacy of four new tern- ary Oxovanadium(IV) complexes in lungs carcinoma (A549) cells was reported. The complexes (1-4), absorbing near IR light ([650 nm) were probed for the generation of singlet oxygen (1O2) on activation with visible light (400–700 nm, 10 J cm-2). The presence of triplet excited state in the complexes was also probed from perylene assay. The photocytotoxic efficacy of the complexes was related to the degree of a photo-activated generation of singlet oxygen. Com- plex 4 with singlet oxygen quantum yield of 0.52, exhibited remarkable cytotoxicity in visible light (400–700 nm, 10 J cm-2) (IC50, 3.81 lM), while complexes were almost less-toxic in dark (IC50, 59.7 lM). The increased local concentration of singlet oxygen (1O2) led to apoptosis in A549 cells. Overall results advocated the Oxovanadium(IV) complexes as the emerging next-generation prodrugs for pho- tochemotherapeutic application.

Supplementary Information (SI)

Scheme S1, Tables S1-S2 and Figures S1-S45 are available at https://www.ias.ac.in/chemsci.

Acknowledgements

We gratefully thank the Board of Research in Nuclear Science (BRNS), Mumbai (37(2)/14/18/2017-BRNS) for funding. We also would like to thank the National Institute of Technology, Manipur, for providing a research facility to carry out the work. We sincerely thank Prof. Akhil R Figure 5. Annexin V-FITC/PI coupled to flow cytometry analysis showing apoptosis induced by (a) complex4(5lM) in dark. (b) the presence of Visible light (400–700 nm, 10 J cm-2).

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Chakravarty, IISc Bangalore for providing support to carry out the project. We gratefully thank the Central Instruments Facility, IIT Guwahati for providing the EPR data.

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