- Research Article
- Open Access
Design, synthesis and anticancer activity of some novel thioureido-benzenesulfonamides incorporated biologically active moieties
© Ghorab et al. 2016
- Received: 15 September 2015
- Accepted: 20 March 2016
- Published: 7 April 2016
Many thiourea derivatives have exhibited biological activities including anticancer activity through several mechanisms. On the other hand, benzenesulfonamide derivatives have proven to be good anticancer agents. Hybrids of both moieties could be further developed to explore their biological activity as anticancer.
Novel series of thioureidobenzenesulfonamides incorporating miscellaneous biologically active moieties 3–17 were designed and synthesized utilizing 4-isothiocyanatobenzenesulfonamide 2 as strategic starting material. The structures of the newly synthesized compounds were established on the basis of elemental analyses, IR, 1H-NMR, 13C-NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against various cancer cell lines. Most of the synthesized compounds showed good activity, especially compounds 3, 6, 8, 9, 10, 15 and 16 which exhibited good activity higher than or comparable to the reference drugs, DCF and Doxorubicin, except breast cancer line. As a trial to suggest the mechanism of action of the active compounds, molecular docking on the active site of mitogen kinase enzyme (MK-2) was performed and good results were obtained especially for compound 3.
- Anticancer activities
Various types of cancer are now considered as the second cause of death after cardiovascular disorders . The inability of the present anticancer chemotherapeutic agents to discriminate between normal cells and cancer cells comprises the biggest challenge for successful cancer treatment . Serious side effects of anticancer chemotherapeutic agents limit their usage and in many cases surgery or radiotherapy replace them . The continuous seek for safer and more effective anticancer agents is still a major goal for medicinal chemists.
Thiourea is a versatile synthetic block for the synthesis of a wide variety of new organic compounds with biological activity including antimicrobial, antifungal, antidiabetic, antimalarial, anti HIV and CNS active drugs [4–11]. Many of aryl thiourea derivatives have applications in medicine, industry and agriculture [12–15]. Thiourea was incorporated in many tyrosine kinase inhibitors because of its ability to form powerful hydrogen bonds in the ATP binding pocket of the enzymes . The thiourea derivative YH345 A has shown strong protein farnesyl transferase inhibition activity . Also several heterocyclic thiourea derivatives have shown strong DNA topoisomerase inhibitory activity .
On the other hand, sulfonamide derivatives posses a wide range of biological activity including antibacterial, anticonvulsant, anti-inflammatory and anticancer activity [19–22]. The mechanism of anticancer activity may involve a wide range of different mechanisms, such as cell cycle arrest in the G1 phase  and inhibition of carbonic anhydrase , histone deacetylases (HDACs) , methionine amino peptidases (MetAPs) , matrix metalloproteinase (MMPs) , nicotinamide adenine dinucleotide (NADH) oxidase , cyclin-dependentkinase (CDK) , binding to β-Tubulin, and disruption of microtubule assembly . Indisulam (E7070) B is an example of an anticancer agent that contains sulfonamide moiety .
Based on the previous facts and as a continuation of our previous work in the seek of novel anticancer agents [32–38], we herein report the synthesis and biological evaluation of new sulfonamide thiourea derivatives 3–17 presented by general structure C as hybrid molecules of benzensulfonamide and thiourea moieties as anticancer agents. Molecular docking of the active newly synthesized compounds was performed on the active site of mitogen activated kinase enzyme (MK-2) in a trial to suggest a mechanism of action for their cytotoxic activity.
In-vitro anticancer evaluation
In vitro anticancer screening of the newly synthesized compounds against four cancer cell lines
A549-Raw (lung cancer cells)
Lovo (colorectal cancer cells)
MDA-MB231 (breast cancer cells)
IC50 (µg ml−1)
Regarding the cytotoxic activity on lung cancer cell line (A549), compounds 2, 3, 6, 8, 9, 15 and 16 were active with IC50 ranging between 29.12 and 114.28 µg ml−1. The most active compound was the n-heptane thiourea derivative 3. In case of cervical cancer cell line (Hela), compounds 3, 6, 8, 9, 10 and 15 were active with IC50 ranging between 35.63 and 93.42 µg ml−1. The most active compounds was again the n-hepatne thiourea derivative 3.
For the colorectal cell line (Lovo), compounds 2, 3, 8, 9 and 10 were active with IC50 ranging between 39.83 and 148.33 µg ml−1 and once again the most active compound was n-hepatne thiourea derivative 3. Finally, the activity on breast cancer cell line (MDA-MB231) was exhibited by compounds 3, 6, 8, 9, 10, 15 and 16 with IC50 ranging between 26.28 and 69.04 µg ml−1 with less activity than Doxorubicin. The same compound (n-hepatne thiourea derivative 3) was the most active compound.
Structure activity relationship
In a closer look to the biological results we can see that: the thiourea derivatives 3, 6, 8, 9, 10, 15 and 16 were the active compounds on most of the cell lines while the rest of the compounds were inactive. It was obvious that incorporating an n-heptane aliphatic substitution as in compound 3 gave the most activity on all cell line. This activity was reduced upon replacing this substituent with another tricyclic aliphatic one as in compound 9. In case of aromatic substitution the activity was retained but markedly decreased as in the 2-methyl-6-nitrophenyl thiourea derivative 6, the 3-benzo[d][1,3]dioxol-5-ylmethyl thiourea derivative 8, the 3-(5,6-dimethylbenzo[d]thiazol-2-yl)thiourea derivative 10, the tetrahydronaphthalen derivative 15 and the quinoline derivative 16.
Comparing compound 3 which was the most active compound among the newly synthesized compounds with the reference drug Doxorubicin we can see that: compound 3 was more active that Doxorubicin as cytotoxic agents on lung cancer cell line, Hella cells and colorectal cancer cells with IC50 value of 29.12, 35.63 and 39.83 µg ml−1, respectively. However, in case of breast cancer cell line compound 3 was less active than Doxorubicin with IC50 value of 26.28 µg ml−1.
Binding scores and amino acid interactions of the docked compounds on the active site of mitogen activated kinase (MK-2)
S Kcal mol−1
Amino acid interactions
Type of interaction
H bond length Å
Melting points (uncorrected) were and determined in open capillary on a Gallen Kamp melting point apparatus (Sanyo Gallen Kamp, UK). Precoated silica gel plates (Kieselgel 0.25 mm, 60 F254, Merck, Germany) were used for thin layer chromatography. A developing solvent system of chloroform/methanol (8:2) was used and the spots were detected by ultraviolet light. IR spectra (KBr disc) were recorded using an FT-IR spectrophotometer (Perkin Elmer, USA). 1H-NMR spectra were scanned on an NMR spectrophotometer (Bruker AXS Inc., Switzerland), operating at 500 MHz for 1H- and 125.76 MHz for 13C. Chemical shifts are expressed in δ-values (ppm) relative to TMS as an internal standard, using DMSO-d 6 as a solvent. Elemental analyses were done on a model 2400 CHNSO analyser (Perkin Elmer, USA). All the values were within ±0.4 % of the theoretical values. All reagents used were of AR grads.
Synthesis of thioureidobenzenesulfonamide derivatives (3–17)
A mixture of 4-isothiocyanatobenzenesulfonamide 2 (2.14 g, 0.01 mol) and amines (0.012 mol) in dry dimethylformamide (15 ml) containing three drops of triethylamine was refluxed for 24 h, then left to cool. The solid product formed upon pouring onto ice/water was collected by filtration and recrystallized from ethanol–dimethylformamide to give 3–17, respectively.
Yield, 92 %; m.p. 124.7 °C. IR (KBr, cm−1): 3218, 3143 (NH, NH2), 3087 (CH arom.), 2926, 2853 (CH aliph.), 1376, 1150 (SO2), 1254 (C=S). 1H-NMR (DMSO-d2): 0.8 [t, 2H, CH3], 1.2–1.4 [m, 10H, 5CH2], 3.3 [m, 2H, NHCH2], 7.3–7.9 [m, 6H, Ar–H + SO2NH2], 9.3, 10.4 [2 s, 2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 14.2, 22.4, 26.2, 28.6, 29.0, 31.5, 43.9, 119.4 (2), 127.4 (2), 134.7, 143.0, 177.4.MS m/z (%): 329 (M+) (14.41), 155 (100). Anal.Calcd. For C14H23N3O2S2 (329): C, 51.03; H, 7.04; N, 12.75. Found: C, 51.29; H, 6.79; N, 12.45.
Yield, 88 %; m.p.192.9 °C. IR (KBr, cm−1): 3363 (OH), 3280, 3143 (NH, NH2), 3090 (CH arom.), 1393, 1182 (SO2), 1274 (C=S).1H-NMR (DMSO-d2): 6.7–7.9 [m, 10H, Ar–H + SO2NH2], 10.2, 11.4, [2 s, 2H, 2NH, exchangeable with D2O], 13.1 [s, 1H, OH, exchangeable with D2O], 13C-NMR (DMSO-d6): 112.9 (2), 122.8 (2), 126.7 (2), 127.1 (2), 127.9, 139.8, 140.3, 157.6, 180.1. MS m/z (%): 323 (M+) (9.03), 91 (100). Anal.Calcd. For C13H13N3O3S2 (323): C, 48.28; H, 4.05; N, 12.99. Found: C, 48.55; H, 4.31; N, 13.29.
Yield, 77 %; m.p. 160.3 °C. IR (KBr, cm−1): 3317, 3254, 3173 (NH, NH2), 3100 (CH arom.), 2963, 2938, 2829 (CH aliph.), 1363, 1156 (SO2), 1259 (C=S). 1H-NMR (DMSO-d2): 3.9 [s, 6H, 2OCH3], 6.3–7.8 [m, 8H, Ar–H + SO2NH2], 9.8 [s, 2H, 2NH, exchangeable with D2O].13C-NMR (DMSO-d6): 56.1 (2), 96.8, 102.0 (2), 123.2 (2), 126.6 (2), 141.4 (2), 143.1, 160.6 (2), 179.3. MS m/z (%): 367 (M+) (17.8), 76 (100). Anal.Calcd. For C15H17N3O4S2 (367): C, 49.03; H, 4. 66; N, 11.44. Found: C, 48.74; H, 4.29; N, 11.17.
Yield, 81 %; m.p. 226.0 °C. IR (KBr, cm−1): 3353, 3243, 3171 (NH, NH2), 3009 (CH arom.), 1340, 1161 (SO2), 1290 (C=S).1H-NMR (DMSO-d2): 2.2 [s, 3H, CH3], 6.5–7.8 [m, 9H, Ar–H + SO2NH2], 10.3 [s, 2H, 2NH exchangeable with D2O]. 13C-NMR (DMSO-d6): 18.3, 123.3, 123.9 (2), 126.7, 126.8, 127.8 (2), 131.3, 136.5 (2), 139.8, 142.8, 180.1. MS m/z (%): 366 (M+) (15.8), 133 (100). Anal.Calcd. For C14H14N4O4S2 (366): C, 45.89; H, 3.85; N, 15.29. Found: C, 45.57; H, 3.54; N, 15.61.
Yield, 86 %; m.p. 136.6 °C. IR (KBr, cm−1): 3325, 3241 (NH, NH2), 3100 (CH arom.), 1331, 1156 (SO2), 1241 (C=S). 1 H-NMR (DMSO-d2): 6.0 [s, 2H, CH2], 6.7–7.9 [m, 9H, Ar–H + SO2NH2], 9.5 [s, 2H, 2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 101.2, 107.1, 109.1, 117.8, 123.1 (2), 126.5 (2), 133.4, 134.6, 142.4, 143.2, 147.3, 180.6. MS m/z (%): 351 (M+) (34.64), 93 (100). Anal.Calcd. For C14H13N3O4S2 (351): C, 47.85; H, 3.73; N, 11.96. Found: C, 47.49; H, 3.43; N, 11.62.
Yield, 68 %; m.p. 140.8 °C. IR (KBr, cm−1): 3384, 3348, 3206 (NH, NH2), 3003 (CH arom.), 1377, 1185 (SO2), 1294 (C=S).1H-NMR (DMSO-d2): 4.3 [s, 2H, CH2], 6.0 [s, 2H, OCH2O], 6.7–7.7 [m, 9H, Ar–H + SO2NH2], 7.8 [s, 2H, +2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 63.8, 101.2, 106.4, 108.2, 120.8, 121.4 (2), 131.2 (2), 133.5, 134.0, 146.4, 147.6, 148.3, 161.1. MS m/z (%): 365 (M+) (18.42), 135 (100). Anal.Calcd. For C15H15N3O4S2 (365): C, 49.30; H, 4.14; N, 11.50. Found: C, 49.05; H, 4.46; N, 11.19.
Yield, 80 %; m.p. 174.5 °C. IR (KBr, cm−1): 3434, 3354 (NH, NH2), 3100 (CH arom.), 2997, 2906, 2851 (CH aliph.), 1396, 1186 (SO2), 1282 (C=S).1H-NMR (DMSO-d2): 1.6–1.9 [m, 12H, 6CH2], 2.2–2.4 [m, 3H, 3 CH], 6.9–7.9 [m, 6H, Ar–H + SO2NH2], 11.4 [s, 2H, 2NH, exchangeable with D2O].13C-NMR (DMSO-d6): 28.8 (3), 35.3 (3), 40.5 (3), 44.9, 126.4 (2), 129.1 (2), 131.8, 142.7, 179.9. MS m/z (%): 366 (M+) (9.32), 154 (100). Anal.Calcd. For C17H23N3O2S2 (366): C, 55.86; H, 6.34; N, 11.50. Found: C, 55.50; H, 6.68; N, 11.18.
Yield, 84 %; m.p. 252.1 °C. IR (KBr, cm−1): 3359, 3257, 3143 (NH, NH2), 3031 (CH arom.), 2954, 2851 (CH aliph.), 1594 (C=N), 1381, 1186 (SO2), 1296 (C=S).1H-NMR (DMSO-d2): 2.2 [s, 6H, 2CH3], 7.2–8.0 [m, 8H, Ar–H + SO2NH2], 10.2, 13.0 [2 s, 2H, 2NH, exchangeable with D2O].13C-NMR (DMSO-d6): 19.9, 20.4, 118.5, 121.5, 123.3 (2), 126.6, 127.1, 127.8 (2), 133.0, 136.2, 139.8, 143.1, 151.9, 180.0 (2).MS m/z (%): 393 (M+) (16.9), 162 (100). Anal.Calcd. For C16H16N4O2S3 (393): C, 48.96; H, 4.11; N, 14.27. Found: C, 48.66; H, 3.85; N, 14.54.
Yield, 78 %;m.p. 153.6 °C. IR (KBr, cm−1): 3410, 3334, 3195 (NH, NH2), 3069 (CH arom.), 2974, 2925, 2843 (CH aliph.), 1595 (C=N), 1393, 1123 (SO2), 1256 (C=S). 1H-NMR (DMSO-d2): 1.3 [t, 3H, CH3], 4.0 [q, 2H, CH2], 6.9–8.0 [m, 9H, Ar–H + SO2NH2], 10.3, 11.2 [2 s, 2H, 2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 15.0, 66.8, 106.0, 115.3, 118.2, 120.4 (2), 127.7 (2), 132.7, 138.2, 140.9, 142.1, 157.7, 177.1, 180.1. MS m/z (%): 409 (M+) (1.85), 156 (100). Anal.Calcd. For C16H16N4O3S3 (409): C, 47.04; H, 3.95;N, 13.71. Found: C, 47.34; H, 3.67; N, 13.39.
Yield, 65 %; m.p. 205.8 °C. IR (KBr, cm−1): 3384, 3261, 3165 (NH, NH2), 3097 (CH arom.), 1595 (C=N), 1331, 1185 (SO2), 1252 (C=S).1H-NMR (DMSO-d2): 7.1–8.9 [m, 9H, Ar–H + SO2NH2], 10.5, 12.0 [2 s, 2H, 2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 119.6 (2), 123.1 (3), 126.6 (3), 139.8 (2), 142.8, 161.2179.9 (2). MS m/z (%): 409 (M+) (13.43), 178 (100). Anal.Calcd. For C14H11N5O4S3 (409): C, 41.07; H, 2.71; N, 17.10. Found: C, 41.31; H, 2.40; N, 17.43.
Yield, 72 %; m.p. 247.0 °C. IR (KBr, cm−1): 3326, 3175 (NH, NH2), 3088 (CH arom.), 1572 (C=N), 1356, 1192 (SO2), 1211 (C=S). 1H-NMR (DMSO-d2): 6.8–8.3 [m, 8H, Ar–H + SO2NH2], 12.4 [s, 2H, 2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 105.5, 124.8 (2), 128.9 (2), 134.6, 140.8, 158.5, 159.3 (2), 178.6.MS m/z (%): 388 (M+) (11.81), 157 (100). Anal.Calcd. For C11H10BrN5O2S2 (388): C, 34.03; H, 2.60; N, 18.04. Found: C, 34.28; H, 2.27; N, 18.37.
Yield, 80 %; m.p. 185.3 °C. IR (KBr, cm−1): 3378, 3240, 3155 (NH, NH2), 3100 (CH arom.), 1601 (C=N), 1346, 1199 (SO2), 1270 (C=S).1H-NMR (DMSO-d2): 7.2–8.7 [m, 9H, Ar–H + SO2NH2], 11.3, 13.0 [2 s, 2H, 2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 123.1 (2), 126.7 (2), 137.1, 138.4, 138.5, 139.9, 140.3, 149.7, 179.0. MS m/z (%): 309 (M+) (12.83), 79 (100). Anal.Calcd. For C11H11N5O2S2 (309): C, 42.71; H, 3.58; N, 22.64. Found: C, 42.38; H, 3.84; N, 22.29.
Yield, 76 %; m.p. 171.8 °C. IR (KBr, cm−1): 3413, 3354, 3152 (NH, NH2), 3083 (CH arom.), 2982, 2935, 2831 (CH aliph.), 1351, 1159 (SO2), 1264 (C=S).1H-NMR (DMSO-d2): 1.8–2.8 [m, 8H, 4CH2, cyclo], 7.0–8.0 [m, 9H, Ar–H + SO2NH2], 9.0[s, 2H, 2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 22.7 (2), 24.8, 29.6, 117.4, 120.8 (2), 124.0, 125.7, 127.4 (2), 134.5, 137.1, 137.4, 137.6, 146.4, 181.5.MS m/z (%): 361 (M+) (26.34), 177 (100). Anal.Calcd. For C17H19N3O2S2 (361): C, 56.48; H, 5.30; N, 11.62. Found: C, 56.12; H, 5.03; N, 11.36.
Yield, 66 %; m.p. 214.6 °C. IR (KBr, cm−1): 3373, 3246, 3164 (NH, NH2), 3077 (CH arom.), 1595 (C=N), 1365, 1150 (SO2), 1293 (C=S). 1H-NMR (DMSO-d2): 6.8–8.5 [m, 12H, Ar–H + SO2NH2], 10.8 [s, 2H, 2NH, exchangeable with D2O].13C-NMR (DMSO-d6): 127.3, 127.7, 128.6, 129.1 (2), 130.0 (2), 132.0, 134.3 (2), 137.9 (2), 142.8, 178.6. MS m/z (%): 358 (M+) (17.53), 156 (100). Anal.Calcd. For C16H14N4O2S2 (358): C, 53.61; H, 3.94; N, 15.63. Found: C, 53.36; H, 3.62; N, 15.36.
Yield, 71 %; m.p. 192.3 °C. IR (KBr, cm−1): 3363, 3218, 3154 (NH, NH2), 3034 (CH arom.), 2943, 2836 (CH aliph.), 1590 (C=N), 1324, 1154 (SO2), 1241 (C=S). 1H-NMR (DMSO-d2): 2.6 [s, 3H, CH3], 6.6–8.8 [m, 11H, Ar–H + SO2NH2], 10.1, 13.8[2 s, 2H, 2NH, exchangeable with D2O]. 13C-NMR (DMSO-d6): 19.9, 102.0, 108.3, 121.1 (2), 122.9, 124.0, 126.1, 127.8, 128.0 (2), 137.3, 139.5, 143.1, 151.7, 158.0, 179.3. MS m/z (%): 372 (M+) (21.22), 141 (100). Anal.Calcd. For C17H16N4O2S2 (372): C, 54.82; H, 4.33; N, 15.04. Found: C, 54.51; H, 4.09; N, 15.31.
In vitro anticancer evaluation
Human cancer cell lines HeLa (cervical), A549 (lungs) and Lovo (colorectal) were grown in DMEM + GlutaMax (Invitrogen), and MDA MB321 (breast) were grown in DMEM-F12 + GlutaMax) medium (invitrogen), supplemented with 10 % heat-inactivated bovine serum (Gibco) and 1× penicillin–streptomycin (Gibco) at 37 °C in a humified chamber with 5 % CO2 supply.
The in vitro anticancer screening was done at pharmacognosy Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Cells were seeded (105 cells/well) in 96-well flat-bottom plates (Becton–Dickinson Labware) a day before treatment and grown overnight. Compounds were dissolved in dimethyl sulfoxide (DMSO; Sigma) and finally prepared as 1.0 mg ml−1 stocks, respectively in the culture media. The final concentration of DMSO never exceeded 0.1 % in the treatment doses. Four different doses of compounds (50, 25, 12.5 and 6.25 µg ml−1) were further prepared by diluting the stocks in culture media, and cells were treated (in triplicate/dose). 2′7′ dichlorofluorescein (DCF) was included as standard reference drug (positive control) and untreated culture was considered as negative control. The treated cultures were further incubated for 48 h. At 48 h post-treatment, cell viability test was performed using TACS MTT Cell Proliferation and Viability Assay Kit (TACS) as per manufacturer’s instructions. The optical density (OD) was recorded at 570 nm in a microplate reader (BioTek, ELx800) and cell survival fraction was determined. The cell survival fraction was calculated as [(A − B)/A], where A and B are the OD of untreated and of treated cells, respectively . The IC50 values of the tested compound were estimated using the best fit regression curve method in Excel.
A direct visual investigation was made under an inverted microscope (Optica, 40× and 100×) to observe any morphological changes in the cells cultured with different treatment doses at 24 and 48 h.
All the molecular modeling studies were carried out on an Intel Pentium 1.6 GHz processor, 512 MB memory with Windows XP operating system using Molecular Operating Environment (MOE, 10.2008) software. All the minimizations were performed with MOE until a RMSD gradient of 0.05 kcal mol−1 Å with MMFF94X force field and the partial charges were automatically calculated. The protein data bank file (PDB: 3WI6) was selected for this purpose. The file contains MK-2 enzyme co-crystalized with a ligand obtained from protein data bank. The enzyme was prepared for docking studies where: (1) Ligand molecule was removed from the enzyme active site. (2) Hydrogen atoms were added to the structure with their standard geometry. (3) MOE Alpha Site Finder was used for the active sites search in the enzyme structure and dummy atoms were created from the obtained alpha spheres. (4). The obtained model was then used in predicting the ligand enzymes interactions at the active site.
In summary, we had synthesized a novel series of sulfonamide thiourea derivatives. Seven compounds 3, 6, 8, 9, 10, 15 and 16 showed good anticancer activity against lung (A594 Raw), Hela, and Colorectal (Lovo) cancer cell lines with better or comparable activity to DCF. Moreover, molecular docking for these active compounds showed proper fitting on the active site of MK-2 enzyme suggesting their action as inhibitors for this enzyme but more investigation should be carried out in the future to explore precisely the mechanism of the action of the synthesized derivatives.
MMG, MSAl said designed and contributed in synthesis. MSAl-Dosari carried out biological screening. YMN carried out molecular docking study. SMA contributed in experimental interpretation. All authors read and approved the final manuscript.
This project was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia, Award number (13-MED 997-02).
The authors declare that they have no competing interests.
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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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