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Journal of Thermal Analysis and Calorimetry

, Volume 133, Issue 2, pp 935–944 | Cite as

Thermal and spectroscopic studies of 2,3,5-trisubstituted and 1,2,3,5-tetrasubstituted indoles as non-competitive antagonists of GluK1/GluK2 receptors

  • Agata Bartyzel
  • Agnieszka A. Kaczor
  • Halina Głuchowska
  • Monika Pitucha
  • Tomasz M. Wróbel
  • Dariusz Matosiuk
Open Access
Article

Abstract

This paper reports the thermal stability and thermal degradation of six derivatives of indole by means of TG-DSC (in air) and TG-FTIR (in nitrogen) techniques. The compounds were also characterized by infrared spectroscopy. In addition, IR spectra were calculated and compared with the experimental data. In particular, the potential energy distribution analysis was performed to assign IR signals. The studied compounds are characterized by good thermal stability in oxidizing and inert atmospheres which is important for potential medical application. Thermogravimetric measurements in air atmosphere showed that the decomposition of compounds proceeds in two or three main stages. The thermal degradation of compounds is preceded by the melting process. The pyrolysis of samples is a one-step process. Together with the analyses performed in nitrogen, the FTIR spectra of the evolved gas phase products were recorded. On the FTIR spectra of gaseous products, only the bands of water, carbon dioxide and carbon oxide molecules are present. In the case of indole derivatives containing the p-chlorobenzyl substituent in position 1, the bands of anisole, p-chlorotoluene and chlorobenzene also appear.

Keywords

Indole derivatives Thermal behaviour IR spectra PED analysis Theoretical computations Non-competitive antagonists of GluK1/GluK2 receptors 

Introduction

Indole is a well-known and important privileged structure scaffold found in many natural and synthetic compounds. This core is recognized as one of the foremost biologically significant moieties in nature. The indoles are characterized by excellent binding affinity for various receptors [1, 2]. The indole-based compounds can also exhibit various biological activities such as anti-inflammatory, analgesic, antifungal, antimicrobial, insecticidal, antioxidant, antiviral, antidepressant, antiarrhythmic, antihistaminic and antidiabetic ones. [3, 4, 5, 6]. According to the literature, there are over ten thousand biologically active compounds containing indole core. More than 200 of them were approved as commercially available drugs or are undergoing clinical trials [7, 8], e.g., vinblastine (anticancer), indomethacin (anti-inflammatory), arbidol (antiviral), delavirdine (anti-HIV), zafirlukast (anti-asthmatic), pravadoline (analgesic), bucindolol (β-blocker) and roxindole (schizophrenia) [4, 5, 6]. The indoles are also used as dyes, pigments, plastics, fungicides, vitamin supplements, flavour enhancers, and perfumery [9].

The main aim of this research was the thermal and spectroscopic characterization of six indole derivatives, i.e., 5-methoxy-2-(4-methoxyphenyl)-3-methylindole (1), 1-ethyl-5-methoxy-2-(4-methoxyphenyl)-3-methylindole (2), 1-[(4-chlorophenyl)methyl]-5-methoxy-2-(4-methoxyphenyl)-3-methylindole (3), 1-ethyl-2-(4-methoxyphenyl)-3-methylindole (4), 1-ethyl-2-phenyl-5-methoxy-3-methylindole (5) and 11-ethyl-8-methoxy-6,11-dihydro-5H-benzo[a]carbazole (6) (Scheme 1). The investigated compounds were synthesized in the Fisher indolization reaction from the respective arylhydrazine hydrochloride and appropriate ketone in anhydrous boiling ethanol saturated with HCl followed by alkylation with alkyl halide (with application of sodium hydride). These compounds are a non-competitive antagonists of kainate GluK1/GluK2 (GluK—glutamatergic kainate receptors) receptors with low micromolar activity, and compound 2 is the most promising from the series [10, 11]. Non-competitive antagonists of kainate receptors [10, 11, 12, 13, 14, 15] can be considered promising compounds for the treatment of neurodegenerative diseases [16, 17] as well as epilepsy [18]. In particular, a non-competitive mode of action can result in a better safety profile as reported for non-competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [19]. In the previous studies, we also constructed 3D models of GluK1 and GluK2 receptors and suggested that indole-derived non-competitive antagonists can bind in the receptor transduction domain [11, 14, 15, 20, 21]. In this study, in order to investigate thermal behaviour of indole derivatives the TG-DSC and TG-FTIR methods were applied. The compounds were also characterized by infrared spectroscopy. In addition, infrared (IR) spectra of the studied indole derivatives were calculated and compared with the experimental data. Theoretical vibrational spectra of the compounds were interpreted in terms of potential energy distribution (PED) analysis. Shortly, in order to describe the vibration of a N-atomic molecule using the PED analysis, the construction of the set of 3N-6 local, linearly independent, internal coordinates is required [22]. This set represents stretching, bending and deformation motions of the functional groups or the chosen fragments of the molecule [22]. The availability of such a coordination set instead of the normal modes causes that the potential energy distribution matrix, the PED matrix, ceases to be diagonal, but the energy distribution originating from the motions of particular functional groups is understandable for the interpreter [22]. The rationale of the performed research results from the necessity of thermal stability of the compounds under investigations which is important for their potential biomedical application.
Scheme 1

The studied indoles

Experimental

Synthesis and short description of compounds 1–6

The investigated compounds were synthesized according to the following procedure: the mixture of 0.05 mol of arylhydrazine hydrochloride, 0.05 mol of ketone, 100 cm3 of anhydrous ethanol and 10 cm3 of ethanol saturated with HCl was refluxed for 4 h. The reaction mixture was left overnight at room temperature. The obtained product was filtered and purified by crystallization from ethanol and washed with n-hexane. In the next step, 0.01 mol of the indole derivative was dissolved in 30 cm3 of anhydrous N,N-dimethylformamide (DMF). The reaction mixture was cooled to 0 °C, and 0.8 g of sodium hydride was added (50% oil suspension). After 30 min of mixing, a solution of 0.012 mol of alkyl halide in 20 cm3 of anhydrous DMF was added dropwise. The reaction was allowed to continue at room temperature for 3 h. The mixture was filtered, and 30–40 cm3 of water was added to the filtrate. The obtained precipitate was filtered off and purified by crystallization from ethanol and washed with n-hexane. The detailed physicochemical and spectral properties of the investigated compounds were described in the previous paper [10].

Methods and physical measurements

The thermal behaviour of compounds was studied in air and nitrogen atmospheres. The thermal stability and decomposition in oxidizing atmosphere were determined using the Setaram Setsys 16/18 derivatograph. The TG and DSC curves were recorded in temperature range between 30 and 800 °C. The samples (6.18–7.56 mg) were heated in a ceramic crucible at the heating rate of 10 °C min−1 in flowing air (v = 0.75 dm3 h−1). The temperature and heat flow of the instrument were calibrated by the melting point and enthalpy of indium standard. The studies in inert atmosphere were carried out using the TGA Q5000 analyser (TA Instruments, New Castle, Delaware, USA). The compounds (15.14–29.69 mg) were heated in an open platinum crucible from ambient temperature (~ 23–25 °C) to 700 °C in flowing nitrogen (25 cm3 min−1). Simultaneously with the TG analysis in nitrogen, the infrared spectra of gaseous products were recorded using the Nicolet 6700 FTIR spectrophotometer (Thermo Scientific) in the spectral range of 600–4000 cm−1 with a resolution of 4 cm−1 and 6 scans per spectrum. ATR-FTIR spectra were collected using the Thermo Scientific Nicolet 6700 FTIR spectrometer equipped with a Smart iTR diamond ATR accessory in the range from 4000 to 500 cm−1. The samples were placed directly on the diamond crystal of ATR accessory, and the spectra were obtained from 16 scans taken at a resolution of 4 cm−1 and normalized.

Computational studies

Energy and geometry of compounds 16 were optimized with the B3LYP DFT method (DFT—density functional theory) and the 6-311G++(2df, 2pd) basis set of Gaussian09 software [23]. Gaussian09 was also used to calculate IR spectra. The computed IR spectra were corrected using the scaling factor of 0.962 as recommended for this level of theory [24]. Moreover, the computed vibrational frequencies have been unambiguously assigned by means of the potential energy distribution (PED) analysis of all the fundamental vibration modes by using VEDA 4 program [25, 26] as described previously [27, 28, 29, 30].

Results and discussion

Thermal behaviour of 1–6

The TG-DSC curves providing information about the thermal properties of 1–6 are shown in Fig. 1. As it can be seen in the TG curves, the compounds are characterized by good thermal stability, which is a very important parameter for their potential application as drugs. The first changes are recorded on the DSC curves as endothermic peaks at temperature 100–140 °C. These peaks are not accompanied by a mass loss and can be attributed to the melting process. They are roughly similar to the values reported earlier and determined using a Boetius apparatus [10]. The melting point onset temperature (Tonset), peak temperature (Tpeak) corresponding to each peak, and enthalpy of fusion taken from the DSC curves for all compounds are listed in Table 1. The melting peaks are sharp which indicates that the compounds were probably synthesised as pure, crystalline substances [31, 32, 33]. Generally, the substitution of the pyrrole hydrogen atom in position 1 leads to a decreased melting point. The exception is compound 4 where the melting point is comparable to that of compound 1. This can be a result of a lack of a substituent in the 5-position of the indole core.
Fig. 1

TG, DTG and DSC curves recorded for 1–6 in air atmosphere

Table 1

Results of the melting process

Sample

Tonset/°C

Tpeak/°C

Hm/J g−1

Hm/J mol−1

1

137

141

82.21

21.98

2

115

118

71.92

21.23

3

124

127

48.94

19.14

4

140

143

82.64

21.91

5

100

104

71.02

18.83

6

117

122

69.51

19.26

The decompositions of the compounds in air are two- or three-step processes that are noted on the TG curves (see Fig. 1). For all compounds, the major mass loss (56.98–95.93%) occurs in the first stage which starts at 183–251 °C (Table 2). Taking into account the initial temperature of the decomposition processes, the following relative thermal stability order: 5 = 4 < 2 < 6 < 1 < 3 can be established. As can be observed, the substitution of hydrogen attached to nitrogen atom with the ethyl group decreases the combustion temperature of compounds while the p-chlorobenzyl substituent stabilizes the molecule and increases the decomposition temperature of 3 in air compared to 1. In the case of compounds 1 and 3, probably during the first stage the substituents of the indole core are broken off and combusted. The theoretical values of the indole residue (C8H7N) are 43.82 and 29.95% while the experimental ones are equal to 43.03 and 29.60% for compounds 1 and 3, respectively. The formed products are unstable and immediately undergo complete destruction and combustion accompanied by a significant exothermic effect. The samples are fully decomposed at 612–652 °C. It is worth mentioning that for compound 1 on the DTG curve two maxima are visible during this stage, but this is not clearly indicated on the TG curve. The remaining compounds are almost completely decomposed during this step (more than 85% of overall mass is lost), and the formed residues are combusted during one (5 and 6) or two (2 and 4) steps. Compounds 4, 5 and 6 are fully combusted at a temperature of 570–603 °C. In the case of 2, it was found that under the measuring conditions a small amount of unburnt organic matrix remains (1.49%).
Table 2

Thermal analysis data for compounds 1–6

Complex

Atm

Temperature range/°C

Tpeak/°C

Mass loss/%

1

Air

222–398

348

56.98

398–652

421; 548

43.02

N2

207–410

350; 373

98.51

2

Air

205–398

339

89.97

398–537

503; 515

5.81

587–787

600

2.73

N2

193–360

331; 346

98.46

3

Air

251–435

383

70.40

435–612

542; 598

29.58

N2

234–444

379

99.00

4

Air

182–381

309

88.73

381–540

503

10.40

540–570

559

0.84

N2

167–334

256; 344

99.52

5

Air

182–384

315

95.93

484–603

544

4.07

N2

164–310

299

99.94

6

Air

217–390

363

95.09

463–575

543

4.90

N2

200–370

360

99.93

Atm atmosphere of analysis, Tpeak DTG peak temperature (maximum change of mass)

Thermal behaviour of 1–6 was also studied in nitrogen atmosphere (see Fig. 2). The order of thermal stabilities in inert and oxidizing atmospheres is similar; taking into account the initial temperature of the decomposition processes under nitrogen stream, the following relative thermal stability order: 5 ≈ 4 < 2 < 6 < 1 < 3 can be established. In contrast to the thermal decomposition in air, the pyrolysis processes start at a lower temperature (about 12–22 °C) than the combustion ones. Thermal decompositions of compounds in nitrogen proceed in one major mass loss step and similar to the combustion, the compounds are almost completely burnt (for compound 2 the residue after the pyrolysis is 1.54%). The total pyrolysis of the compounds can be associated with the presence of methoxy groups as observed for other compounds containing such substituent [30, 31]. Simultaneously with the TG analysis in nitrogen, the FTIR spectra of gaseous products were recorded. The FTIR spectra of gaseous products evolved during the decomposition of compounds 1 and 3 are given in Fig. 3. In the spectra of gaseous products, except for the compound 3, only the bands characteristic of water, carbon monoxide and carbon dioxide were present. The peaks at 2240–2400 cm−1 are assigned to stretching vibration ν(C–O) of carbon dioxide molecule. In addition, a band at 669 cm−1 is observed due to the deformation vibration of CO2. The double peaks in the range 2050–2275 cm−1 correspond to the vibrations of CO molecule. The characteristic bands of water molecules are observed in the range 3450–4000 and 1300–1950 cm−1 for stretching and deformation vibrations, respectively [31, 32, 34]. Probably other compounds such as indole can be condensed in the transfer line and do not reach the detector. In the case of compound 3, at a temperature between 340 and 420 °C of the pyrolysis process on the FTIR spectra of evolved gases, several bands in the range 2700–3100 and 750–1800 cm−1 were recorded. These peaks are probably due to the presence of anisole, p-chlorotoluene and chlorobenzene (see Fig. 4).
Fig. 2

TG curves of 1–6 in nitrogen

Fig. 3

3D FTIR spectra of pyrolysis products during the thermal degradation of 1 and 3

Fig. 4

FTIR spectrum of volatile products of thermal decomposition of 3 recorded at 360 °C and the spectra of anisole, p-chlorotoluene and chlorobenzene

Infrared spectroscopy

The FTIR spectra of 1–6 are given in Figs. S1–S6. The observed and calculated frequencies in the infrared spectra of studied compounds together with their PED assignment of signals are presented in Tables 3 and S1–S5 (Supplementary material). The scaled computed IR spectra are in accordance with the experimental values. The strong, sharp peak at 3379 cm−1 in the FTIR spectrum of 1 is characteristic of ν(N–H) vibrations of the pyrrole ring. This is consistent with the literature data; the indoles unsubstituted in the l-position (N) give a sharp absorption peak in the range 3500–3300 cm−1 [35, 36, 37, 38, 39, 40]. This band was not recorded in the spectra of other studied compounds due to the substitution of hydrogen atom in position 1 by ethyl or 4-chlorobenzyl group. The peaks at 3100–2990 cm−1 can be assigned to the C–H stretching vibrations of the aromatic bonds. The symmetric and asymmetric C–H stretching bands of the methyl/ethyl groups are observed in 2990–2800 cm−1. The other important peaks are observed at the range 1620–1400 cm−1, and they are mainly due to the stretching vibrations ν(CC) of indole and benzene rings. The varying intensity bands observed in the FTIR spectra at 1373–1342 and 1287–1283 cm−1 can be assigned to the C–N stretching modes of pyrrolic ring. These assignments are in agreement with the literature [35, 39, 41] and correlate with the theoretical calculations. The remaining bands characteristic of 16 with their detailed description is given in Tables 3 and S1–S5.
Table 3

Experimental and computed IR frequencies and PED assignment of signals for compound 2 (the most promising compound within the studied series)

Experimental

Computed

Raw

Scaled

PED

 

3241

3117

νCH (99)

 

3215

3092

νCH (94)

 

3211

3089

νCH (92)

 

3197

3075

νCH (99)

 

3189

3068

νCH (99)

 

3182

3061

νCH (92)

 

3180

3059

νCH (94)

 

3177

3056

νCH (99)

 

3135

3015

νCH (92)

 

3124

3005

νCH (99)

2996 (m)

3123

3004

νCH (92)

 

3103

2985

νCH (99)

 

3100

2982

νCH (83)

2951 (m)

3066

2949

νCH (100)

 

3055

2939

νCH (88)

2830 (w)

3051

2935

νCH (99)

1898 (vw)

3037

2922

νCH (99)

1868 (vw)

3009

2895

νCH (92)

1835 (vw)

2999

2885

νCH (93)

1612 (m)

1658

1595

νCC (60)

1588 (w)

1650

1587

νCC (31)

1576 (w)

1610

1549

νCC (19)

1562 (w)

1604

1543

νCC (35)

1506 (m)

1580

1520

νCC (45)

1481 (s)

1538

1480

δHCC (12)

 

1513

1456

δHCH (53)

 

1510

1454

δHCH (45)

1448 (s)

1507

1448

δHCH (61), ΓHCOC (10)

 

1502

1445

δHCH (12)

 

1497

1440

δHCH (70)

 

1496

1439

δHCH (75), ΓHCOC (16)

 

1495

1438

δHCH (78), ΓHCOC (14)

1431 (m)

1493

1436

δHCH (72), ΓHCCN (15)

 

1481

1425

νCC (33), δHCC (10)

 

1479

1423

δHCC (76)

1418 (m)

1473

1417

δHCC (10), δHCH (48)

1386 (m)

1446

1391

νCC (32), δHCC (22)

1377 (w)

1421

1367

δHCC (17)

1366 (m)

1412

1358

δHCH (82)

1351 (m)

1400

1347

δHCH (15), ΓHCNC (30)

 

1374

1322

νNC (26)

1307 (m)

1356

1304

νCC (33), δHCC (12)

1286 (s)

1337

1286

δHCC (72)

 

1325

1275

δCCC (10)

 

1318

1268

νCC (17), δCCC (11)

1246 (s)

1303

1253

δHCC (22), ΓHCNC (10)

1231 (vs)

1276

1228

νCC (28), νOC (32)

 

1261

1213

νCC (11), δHCC (10)

1202 (s)

1251

1203

νOC (20), δHCC (28)

1182 (m)

1213

1167

νOC (26)

1171 (s)

1205

1159

δHCH (17), ΓHCOC (58)

 

1201

1155

δHCH (10),), ΓHCOC (32)

1142 (m)

1198

1153

δHCC (51)

 

1174

1130

νCC (15), δHCC (36)

 

1173

1128

δHCH (29), ΓHCOC (67)

1108 (m)

1166

1122

δHCC (26)

 

1134

1091

δHCC (25)

1072 (s)

1096

1054

νCC (19), ΓHCCN (39)

1035 (vs)

1067

1027

νOC (64)

 

1064

1024

νOC (53), δHCC (13)

1003 (w)

1025

986

δCCC (43)

963 (vw)

993

955

ΓHCCC (70), ΓCCCC (13)

948 (w)

969

932

ΓHCCC (71)

 

955

919

νCC (44), δCCC (15)

 

950

914

νCC (45), δCCN (12)

895 (m)

927

892

ΓHCCC (85), ΓCCCC (11)

848 (m)

887

853

ΓHCCC (71)

833 (s)

868

835

ΓHCCC (65)

818 (s)

862

829

ΓHCCC (54), ΓOCCC (17)

794 (vs)

832

800

ΓHCCC (100)

 

810

779

ΓHCCC (48)

775 (m)

807

776

νCC (24), νOC (14), ΓHCCC (11)

 

797

766

ΓHCCC (84)

 

785

755

νNC (11), ΓHCCN (10)

 

780

750

νCC (13), δCCC (12)

738 (w)

761

732

ΓCCCC (69)

702 (m)

752

723

ΓCCCC (34)

 

699

672

ΓCNCC (34)

658 (w)

675

649

νNC (11), ΓCNCC (12)

630 (m)

654

629

δCCC (11)

617 (w)

642

617

δCCC (31), ΓCNCC (10)

606 (m)

632

608

ΓHCCC (14), ΓCCCC (34), ΓOCCC (20)

583 (w)

597

574

δCCC (12), δOCC (11)

564 (w)

575

553

ΓOCCC (10)

526 (vw)

551

530

δCCC (14), δCOC (21)

 

519

499

ΓOCCC (20)

 

488

469

δOCC (21), δCOC (18)

 

470

452

δCCN (21)

 

447

430

ΓHCCC (11), ΓCCNC (14), ΓCCCC (36), ΓOCCC (13)

 

433

417

ΓHCCC (32), ΓCCCC (58)

 

404

389

δCOC (10)

 

366

352

δCCN (23), ΓCNCC (10)

 

359

345

δCOC (10), ΓOCCC (11), ΓCCCC (10)

 

337

324

δCCC (12), ΓCCCN (15), ΓOCCC (16)

 

311

299

δCNC (26), ΓHCCN (10)

 

265

255

δOCC (20), δCOC (13), ΓCCNC (10)

 

250

241

ΓHCOC (64)

 

228

219

δOCC (14), ΓHCOC (10), ΓHCCN (13)

 

213

205

νCC (19), δCCC (11)

 

195

188

δCNC (19), ΓHCCN (11)

 

190

183

δOCC (13), ΓCCNC (14)

 

147

141

δCCC (10), ΓCOCC (10)

 

95

91

ΓCOCC (55)

 

81

78

ΓCOCC (25), ΓCCCN (35)

 

67

64

ΓCOCC (27), ΓCCNC (11), ΓCCCN (22)

 

60

58

ΓNCCC (44), ΓCCCC (10)

 

55

53

ΓCOCC (13), ΓCCNC (39)

 

37

36

δNCC (14), δCCC (16), ΓCNCC (18), ΓNCCC (22)

 

32

31

ΓCNCC (18), ΓNCCC (13), ΓCCCC (23)

s strong, m medium, w weak, v very, br broad, sh shoulder, ν stretching, δ bending in plane, Γ torsional vibrations

Conclusions

Thermal analysis of six indoles derivatives was performed. The investigated compounds are stable at room temperature which is important for their medical application. The DSC melting peaks of compounds are sharp indicating that they are probably crystalline, pure substances. In air atmosphere, the decomposition process of 1–6 occurs in two or three stages where the main mass loss occurs during the first one. On the basis of the TG-DSC analysis, it can be concluded that the substitution of hydrogen atom by the ethyl group on the pyrrole ring in 1 position leads to decrease in the thermal stability of the studied indoles. Changing the substituent to the p-chlorobenzyl group causes the compound stabilization and, consequently, an increase in the decomposition temperature of 3 compared to that of the other compounds. The performed TG-FTIR analysis showed there are no residual solvents in the structure of studied compounds.

Notes

Acknowledgements

The paper was developed using the equipment purchased within the projects “The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases” and “Enhancement of the Research and Development Potential of the UMCS Faculty of Chemistry and the Faculty of Biology and Earth Sciences” within the Operational Program Development of Eastern Poland 2007–2013, Priority Axis I Modern Economy, operations I.3 Innovation promotion. Calculations with Gaussian 09 were performed under a computational grant by Interdisciplinary Center for Mathematical and Computational Modeling (ICM), Warsaw, Poland, grant number G30-18 and under resources and licenses by CSC, Finland.

Supplementary material

10973_2018_7146_MOESM1_ESM.docx (290 kb)
Supplementary material 1 (DOCX 290 kb)

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© Akadémiai Kiadó, co-published with Springer 2018

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Department of General and Coordination ChemistryMaria Curie-Skłodowska UniversityLublinPoland
  2. 2.Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical AnalyticsMedical UniversityLublinPoland
  3. 3.Department of Pharmaceutical Chemistry, School of PharmacyUniversity of Eastern FinlandKuopioFinland
  4. 4.Department of Organic Chemistry, Faculty of Pharmacy with Division of Medical AnalyticsMedical UniversityLublinPoland
  5. 5.Department of Drug Design and Pharmacology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagen ØDenmark

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